Immunology_Janeway

Immunology_Janeway. the effect needs to be chronic. These layers begin with central tolerance in the bone marrow and thymus, and include peripheral mechanisms such as anergy, cytokine deviation, and regulatory T cells. Sometimes immune responses do not occur simply because the antigens are not available, as in immune sequestration.


Immunology_Janeway

Immunology_Janeway. Perhaps because of selective pressure to mount effective immune responses to pathogens, the dampening of immune responses to promote self-tolerance is limited and prone to failure. Genetic predisposition has an important role in determining which individuals will develop an autoimmune disease. Environmental forces also have a significant role, because even identical twins are not always both affected by the same autoimmune disease. Influences from the environment include infections, toxins, and chance events.


Immunology_Janeway

Immunology_Janeway. When self-tolerance is broken and autoimmune disease ensues, the effector mechanisms are quite similar to those employed in responses to pathogens. Although the details vary from disease to disease, both antibody and T cells can be involved. Much has been learned about immune responses made to tissue antigens by examining the response to nonself transplanted organs and tissues; lessons learned in the study of graft rejection apply to autoimmunity and vice versa. Transplantation has brought on syndromes of rejection that are in many ways similar to autoimmune disease, but the targets are either major or minor histocompatibility antigens. T cells are the main effectors in graft rejection and graft-versus-host disease, although antibodies can also contribute.


Immunology_Janeway

Immunology_Janeway. For each of the undesirable responses discussed here, the question is how to control the response without adversely affecting protective immunity to infection. The answer may lie in a more complete understanding of the regulation of the immune response, especially the suppressive mechanisms important in tolerance. The deliberate control of the immune response is examined further in Chapter 16. Questions. 15.1 True or False: Inflammatory bowel disease—Crohn's disease and ulcerative colitis—is a disease in which the adaptive immune system causes tissue damage in response to self antigens. 15.2 Matching: Match the following monogenic autoimmune diseases with the associated defective gene. 15.3 Multiple Choice: Which of the following statements is incorrect? A. The autoantibodies induced by procainamide, a drug widely used to treat abnormal heart rhythms, are similar to the autoantibodies that characterize systemic lupus erythematosus.


Immunology_Janeway

Immunology_Janeway. A. The autoantibodies induced by procainamide, a drug widely used to treat abnormal heart rhythms, are similar to the autoantibodies that characterize systemic lupus erythematosus. B. Inflammatory mediators released during the course of an infection can lead to activation of self‑reactive lymphocytes and thus cause an autoimmune response. C. Crohn’s disease and Blau syndrome are both strongly associated with loss‑of‑function mutations in NOD2, among other causes. D. ATG16L1 and IRGM are genes that contribute to autophagy under normal circumstances, and defects in these have been linked to Crohn’s disease. 15.4 Multiple Choice: Which of the following options correctly describe a transplantation scenario? A. A syngeneic skin graft from a young mouse is rejected by an adult mouse. B. An allogeneic skin graft from a male mouse is not rejected by a female mouse. C. A syngeneic skin graft from a male mouse is rejected by a female mouse.


Immunology_Janeway

Immunology_Janeway. B. An allogeneic skin graft from a male mouse is not rejected by a female mouse. C. A syngeneic skin graft from a male mouse is rejected by a female mouse. D. A skin autograft is rejected 3 weeks after transplantation. 15.5 Short Answer: How can graft‑versus‑host disease (GVHD) be of benefit to patients with leukemia? 15.6 Multiple Choice: Which of the following options incorrectly describes a mechanism used to prevent fetal rejection? A. High expression of 2,3‑dioxygenase (IDO), which starves T cells of tryptophan B. Absence of MHC class II expression and low levels of MHC class I expression by the trophoblast C. Downregulation of HLA‑G expression by the trophoblast D. Secretion of TGF‑β and IL‑10 by the uterine epithelium and the trophoblast. 15.7 Multiple Choice: Which of the following is not a mechanism by which immunologically privileged sites maintain tolerance? A. Exclusion of effector T cells during infection


Immunology_Janeway

Immunology_Janeway. 15.7 Multiple Choice: Which of the following is not a mechanism by which immunologically privileged sites maintain tolerance? A. Exclusion of effector T cells during infection B. Tissue barriers that exclude naive lymphocytes (for example, the blood–brain barrier) C. Anti‑inflammatory cytokine production (for example, TGF‑β) D. Expression of Fas ligand to induce apoptosis of Fas‑bearing effector lymphocytes E. Decreased communication via conventional lymphatics 15.8 Multiple Choice: Which of the following is not a mechanism of peripheral tolerance? A. Anergy B. Negative selection C. Induction of Tregs D. Deletion E. Suppression by Tregs 15.9 Short Answer: The phenomenon of epitope spreading occurs in systemic lupus erythematosus (SLE), where anti‑DNA autoantibodies are present and may progress to the production of anti‑histone antibodies. Describe mechanistically how this occurs.


Immunology_Janeway

Immunology_Janeway. 15.10 Short Answer: Autoimmune polyendocrinopathy– candidiasis–ectodermal dysplasia (APECED) is caused by defects in the transcription factor AIRE, which result in impaired expression of peripheral genes and reduced negative selection (that is, impaired central tolerance). Patients afflicted with APECED suffer destruction of multiple endocrine tissues and exhibit impaired antifungal immunity. However, these autoimmune phenomena take time to develop and do not develop in all potential organ targets in all patients. Explain why this is the case.


Immunology_Janeway

Immunology_Janeway. 15.11 Fill-in-the-Blanks: Autoantibodies that develop in certain autoimmune disorders can act as either antagonists or agonists, depending on whether they inhibit or stimulate a function. In _______________, autoantibodies against the _______________ receptor block its function in the neuromuscular junction, resulting in a syndrome of muscle weakness. Another example is _________________, where autoantibodies against the __________________ receptor stimulate excessive production of thyroid hormone. 15.12 Matching: Match the autoimmune disease with its pathophysiology: A. Rheumatoid arthritis i. Chronic hepatitis C infection leading to production of immune complexes that deposit in joints and tissues Section references. 15-1 A critical function of the immune system is to discriminate self from nonself. Ehrlich, P., and Morgenroth, J.: On haemolysins, in Himmelweit, F. (ed): The Collected Papers of Paul Ehrlich. London, Pergamon, 1957, 246–255.


Immunology_Janeway

Immunology_Janeway. Ehrlich, P., and Morgenroth, J.: On haemolysins, in Himmelweit, F. (ed): The Collected Papers of Paul Ehrlich. London, Pergamon, 1957, 246–255. Janeway, C.A., Jr: The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 1992, 13:11–16. Matzinger, P.: The danger model: a renewed sense of self. Science 2002, 296:301–305. 15-2 Multiple tolerance mechanisms normally prevent autoimmunity. Goodnow, C.C., Sprent, J., Fazekas de St Groth, B., and Vinuesa, C.G.: Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 2005, 435:590–597. Shlomchik, M.J.: Sites and stages of autoreactive B cell activation and regulation. Immunity 2008, 28:18–28. 15-3 Central deletion or inactivation of newly formed lymphocytes is the first checkpoint of self-tolerance. Hogquist, K.A., Baldwin, T.A., and Jameson, S.C.: Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 2005, 5:772–782.


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Immunology_Janeway. Hogquist, K.A., Baldwin, T.A., and Jameson, S.C.: Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 2005, 5:772–782. Kappler, J.W., Roehm, N., and Marrack, P.: T cell tolerance by clonal elimination in the thymus. Cell 1987, 49:273–280. Kyewski, B., and Klein, L.: A central role for central tolerance. Annu. Rev. Immunol. 2006, 24:571–606. B. Type I diabetes mellitus ii. T‑cell‑mediated autoimmune attack against central nervous system myelin antigens, leading to demyelinating disease with neurological phenotypes C. Multiple sclerosis iii. Autoantibodies against IgG D. Hashimoto’s thyroiditis iv. Autoantibodies against the GpIIb:IIIa fibrinogen receptor on platelets E. Autoimmune hemolytic v. Autoantibodies against anemia red blood cells F. Autoimmune vi. TH1‑dependent thrombocytopenic autoimmune attack of purpura β cells in the pancreas


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Immunology_Janeway. E. Autoimmune hemolytic v. Autoantibodies against anemia red blood cells F. Autoimmune vi. TH1‑dependent thrombocytopenic autoimmune attack of purpura β cells in the pancreas G. Goodpasture’s vii. Autoantibodies against syndrome the α3 chain of basement membrane collagen (type IV collagen) H. Mixed essential viii. Cell‑ and autoantibody cryoglobulinemia mediated autoimmune attack of the thyroid leading to hypothyroidism Nemazee, D.A., and Burki, K.: Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class-I antibody genes. Nature 1989, 337:562–566. Steinman, R.M., Hawiger, D., and Nussenzweig, M.C.: Tolerogenic dendritic cells. Annu. Rev. Immunol. 2003, 21:685–711. 15-4 Lymphocytes that bind self antigens with relatively low affinity usually ignore them but in some circumstances become activated. Billingham, R.E., Brent, L., and Medawar, P.B.: Actively acquired tolerance of foreign cells. Nature 1953, 172:603–606.


Immunology_Janeway

Immunology_Janeway. Billingham, R.E., Brent, L., and Medawar, P.B.: Actively acquired tolerance of foreign cells. Nature 1953, 172:603–606. Hannum, L.G., Ni, D., Haberman, A.M., Weigert, M.G., and Shlomchik, M.J.: A disease-related RF autoantibody is not tolerized in a normal mouse: implications for the origins of autoantibodies in autoimmune disease. J. Exp. Med. 1996, 184:1269–1278. Kurts, C., Sutherland, R.M., Davey, G., Li, M., Lew, A.M., Blanas, E., Carbone, F.R., Miller, J.F., and Heath, W.R.: CD8 T cell ignorance or tolerance to islet antigens depends on antigen dose. Proc. Natl Acad. Sci. USA 1999, 96:12703–12707. Marshak-Rothstein, A.: Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 2006, 6:823–835. 15-5 Antigens in immunologically privileged sites do not induce immune attack but can serve as targets. Forrester, J.V., Xu, H., Lambe, T., and Cornall, R.: Immune privilege or privileged immunity? Mucosal Immunol. 2008, 1:372–381.


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Immunology_Janeway. Forrester, J.V., Xu, H., Lambe, T., and Cornall, R.: Immune privilege or privileged immunity? Mucosal Immunol. 2008, 1:372–381. Mellor, A.L., and Munn, D.H.: Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat. Rev. Immunol. 2008, 8:74–80. Simpson, E.: A historical perspective on immunological privilege. Immunol. Rev. 2006, 213:12–22. 15-6 Autoreactive T cells that express particular cytokines may be nonpathogenic or may suppress pathogenic lymphocytes. von Herrath, M.G., and Harrison, L.C.: Antigen-induced regulatory T cells in autoimmunity. Nat. Rev. Immunol. 2003, 3:223–232. 15-7 Autoimmune responses can be controlled at various stages by regulatory T cells. Asano, M., Toda, M., Sakaguchi, N., and Sakaguchi, S.: Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 1996, 184:387–396.


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Immunology_Janeway. Asano, M., Toda, M., Sakaguchi, N., and Sakaguchi, S.: Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 1996, 184:387–396. Fillatreau, S., Sweenie, C.H., McGeachy, M.J., Gray, D., and Anderton, S.M.: B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 2002, 3:944–950. Fontenot, J.D., and Rudensky, A.Y.: A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 2005, 6:331–337. Izcue, A., Coombes, J.L., and Powrie, F.: Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 2009, 27:313–338. Mayer, L., and Shao, L.: Therapeutic potential of oral tolerance. Nat. Rev. Immunol. 2004, 4:407–419. Maynard, C.L., and Weaver, C.T.: Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol. Rev. 2008, 226:219–233.


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Immunology_Janeway. Maynard, C.L., and Weaver, C.T.: Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol. Rev. 2008, 226:219–233. Sakaguchi, S.: Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 2004, 22:531–562. Wildin, R.S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., et al.: X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 2001, 27:18–20. Yamanouchi, J., Rainbow, D., Serra, P., Howlett, S., Hunter, K., Garner, V.E.S., Gonzalez-Munoz, A., Clark, J., Veijola, R., Cubbon, R., et al.: Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 2007, 39:329–337. 15-8 Specific adaptive immune responses to self antigens can cause autoimmune disease.


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Immunology_Janeway. 15-8 Specific adaptive immune responses to self antigens can cause autoimmune disease. Lotz, P.H.: The autoantibody repertoire: searching for order. Nat. Rev. Immunol. 2003, 3:73–78. Santamaria, P.: The long and winding road to understanding and conquering type 1 diabetes. Immunity 2010, 32:437–445. Steinman, L.: Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 1996, 85:299–302. 15-9 Autoimmunity can be classified into either organ-specific or systemic disease. Davidson, A., and Diamond, B.: Autoimmune diseases. N. Engl. J. Med. 2001, 345:340–350. D’Cruz, D.P., Khamashta, M.A., and Hughes, G.R.V.: Systemic lupus erythematosus. Lancet 2007, 369:587–596. Marrack, P., Kappler, J., and Kotzin, B.L.: Autoimmune disease: why and where it occurs. Nat. Med. 2001, 7:899–905. 15-10 Multiple components of the immune system are typically recruited in autoimmune disease.


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Immunology_Janeway. 15-10 Multiple components of the immune system are typically recruited in autoimmune disease. Drachman, D.B.: Myasthenia gravis. N. Engl. J. Med. 1994, 330:1797–1810. Firestein, G.S.: Evolving concepts of rheumatoid arthritis. Nature 2003, 423:356–361. Lehuen, A., Diana, J., Zaccone, P., and Cooke, A.: Immune cell crosstalk in type 1 diabetes. Nat. Rev. Immunol. 2010, 10:501–513. Shlomchik, M.J., and Madaio, M.P.: The role of antibodies and B cells in the pathogenesis of lupus nephritis. Springer Semin. Immunopathol. 2003, 24:363–375. from inflammation, inability to clear the self antigen, and a broadening of the autoimmune response. Marshak-Rothstein, A.: Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 2006, 6:823–835. Nagata, S., Hanayama, R., and Kawane, K.: Autoimmunity and the clearance of dead cells. Cell 2010, 140:619–630.


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Immunology_Janeway. Nagata, S., Hanayama, R., and Kawane, K.: Autoimmunity and the clearance of dead cells. Cell 2010, 140:619–630. Salato, V.K., Hacker-Foegen, M.K., Lazarova, Z., Fairley, J.A., and Lin, M.S.: Role of intramolecular epitope spreading in pemphigus vulgaris. Clin. Immunol. 2005, 116:54–64. Steinman, L.: A few autoreactive cells in an autoimmune infiltrate control a vast population of nonspecific cells: a tale of smart bombs and the infantry. Proc. Natl Acad. Sci. USA 1996, 93:2253–2256. Vanderlugt, C.L., and Miller, S.D.: Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2002, 2:85–95. 15-12 Both antibody and effector T cells can cause tissue damage in autoimmune disease. Naparstek, Y., and Plotz, P.H.: The role of autoantibodies in autoimmune disease. Annu. Rev. Immunol. 1993, 11:79–104.


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Immunology_Janeway. Naparstek, Y., and Plotz, P.H.: The role of autoantibodies in autoimmune disease. Annu. Rev. Immunol. 1993, 11:79–104. Vlahakos, D., Foster, M.H., Ucci, A.A., Barrett, K.J., Datta, S.K., and Madaio, M.P.: Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo. J. Am. Soc. Nephrol. 1992, 2:1345–1354. 15-13 Autoantibodies against blood cells promote their destruction. Beardsley, D.S., and Ertem, M.: Platelet autoantibodies in immune thrombocytopenic purpura. Transfus. Sci. 1998, 19:237–244. Clynes, R., and Ravetch, J.V.: Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity 1995, 3:21–26. Domen, R.E.: An overview of immune hemolytic anemias. Cleveland Clin. J. Med. 1998, 65:89–99. 15-14 The fixation of sublytic doses of complement to cells in tissues stimulates a powerful inflammatory response.


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Immunology_Janeway. 15-14 The fixation of sublytic doses of complement to cells in tissues stimulates a powerful inflammatory response. Brandt, J., Pippin, J., Schulze, M., Hansch, G.M., Alpers, C.E., Johnson, R.J., Gordon, K., and Couser, W.G.: Role of the complement membrane attack complex (C5b-9) in mediating experimental mesangioproliferative glomerulonephritis. Kidney Int. 1996, 49:335–343. Hansch, G.M.: The complement attack phase: control of lysis and non-lethal effects of C5b-9. Immunopharmacology 1992, 24:107–117. 15-15 Autoantibodies against receptors cause disease by stimulating or blocking receptor function. Bahn, R.S., and Heufelder, A.E.: Pathogenesis of Graves’ ophthalmopathy. N. Engl. J. Med. 1993, 329:1468–1475. Drachman, D.B.: Myasthenia gravis. N. Engl. J. Med. 1994, 330:1797–1810. Vincent, A., Lily, O., and Palace, J.: Pathogenic autoantibodies to neuronal proteins in neurological disorders. J. Neuroimmunol. 1999, 100:169–180.


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Immunology_Janeway. Vincent, A., Lily, O., and Palace, J.: Pathogenic autoantibodies to neuronal proteins in neurological disorders. J. Neuroimmunol. 1999, 100:169–180. 15-16 Autoantibodies against extracellular antigens cause inflammatory injury. Casciola-Rosen, L.A., Anhalt, G., and Rosen, A.: Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J. Exp. Med. 1994, 179:1317–1330. Clynes, R., Dumitru, C., and Ravetch, J.V.: Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 1998, 279:1052–1054. Kotzin, B.L.: Systemic lupus erythematosus. Cell 1996, 85:303–306. Lee, R.W., and D’Cruz, D.P.: Pulmonary renal vasculitis syndromes. Autoimmun. Rev. 2010, 9:657–660. Mackay, M., Stanevsky, A., Wang, T., Aranow, C., Li, M., Koenig, S., Ravetch, J.V., and Diamond, B.: Selective dysregulation of the FcgIIB receptor on memory B cells in SLE. J. Exp. Med. 2006, 203:2157–2164.


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Immunology_Janeway. Xiang, Z., Cutler, A.J., Brownlie, R.J., Fairfax, K., Lawlor, K.E., Severinson, E., Walker, E.U., Manz, R.A., Tarlinton, D.M., and Smith, K.G.: FcgRIIb controls bone marrow plasma cell persistence and apoptosis. Nat. Immunol. 2007, 8:419–429. 15-17 T cells specific for self antigens can cause direct tissue injury and sustain autoantibody responses. Feldmann, M., and Steinman, L.: Design of effective immunotherapy for human autoimmunity. Nature 2005, 435:612–619. Firestein, G.S.: Evolving concepts of rheumatoid arthritis. Nature 2003, 423:356–361. Frohman, E.M., Racke, M.K., and Raine, C.S.: Multiple sclerosis—the plaque and its pathogenesis. N. Engl. J. Med. 2006, 354:942–955. Klareskog, L., Stolt, P., Lundberg, K. et al.: A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2005, 54:38–46.


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Immunology_Janeway. Lassmann, H., van Horssen, J., and Mahad, D.: Progressive multiple sclerosis: pathology and pathogenesis. Nat. Rev. Neurol. 2012, 8:647–656. Ransohoff, R.M., and Engelhardt, B.: The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 2012, 12:623–635. Zamvil, S., Nelson, P., Trotter, J., Mitchell, D., Knobler, R., Fritz, R., and Steinman, L.: T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature 1985, 317:355–358. 15-18 Autoimmune diseases have a strong genetic component. Fernando, M.M.A., Stevens, C.R., Walsh, E.C., De Jager, P.L., Goyette, P., Plenge, R.M., Vyse, T.J., and Rioux, J.D.: Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 2008, 4:e1000024.


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Immunology_Janeway. Parkes, M., Cortes, A., Van Heel, D.A., and Brown, M.A.: Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 2013, 14:661–673. Rioux, J.D., and Abbas, A.K.: Paths to understanding the genetic basis of autoimmune disease. Nature 2005, 435:584–589. Wakeland, E.K., Liu, K., Graham, R.R., and Behrens, T.W.: Delineating the genetic basis of systemic lupus erythematosus. Immunity 2001, 15:397–408. 15-19 Genomics-based approaches are providing new insight into the immunogenetic basis of autoimmunity. Botto, M., Kirschfink, M., Macor, P., Pickering, M.C., Wurzner, R., and Tedesco, F.: Complement in human diseases: lessons from complement deficiencies. Mol. Immunol. 2009, 46:2774–2783. Cotsapas, C., and Hafler, D.A.: Immune-mediated disease genetics: the shared basis of pathogenesis. Trends Immunol. 2013, 34:22–26.


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Immunology_Janeway. Cotsapas, C., and Hafler, D.A.: Immune-mediated disease genetics: the shared basis of pathogenesis. Trends Immunol. 2013, 34:22–26. Duerr, R.H., Taylor, K.D., Brant, S.R., Rioux, J.D., Silverberg, M.S., Daly, M.J., Steinhart, A.H., Abraham, C., Regueiro, M., Griffiths, A., et al.: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006, 314:1461–1463. Farh, K.K.-H., Marson, A., Zhu, J., Kleinewietfeld, M., Housley, W.J., Beik, S., Shoresh, N., Whitton, H., Ryan, R.J.H., Shishkin, A.A. et al.: Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 2014, 518:337–343. Gregersen, P.K.: Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond. Immunol. Rev. 2005, 204:74–86. Xavier, R.J., and Rioux, J.D.: Genome-wide association studies: a new window into immune-mediated diseases. Nat. Rev. Immunol. 2008, 8:631–643.


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Immunology_Janeway. Xavier, R.J., and Rioux, J.D.: Genome-wide association studies: a new window into immune-mediated diseases. Nat. Rev. Immunol. 2008, 8:631–643. 15-20 Many genes that predispose to autoimmunity fall into categories that affect one or more tolerance mechanisms. Goodnow, C.C.: Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity 1998, 8:497–508. Tivol, E.A., Borriello, F., Schweitzer, A.N., Lynch, W.P., Bluestone, J.A., and Sharpe, A.H.: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995, 3:541–547. Wakeland, E.K., Liu, K., Graham, R.R., and Behrens, T.W.: Delineating the genetic basis of systemic lupus erythematosus. Immunity 2001, 15:397–408. Walport, M.J.: Lupus, DNase and defective disposal of cellular debris. Nat. Genet. 2000, 25:135–136.


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Immunology_Janeway. Walport, M.J.: Lupus, DNase and defective disposal of cellular debris. Nat. Genet. 2000, 25:135–136. 15-21 Monogenic defects of immune tolerance. Anderson, M.S., Venanzi, E.S., Chen, Z., Berzins, S.P., Benoist, C., and Mathis, D.: The cellular mechanism of Aire control of T cell tolerance. Immunity 2005, 23:227–239. Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S.E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., et al.: Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J. Clin. Invest. 2006, 116:1713–1722. Ueda, H., Howson, J.M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D.B., Hunter, K.M., Smith, A.N., DiGenova, G., et al.: Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003, 423:506–511.


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Immunology_Janeway. Wildin, R.S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., et al.: X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 2001, 27:18–20. 15-22 MHC genes have an important role in controlling susceptibility to autoimmune disease. Fernando, M.M.A., Stevens, C.R., Walsh, E.C., De Jager, P.L., Goyette, P., Plenge, R.M., Vyse, T.J., and Rioux, J.D.: Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 2008, 4:e1000024. McDevitt, H.O.: Discovering the role of the major histocompatibility complex in the immune response. Annu. Rev. Immunol. 2000, 18:1–17. 15-23 Genetic variants that impair innate immune responses can predispose to T cell-mediated chronic inflammatory disease.


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Immunology_Janeway. 15-23 Genetic variants that impair innate immune responses can predispose to T cell-mediated chronic inflammatory disease. Cadwell, K., Liu, J.Y., Brown, S.L., Miyoshi, H., Loh, J., Lennerz, J.K., Kishi, C., Kc, W., Carrero, J.A., Hunt, S., et al.: A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 2008, 456:259–263. Eckmann, L., and Karin, M.: NOD2 and Crohn’s disease: loss or gain of function? Immunity 2005, 22:661–667. Xavier, R.J., and Podolsky, D.K.: Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007, 448:427–434. 15-24 External events can initiate autoimmunity. Klareskog, L., Padyukov, L., Ronnelid, J., and Alfredsson, L.: Genes, environment and immunity in the development of rheumatoid arthritis. Curr. Opin. Immunol. 2006 18:650–655.


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Immunology_Janeway. Klareskog, L., Padyukov, L., Ronnelid, J., and Alfredsson, L.: Genes, environment and immunity in the development of rheumatoid arthritis. Curr. Opin. Immunol. 2006 18:650–655. Munger, K.L., Levin, L.I., Hollis, B.W., Howard, N.S., and Ascherio, A.: Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. J. Am. Med. Assoc. 2006, 296:2832–2838. 15-25 Infection can lead to autoimmune disease by providing an environment that promotes lymphocyte activation. Bach, J.F.: Infections and autoimmune diseases. J. Autoimmunity 2005, 25:74–80. Moens, U., Seternes, O.M., Hey, A.W., Silsand, Y., Traavik, T., Johansen, B., and Hober, D., and Sauter, P.: Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host. Nat. Rev. Endocrinol. 2010, 6:279–289. Sfriso, P., Ghirardello, A., Botsios, C., Tonon, M., Zen, M., Bassi, N., Bassetto, F., and Doria, A.: Infections and autoimmunity: the multifaceted relationship. J. Leukocyte Biol. 2010, 87:385–395.


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Immunology_Janeway. Sfriso, P., Ghirardello, A., Botsios, C., Tonon, M., Zen, M., Bassi, N., Bassetto, F., and Doria, A.: Infections and autoimmunity: the multifaceted relationship. J. Leukocyte Biol. 2010, 87:385–395. Takeuchi, O., and Akira, S.: Pattern recognition receptors and inflammation. Cell 2010, 140:805–820. 15-26 Cross-reactivity between foreign molecules on pathogens and self molecules can lead to anti-self responses and autoimmune disease. Barnaba, V., and Sinigaglia, F.: Molecular mimicry and T cell-mediated autoimmune disease. J. Exp. Med. 1997, 185:1529–1531. Rose, N.R.: Infection, mimics, and autoimmune disease. J. Clin. Invest. 2001, 107:943–944. Rose, N.R., Herskowitz, A., Neumann, D.A., and Neu, N.: Autoimmune myocarditis: a paradigm of post-infection autoimmune disease. Immunol. Today 1988, 9:117–120. 15-27 Drugs and toxins can cause autoimmune syndromes. 15-28 Random events may be required for the initiation of autoimmunity.


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Immunology_Janeway. 15-27 Drugs and toxins can cause autoimmune syndromes. 15-28 Random events may be required for the initiation of autoimmunity. Eisenberg, R.A., Craven, S.Y., Warren, R.W., and Cohen, P.L.: Stochastic control of anti-Sm autoantibodies in MRL/Mp-lpr/lpr mice. J. Clin. Invest. 1987, 80:691–697. Yoshida, S., and Gershwin, M.E.: Autoimmunity and selected environmental factors of disease induction. Semin. Arthritis Rheum. 1993, 22:399–419. 15-29 Graft rejection is an immunological response mediated primarily by T cells. Cornell, L.D., Smith, R.N., and Colvin, R.B.: Kidney transplantation: mechanisms of rejection and acceptance. Annu. Rev. Pathol. 2008, 3:189–220. Wood, K.J., and Goto, R.: Mechanisms of rejection: current perspectives. Transplantation. 2012, 93:1–10. 15-30 Transplant rejection is caused primarily by the strong immune response to nonself MHC molecules.


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Immunology_Janeway. 15-30 Transplant rejection is caused primarily by the strong immune response to nonself MHC molecules. Macdonald, W.A., Chen, Z., Gras, S., Archbold, J.K., Tynan, F.E., Clements, C.S., Bharadwaj, M., Kjer-Nielsen, L., Saunders, P.M., Wilce, M.C.J., et al.: T cell allorecognition via molecular mimicry. Immunity 2009, 31:897–908. Macedo, C., Orkis, E.A., Popescu, I., Elinoff, B.D., Zeevi, A., Shapiro, R., Lakkis, F.G., and Metes, D.: Contribution of naive and memory T-cell populations to the human alloimmune response. Am. J. Transplant. 2009, 9:2057–2066. Opelz, G., and Wujciak, T.: The influence of HLA compatibility on graft survival after heart transplantation. The Collaborative Transplant Study. N. Engl. J. Med. 1994, 330:816–819. 15-31 In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules.


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Immunology_Janeway. 15-31 In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules. Dierselhuis, M., and Goulmy, E.: The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Organ Transplant. 2009, 14:419–425. den Haan, J.M., Meadows, L.M., Wang, W., Pool, J., Blokland, E., Bishop, T.L., Reinhardus, C., Shabanowitz, J., Offringa, R., Hunt, D.F., et al.: The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism. Science 1998, 279:1054–1057. Mutis, T., Gillespie, G., Schrama, E., Falkenburg, J.H., Moss, P., and Goulmy, E.: Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nat. Med. 1999, 5:839–842. 15-32 There are two ways of presenting alloantigens on the transplanted donor organ to the recipient’s T lymphocytes.


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Immunology_Janeway. 15-32 There are two ways of presenting alloantigens on the transplanted donor organ to the recipient’s T lymphocytes. Jiang, S., Herrera, O., and Lechler, R.I.: New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr. Opin. Immunol. 2004, 16:550–557. Safinia, N., Afzali, B., Atalar, K., Lombardi, G., and Lechler, R.I.: T-cell alloimmunity and chronic allograft dysfunction. Kidney Int. 2010, 78(Suppl 119):S2–S12. Lakkis, F.G., Arakelov, A., Konieczny, B.T., and Inoue, Y.: Immunologic ignorance of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat. Med. 2000, 6:686–688. 15-33 Antibodies that react with endothelium cause hyperacute graft rejection. Griesemer, A., Yamada, K., and Sykes, M.: Xenotransplantation: immunological hurdles and progress toward tolerance. Immunol. Rev. 2014, 258:241–258.


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Immunology_Janeway. Griesemer, A., Yamada, K., and Sykes, M.: Xenotransplantation: immunological hurdles and progress toward tolerance. Immunol. Rev. 2014, 258:241–258. Montgomery, R.A., Cozzi, E., West, L.J., and Warren, D.S.: Humoral immunity and antibody-mediated rejection in solid organ transplantation. Semin. Immunol. 2011, 23:224–234. Williams, G.M., Hume, D.M., Hudson, R.P., Jr, Morris, P.J., Kano, K., and Milgrom, F.: ‘Hyperacute’ renal-homograft rejection in man. N. Engl. J. Med. 1968, 279:611–618. 15-34 Late failure of transplanted organs is caused by chronic injury to the graft. Smith, R.N., and Colvin, R.B.: Chronic alloantibody mediated rejection. Semin. Immunol. 2012, 24:115–121. Libby, P., and Pober, J.S.: Chronic rejection. Immunity 2001, 14:387–397. 15-35 A variety of organs are transplanted routinely in clinical medicine.


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Immunology_Janeway. 15-35 A variety of organs are transplanted routinely in clinical medicine. Ekser, B., Ezzelarab, M., Hara, H., van der Windt, D.J., Wijkstrom, M., Bottino, R., Trucco, M., and Cooper, D.K.C.: Clinical xenotransplantation: the next medical revolution? Lancet 2012, 379:672–683. Lechler, R.I., Sykes, M., Thomson, A.W., and Turka, L.A.: Organ transplantation—how much of the promise has been realized? Nat. Med. 2005, 11:605–613. Ricordi, C., and Strom, T.B.: Clinical islet transplantation: advances and immunological challenges. Nat. Rev. Immunol. 2004, 4:259–268. 15-36 The converse of graft rejection is graft-versus-host disease. Blazar, B.R., Murphy, W.J., and Abedi, M.: Advances in graft-versus-host disease biology and therapy. Nat. Rev. Immunol. 2012, 12:443–458. Shlomchik, W.D.: Graft-versus-host disease. Nat. Rev. Immunol. 2007, 7:340–352. 15-37 Regulatory T cells are involved in alloreactive immune responses.


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Immunology_Janeway. 15-37 Regulatory T cells are involved in alloreactive immune responses. Ferrer, I.R., Hester, J., Bushell, A., and Wood, K.J.: Induction of transplantation tolerance through regulatory cells: from mice to men. Immunol. Rev. 2014, 258:102–116. Qin, S., Cobbold, S.P., Pope, H., Elliott, J., Kioussis, D., Davies, J., and Waldmann, H.: “Infectious” transplantation tolerance. Science 1993, 259:974–977. Tang, Q., and Bluestone, J.A.: Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harb. Perspect. Med. 2013, 3:1–15. 15-38 The fetus is an allograft that is tolerated repeatedly. Erlebacher, A.: Mechanisms of T cell tolerance towards the allogeneic fetus. Nat. Rev. Immunol. 2013, 13:23–33. Samstein, R.M., Josefowicz, S.Z., Arvey, A., Treuting, P.M., and Rudensky A.Y.: Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 2012, 150:29–38. Manipulation of the Immune Response


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Immunology_Janeway. In this chapter, we consider the various ways in which the immune system can be manipulated to suppress unwanted immune responses in the form of autoimmunity, allergy, and graft rejection, or to stimulate protective immune responses. Intentional manipulations of the immune system date back over 500 years to the use of variolation as a measure to protect against smallpox. In the late 1800s these measures advanced greatly with the development of numerous vaccines and antisera against other infectious agents. Later progress, against unwanted immune responses, came with the introduction of a number of now-conventional pharmaceutical agents; although these allow only relatively nonspecific control over unwanted immune reactions, they remain an important component of clinical medicine. More recently, these standard therapeutics have been joined by so-called biological therapeutics, or biologics, which are artificially produced versions of natural products, such as hormones, cytokines, and


Immunology_Janeway

Immunology_Janeway. these standard therapeutics have been joined by so-called biological therapeutics, or biologics, which are artificially produced versions of natural products, such as hormones, cytokines, and monoclonal antibodies, or derivatives of these such as engineered fusion proteins. These biologics possess extraordinary specificity, and though some have been used for decades, such as the hormone insulin in patients with type 1 diabetes, recent advances in cell biology and engineering have allowed for the introduction of a broad array of new biologics that allow for very precise manipulation of the immune system. Finally, long-standing efforts to deploy the power of the adaptive immune system against tumors have made major advances, and biologics that target negative regulators of immunity to stimulate protective responses against cancers have made a significant impact in clinical medicine. The categories of agents used to manipulate immune responses are listed in Fig. 16.1. This chapter will


Immunology_Janeway

Immunology_Janeway. protective responses against cancers have made a significant impact in clinical medicine. The categories of agents used to manipulate immune responses are listed in Fig. 16.1. This chapter will discuss these approaches, beginning with pharmaceutical agents used in clinical practice. In the first part of the chapter, we focus on efforts to relieve unwanted immune responses, and on advances in cancer treatment based on immune-system therapies. In the last part of the chapter, we discuss current vaccination strategies against infectious diseases, and consider how a more rational approach to the design and development of vaccines promises to increase their efficacy and widen their usefulness and application.


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Immunology_Janeway. Treatment of unwanted immune responses. Unwanted immune responses occur in many settings, such as autoimmune disease, transplant rejection, and allergy, which present different therapeutic challenges. The goal of treatment in all cases is to avoid tissue damage and prevent the disruption of tissue function. Some unwanted immune responses can be anticipated so that preventive measures may be taken, as in the case of allograft rejection. Other unwanted responses may be undetectable until after they become established, as is the case with autoimmune or allergic reactions. The relative difficulty of suppressing established immune responses is seen in animal models of autoimmunity, in which treatments that could have prevented induction of the disease are generally unable to halt it once it is established. Treatment of unwanted immune responses. Using the immune response to attack tumors. Fighting infectious diseases with vaccination.


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Immunology_Janeway. Treatment of unwanted immune responses. Using the immune response to attack tumors. Fighting infectious diseases with vaccination. categories (Fig. 16.2). There are the powerful anti-inflammatory drugs of the corticosteroid family such as prednisone, the cytotoxic drugs such as azathioprine and cyclophosphamide, and the noncytotoxic fungal and bacterial derivatives such as cyclosporin A, tacrolimus (FK506 or fujimycin), and rapamycin (sirolimus), which inhibit intracellular signaling pathways within T lymphocytes. Finally, a recently introduced drug, fingolimod, interferes with signaling by the sphingosine 1-phosphate receptor that controls the egress of B and T cells from lymphoid organs, thus preventing effector lymphocytes from reaching peripheral tissues. Most of these drugs exert broad inhibition of the immune system, and suppress helpful as well as harmful responses. Opportunistic infection is therefore a common complication of immunosuppressive drug therapy.


Immunology_Janeway

Immunology_Janeway. Newer treatments attempt to target the aspects of the immune response that cause tissue damage, such as cytokine action, while avoiding wholesale immunosuppression, but even these therapeutic agents can affect important components of the response to infectious disease. The most immediate way of inhibiting a particular part of the immune response is via highly specific antibodies, usually directed against specific proteins expressed and/or secreted by immune cells. Approaches of this type that were experimental at the time of previous editions of this book are now part of established medical practice. Anticytokine monoclonal antibodies, such as the drug infliximab (anti-TNF-α) used in the treatment of rheumatoid arthritis, can neutralize local excesses of cytokines or chemokines or target natural cellular regulatory mechanisms to inhibit unwanted immune responses. Proteins besides antibodies are also in use to control immune responses, an example being abatacept, a fusion protein


Immunology_Janeway

Immunology_Janeway. natural cellular regulatory mechanisms to inhibit unwanted immune responses. Proteins besides antibodies are also in use to control immune responses, an example being abatacept, a fusion protein consisting of the Fc region of an immunoglobulin fused to the extracellular domain of CTLA-4. Abatacept reduces co-stimulation of T cells by binding to B7 molecules and blocking their interactions with CD28, and it is currently used to treat patients with rheumatoid arthritis who fail to respond to antiTNF-α therapy.


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Immunology_Janeway. 16-1 Corticosteroids are powerful anti-inflammatory drugs that alter the transcription of many genes. Corticosteroid drugs are powerful anti-inflammatory and immunosuppressive agents that are used widely to attenuate the harmful effects of autoimmune or allergic immune responses (see Chapters 14 and 15), as well as responses against transplanted organs. Corticosteroids are derivatives of the glucocorticoid family of steroid hormones that play a crucial role in maintaining the body’s homeostasis; one of the most widely used is prednisone, a synthetic version of the hormone cortisol. Corticosteroids cross the cell’s plasma Treatment of unwanted immune responses.


Immunology_Janeway

Immunology_Janeway. Treatment of unwanted immune responses. membrane and bind to intracellular receptors of the nuclear receptor family. Activated glucocorticoid receptors are transported to the nucleus, where they bind directly to DNA and interact with other transcription factors to regulate as many as 20% of the genes expressed in leukocytes. The response to steroid therapy is complex, given the large number of genes regulated in leukocytes and in other tissues. With respect to immunosuppression, corticosteroids exert multiple anti-inflammatory effects, which are briefly summarized in Fig. 16.3.


Immunology_Janeway

Immunology_Janeway. Corticosteroids target the pro-inflammatory functions of monocytes and macrophages and reduce the number of CD4 T cells. They can induce the expression of certain anti-inflammatory genes, such as AnxaI, which encodes a protein inhibitor of phospholipase A2 and thereby prevents this enzyme from generating pro-inflammatory prostaglandins and leukotrienes (see Sections 3-3 and 14-7). Conversely, corticosteroids can also suppress the expression of pro-inflammatory genes, including those encoding the cytokines IL-1β and TNF-α.


Immunology_Janeway

Immunology_Janeway. The therapeutic effects of corticosteroid drugs are due to their presence at much higher concentrations than the natural concentration of glucocorticoid hormones, causing exaggerated responses with both toxic and beneficial effects. Adverse effects include fluid retention, weight gain, diabetes, bone mineral loss, and thinning of the skin, requiring a careful balance to be maintained between beneficial and harmful effects. These drugs can also decrease in effectiveness over time. Despite these drawbacks, inhaled corticosteroids have proven highly beneficial in the treatment of chronic asthma (see Section 14-13). In the treatment of autoimmunity or allograft rejection, in which high doses of oral corticosteroids are needed to be effective, they are most often administered in combination with other immunosuppressant drugs to keep the corticosteroid dose and side-effects to a minimum. These other drugs include cytotoxic agents that act as immunosuppressants by killing rapidly dividing


Immunology_Janeway

Immunology_Janeway. with other immunosuppressant drugs to keep the corticosteroid dose and side-effects to a minimum. These other drugs include cytotoxic agents that act as immunosuppressants by killing rapidly dividing lymphocytes, and drugs that more specifically target lymphocyte signaling pathways.


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Immunology_Janeway. 16-2 Cytotoxic drugs cause immunosuppression by killing dividing cells and have serious side-effects.


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Immunology_Janeway. The three cytotoxic drugs most commonly used as immunosuppressants are azathioprine, cyclophosphamide, and mycophenolate. These drugs interfere with DNA synthesis, and their major pharmacological action is on tissues in which cells are continually dividing. Developed originally to treat cancer, these drugs were found to be immunosuppressive after observations that they were cytotoxic to dividing lymphocytes. Azathioprine also interferes with CD28 co-stimulation in T cells, thus promoting T-cell apoptosis (see Section 7-24). The use of these compounds is, however, limited by their toxic effects on all tissues in which cells are dividing, such as the skin, gut lining, and bone marrow. Effects include decreased immune function, as well as anemia, leukopenia, thrombocytopenia, damage to intestinal epithelium, hair loss, and fetal death or injury. As a result of their toxicity, these drugs are used at high doses only when the aim is to eliminate all dividing lymphocytes, as in the


Immunology_Janeway

Immunology_Janeway. to intestinal epithelium, hair loss, and fetal death or injury. As a result of their toxicity, these drugs are used at high doses only when the aim is to eliminate all dividing lymphocytes, as in the treatment of lymphoma and leukemia; in these cases, treated patients require subsequent bone marrow transplantation to restore their hematopoietic function. When used to treat unwanted immune responses such as autoimmune conditions, they are used at lower doses and in combination with other drugs such as corticosteroids.


Immunology_Janeway

Immunology_Janeway. Azathioprine is converted in vivo to the purine analog 6-thioguanine (6-TG), which is metabolized to 6-thioinosinic acid. This competes with inosine monophosphate, blocking the de novo synthesis of adenosine monophosphate and guanosine monophosphate, thus inhibiting DNA synthesis. 6-TG is also incorporated into the DNA in place of guanine, and accumulation of


Immunology_Janeway

Immunology_Janeway. Fig. 16.3 Anti-inflammatory effects of corticosteroid therapy. Corticosteroids regulate the expression of many genes, with a net anti-inflammatory effect. First, they reduce the production of inflammatory mediators, including cytokines, prostaglandins, and nitric oxide (NO). Second, they inhibit inflammatory cell migration to sites of inflammation by inhibiting the expression of adhesion molecules. Third, corticosteroids promote the death by apoptosis of leukocytes. The layers of complexity are illustrated by the actions of annexin-1 (originally identified as a factor induced by corticosteroids and named lipocortin), which has been shown to participate in all of the effects of corticosteroids listed on the right. NOS, NO synthase.


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Immunology_Janeway. MOVIE 16.1 6-TG increases the DNA’s sensitivity to mutations induced by the ultraviolet radiation in sunlight. Thus, patients treated with azathioprine have the longterm side-effect of increased risk of skin cancer. Azathioprine also generates 6-thioguanine triphosphate (6-thio-GTP), which in T cells binds to the small GTPase Rac1 in place of GTP and suppresses its activity. Signaling from CD28 co-stimulation requires Rac1, and T cells therefore do not receive the anti-apoptotic signals from co-stimulation and instead undergo apoptosis. Mycophenolate mofetil, the 2-morpholinoethyl ester of mycophenolic acid, is the newest addition to the family of cytotoxic immunosuppressive drugs; it works in a similar fashion to azathioprine. It is metabolized to mycophenolic acid, which inhibits the enzyme inosine monophosphate dehydrogenase, thus blocking the de novo synthesis of guanosine monophosphate.


Immunology_Janeway

Immunology_Janeway. Azathioprine and mycophenolate are less toxic than cyclophosphamide, which is metabolized to phosphoramide mustard, which alkylates DNA. Cyclophosphamide is a member of the nitrogen mustard family of compounds, which were originally developed as chemical weapons. It has a range of highly toxic effects including inflammation of and hemorrhage from the bladder, known as hemorrhagic cystitis, and induction of bladder neoplasia. 16-3 Cyclosporin A, tacrolimus, rapamycin, and JAK inhibitors with various T-cell signaling pathways.


Immunology_Janeway

Immunology_Janeway. Three noncytotoxic alternatives to the cytotoxic drugs are available as immunosuppressants and are widely used to treat transplant recipients. These are cyclosporin A, tacrolimus (previously known as FK506), and rapamycin (also known as sirolimus). Cyclosporin A is a cyclic decapeptide derived from a soil fungus found in Norway, Tolypocladium inflatum. Tacrolimus is a macrolide compound from the filamentous bacterium Streptomyces tsukabaensis, found in Japan; macrolides are compounds that contain a many-membered lactone ring to which is attached one or more deoxysugars. Rapamycin, another macrolide, is derived from Streptomyces hygroscopicus, found on Easter Island (‘Rapa Nui’ in Polynesian—hence the name of the drug). All three compounds exert their pharmacological effects by binding to members of a family of intracellular proteins known as the immunophilins, forming complexes that interfere with signaling pathways important for the clonal expansion of lymphocytes.


Immunology_Janeway

Immunology_Janeway. As explained in Section 7-14, cyclosporin A and tacrolimus block T-cell proliferation by inhibiting the phosphatase activity of the Ca2+-activated protein phosphatase calcineurin, which is required for the activation of the transcription factor NFAT. Both drugs reduce the expression of several cytokine genes that are normally induced on T-cell activation (Fig. 16.4), including the gene encoding interleukin (IL)-2, which is an important growth factor for T cells (see Section 9-16). Cyclosporin A and tacrolimus inhibit T-cell proliferation in response to either specific antigens or allogeneic cells, and are used extensively in medical practice to prevent the rejection of allogeneic organ grafts. Although the major immunosuppressive effects of both drugs are probably the result of inhibition of T-cell proliferation, they also act on other cells and have a large variety of other immunological effects (see Fig. 16.4).


Immunology_Janeway

Immunology_Janeway. These two drugs inhibit calcineurin by first binding to an immunophilin molecule; cyclosporin A binds to the cyclophilins, and tacrolimus to the FK-binding proteins (FKBPs). Immunophilins are peptidyl-prolyl cis–trans isomerases, but their isomerase activity is not relevant to the immunosuppressive activity of the drugs that bind them. Rather, the immunophilin:drug complexes bind and inhibit the Ca2+-activated serine/threonine phosphatase calcineurin. In a normal immune response, the increase in intracellular calcium ions in response to T-cell receptor signaling activates the calcium-binding protein Fig. 16.4 Cyclosporin A and tacrolimus inhibit lymphocyte and some granulocyte responses.


Immunology_Janeway

Immunology_Janeway. Fig. 16.4 Cyclosporin A and tacrolimus inhibit lymphocyte and some granulocyte responses. T lymphocyte Reduced expression of IL-2, IL-3, IL-4, GM-CSF, TNF-˜ Reduced proliferation following decreased IL-2 production Reduced Ca2+-dependent exocytosis of granule-associated serine esterases Inhibition of antigen-driven apoptosis calmodulin; calmodulin then activates calcineurin (see Fig. 7.18). Binding of the immunophilin:drug complex to calcineurin prevents the latter’s activation by calmodulin; the bound calcineurin is unable to dephosphorylate and activate NFAT (Fig. 16.5). Calcineurin is found in other cells besides T cells, but its levels in T cells are much lower than in other tissues. T cells are therefore particularly susceptible to the inhibitory effects of these drugs.


Immunology_Janeway

Immunology_Janeway. Cyclosporin A and tacrolimus are effective immunosuppressants but are not problem-free. As with the cytotoxic agents, they affect all immune responses indiscriminately. This can be countered by carefully varying the dose of drug given during the course of a response. During organ transplantation, for example, high doses are required during the time of grafting, but once the graft has become established the dose can be decreased in order to allow useful protective immune responses while maintaining adequate suppression of the residual response to the grafted tissue. This balance is difficult to achieve and requires careful monitoring of the patient. These drugs also have effects on many different tissues and thus can have broad side-effects, such as injury to kidney tubule epithelial cells. Finally, treatment with these drugs is relatively expensive, because they are complex natural products that must be taken for long periods. Nevertheless, at present they are the immunosuppressants


Immunology_Janeway

Immunology_Janeway. Finally, treatment with these drugs is relatively expensive, because they are complex natural products that must be taken for long periods. Nevertheless, at present they are the immunosuppressants of choice in clinical transplantation, and they are also being tested in a variety of autoimmune diseases, especially those that, like graft rejection, are mediated by T cells.


Immunology_Janeway

Immunology_Janeway. Rapamycin has a different mode of action from either cyclosporin A or tacrolimus. Like tacrolimus, rapamycin binds to the FKBP family of immunophilins, but the rapamycin:immunophilin complex does not inhibit calcineurin activity. Instead, it inhibits a serine/threonine kinase known as mTOR (mammalian target of rapamycin), which is involved in regulating cell growth and proliferation (see Section 7-17). The mTOR pathway can be activated by different upstream signaling pathways, including the Ras/MAPK pathway and


Immunology_Janeway

Immunology_Janeway. Fig. 16.5 Cyclosporin A and tacrolimus inhibit T-cell activation by interfering with the serine/threonine-specific phosphatase calcineurin. As shown in the upper panel, signaling via T-cell receptor-associated tyrosine kinases leads to opening of calciumrelease-activated calcium (CRAC) channels in the plasma membrane. This increases the concentration of Ca2+ in the cytoplasm and promotes calcium binding to the regulatory protein calmodulin (see Fig. 7.18). Calmodulin is activated by binding Ca2+ and can then target many downstream effector proteins such as the phosphatase calcineurin. Binding by calmodulin activates calcineurin to dephosphorylate the transcription factor NFAT (see Section 7-14), which then enters the nucleus and transcribes genes that are required for T-cell activation to progress. As shown in the lower panel, when cyclosporin A or tacrolimus or both are present, they form complexes with their immunophilin targets, cyclophilin and FK-binding protein, respectively.


Immunology_Janeway

Immunology_Janeway. to progress. As shown in the lower panel, when cyclosporin A or tacrolimus or both are present, they form complexes with their immunophilin targets, cyclophilin and FK-binding protein, respectively. These complexes bind to calcineurin, preventing it from becoming activated by calmodulin, and thereby preventing the dephosphorylation of NFAT.


Immunology_Janeway

Immunology_Janeway. Fig. 16.6 Rapamycin inhibits cell growth and proliferation by selectively blocking activation of the kinase mTOR by Raptor. Rapamycin binds FK-binding protein (FKBP), the same immunophilin protein that binds to tacrolimus (FK506). The rapamycin:FKBP complex does not inhibit calcineurin, but instead blocks one of two complexes that activate mTOR, a large kinase that regulates many metabolic pathways. mTOR is activated downstream of various growth factor signaling pathways, and becomes associated with either of two proteins, Raptor (regulatory associated protein of mTOR) and Rictor (rapamycininsensitive companion of mTOR). The complex with Raptor, mTORC1, promotes cell proliferation, translation of proteins, and autophagy, and the complex with Rictor, mTORC2, influences cell adhesion and migration by controlling the actin cytoskeleton. The rapamycin:FKBP complex acts to inhibit the Raptorassociated mTORC1, and thereby selectively reduces cell growth and proliferation.


Immunology_Janeway

Immunology_Janeway. the PI 3-kinase pathway. These pathways activate AKT, which phosphorylates and inactivates a regulatory complex called TSC. This complex normally acts as an inhibitor of the small GTPase Rheb; after TSC is phosphorylated, Rheb is free to activate mTOR (see Fig. 7.22). Two distinct mTOR complexes can be formed, mTORC1 and mTORC2, which are controlled by two regulatory proteins called Raptor and Rictor, respectively, and which activate different downstream cellular pathways (Fig. 16.6). Rapamycin appears to inhibit only the mTORC1 complex, as the rapamycin:FKBP complex selectively inhibits the Raptor-dependent pathway that regulates this complex (see Fig. 16.6). Blockade of this pathway markedly reduces T-cell proliferation, arresting cells in the G1 phase of the cell cycle and promoting apoptosis. Rapamycin inhibits lymphocyte proliferation driven by growth factors such as IL-2, IL-4, and IL-6, and increases the number of regulatory T cells, perhaps because these cells use different


Immunology_Janeway

Immunology_Janeway. apoptosis. Rapamycin inhibits lymphocyte proliferation driven by growth factors such as IL-2, IL-4, and IL-6, and increases the number of regulatory T cells, perhaps because these cells use different signaling pathways from those of effector T cells. Rapamycin also selectively reduces the outgrowth of effector T cells while apparently enhancing the formation of memory T cells. Because of this, the use of rapamycin to augment T-cell memory induced by vaccines is being considered.


Immunology_Janeway

Immunology_Janeway. One recently introduced drug manipulates immune responses by regulating the migration of immune effector cells to the sites of a graft or of autoimmune disease. In Section 9-7, we described how emigration of lymphocytes out of the lymphoid tissues requires recognition of the lipid molecule sphingosine 1-phosphate (S1P) by the G-protein-coupled receptor S1PR1. Fingolimod (FTY720), a sphingosine 1-phosphate analog, is a relatively newer drug that causes the retention of effector lymphocytes in lymphoid organs, thus preventing these cells from mediating their effector activities in target tissues. Fingolimod was approved in 2010 for treatment of the autoimmune disease multiple sclerosis, and has shown promise in the treatment of kidney graft rejection and asthma.


Immunology_Janeway

Immunology_Janeway. Cytokines activate many aspects of the immune response, and many cytokine receptors use Janus kinases (JAKs) in signal transduction (see Section 3-16). The four JAK family members, JAK1, JAK2, JAK3, and TYK2, bind and phosphorylate the cytoplasmic regions of cytokine receptors and initiate the activation of different STAT transcription factors. Selective JAK inhibitors have been developed over the last decade that can block the kinase activity of one or more members of this family. Since different JAKs binds to different cytokine receptors, JAK inhibitors, or Jakinibs, can therefore exert potentially specific effects on the quality of T-cell development. Two Jakinibs are now approved for use in treating inflammatory diseases and are being investigated for their application in cancer. For example, tofacitinib inhibits JAK3, interfering with signaling by IL-2 and IL-4, and somewhat more weakly JAK1, interfering with signaling by IL-6. Tofacitinib is approved for treatment of rheumatoid


Immunology_Janeway

Immunology_Janeway. example, tofacitinib inhibits JAK3, interfering with signaling by IL-2 and IL-4, and somewhat more weakly JAK1, interfering with signaling by IL-6. Tofacitinib is approved for treatment of rheumatoid arthritis. Ruxolitinib inhibits JAK1 and JAK2 and has been approved for treating myelofibrosis, an abnormal proliferation of bone marrow progenitor cells that causes fibrosis.


Immunology_Janeway

Immunology_Janeway. used to eliminate lymphocyte subsets or to inhibit lymphocyte function.


Immunology_Janeway

Immunology_Janeway. All the drugs discussed so far exert a general inhibition on immune responses and can have severe side effects, but antibodies can act in a more specific manner and with less direct toxicity. The initial therapeutic use of antibodies extends back to the late 1800s with the development of equine sera for treatment of diphtheria and tetanus. Today, intravenous immunoglobulin (IVIG), a collection of polyvalent IgG antibodies pooled from many blood donors, is still widely used as a treatment for various primary and acquired immune deficiencies. It is also used in some acute infections, where it likely works by providing antibodies that may neutralize certain pathogens or their toxins. Finally, IVIG is also used to treat certain autoimmune and inflammatory diseases, such as immune thrombocytopenia and Kawasaki disease. In these cases, IVIG exerts an immunomodulatory effect that seems to operate through interactions with inhibitory Fc receptors that inhibit immune-cell activation.


Immunology_Janeway

Immunology_Janeway. The relatively recent expansion in the use of antibodies as therapeutic agents has extended their function from targeting pathogens to targeting components of the immune system itself in order to achieve a specific regulatory result. For example, the potential of antibodies to eliminate unwanted lymphocytes is demonstrated by anti-lymphocyte globulin, a preparation of polyclonal immunoglobulin from rabbits (and previously horses) immunized with human lymphocytes, which has been used for many years to treat episodes of acute graft rejection. Anti-lymphocyte globulin does not, however, discriminate between useful lymphocytes and those responsible for the unwanted responses and therefore leads to global immunosuppression. Foreign immunoglobulins are also highly antigenic in humans, and the large doses of anti-lymphocyte globulin used in therapy often cause a condition called serum sickness, resulting from the formation of immune complexes of the animal immunoglobulin and human antibodies


Immunology_Janeway

Immunology_Janeway. doses of anti-lymphocyte globulin used in therapy often cause a condition called serum sickness, resulting from the formation of immune complexes of the animal immunoglobulin and human antibodies against it (see Section 14-15).


Immunology_Janeway

Immunology_Janeway. Anti-lymphocyte globulin is nevertheless still used to treat acute rejection, and this has stimulated the quest for monoclonal antibodies (see Appendix I, Section A-7) that would achieve more specifically targeted effects. One such antibody is alemtuzumab (marketed as Campath-1H), which is directed at the cell-surface protein CD52 expressed by most lymphocytes. It has similar actions to anti-lymphocyte globulin, causing long-standing lymphopenia. It is also used to eliminate cancer cells in the treatment of chronic lymphocytic leukemia.


Immunology_Janeway

Immunology_Janeway. Immunosuppressive monoclonal antibodies act by one of two general mechanisms. Some, such as alemtuzumab, trigger the destruction of lymphocytes in vivo and are referred to as depleting antibodies, whereas others are nondepleting and act by blocking the function of their target protein without killing the cell that bears it. Depleting monoclonal IgG antibodies bind to lymphocytes and target them to macrophages and NK cells, which bear Fc receptors and kill the lymphocytes by phagocytosis or antibody-dependent cell-mediated cytotoxicity (ADCC), respectively. Complement-mediated lysis may also play a part in lymphocyte destruction. 16-5 Antibodies can be engineered to reduce their immunogenicity in humans.


Immunology_Janeway

Immunology_Janeway. 16-5 Antibodies can be engineered to reduce their immunogenicity in humans. A major impediment to therapy with monoclonal antibodies in humans has been that these antibodies are most readily made by immunizing nonhuman species, such as the mouse, to generate antibodies of the desired specificity (see Appendix I, Section A-7). Humans may develop an antibody response against such nonhuman antibodies, since aggregated forms of foreign antibodies can be immunogenic. Such a reaction not only interferes with the therapeutic actions of the antibodies, but also leads to allergic reactions, and, if treatment is continued, may result in anaphylaxis (see Section 14-10). Once a patient has made a response to an antibody, it can no longer be used for future treatment. This problem can, in principle, be avoided by making antibodies that are not recognized as foreign by the human immune system, a process called humanization.


Immunology_Janeway

Immunology_Janeway. Various approaches have been tried to humanize antibodies. The variable regions encoding the antigen-recognition determinants from a murine antibody can be spliced onto the Fc regions of human IgG by gene manipulation. Antibodies of this type are called chimeric antibodies. However, this approach leaves regions within the murine variable regions that could potentially induce


Immunology_Janeway

Immunology_Janeway. Fig. 16.7 Monoclonal antibodies used to treat human diseases can be engineered to decrease immunogenicity but maintain their antigen specificity. Antibodies that are derived fully from mice, named with the suffix -omab, are immunogenic in humans. This causes patients to generate antibodies against them, limiting their usefulness over time. This immunogenicity can be reduced by making chimeric antibodies in which the V regions from the mouse are spliced onto human antibody constant regions; such antibodies are named with the suffix -ximab. Humanization is the process of splicing in just the complementarity-determining regions from the mouse antibody, further reducing immunogenicity; humanized antibodies are named with the suffix -zumab. New techniques now allow fully human (-umab) monoclonal antibodies to be derived, which are the least immunogenic type of antibody currently used for treating humans.


Immunology_Janeway

Immunology_Janeway. immune responses (Fig. 16.7). Genetically engineered mice that harbor human immunoglobulin genes inserted into their immunoglobulin locus represent one way that human antibodies may be obtained from the immunization of mice. Newer methods are aimed at generating fully human monoclonal antibodies directly from human cells through the use of viral transformation of human primary B-cell lines or antibody-secreting plasmablasts, or by generating human B-cell hybridomas.


Immunology_Janeway

Immunology_Janeway. Monoclonal antibodies belong to a new class of therapeutic compounds called biologics, which includes other natural proteins such as anti-lymphocyte globulin, cytokines, protein fragments, and even whole cells, which are used, for example, in the adoptive transfer of T cells in cancer immunotherapy. Many monoclonal antibodies have been, or are in the process of being, approved for clinical use by the US Food and Drug Administration (Fig. 16.8), and a systematic naming process identifies the type of antibody. Murine monoclonal antibodies are designated by the suffix -omab, such as muromomab (originally called OKT3), a murine antibody against CD3. Chimeric antibodies in which the entire variable region is spliced into human constant regions have the suffix -ximab, such as basiliximab, an anti-CD25 antibody approved for the treatment of transplantation rejection. Humanized antibodies in which the murine hypervariable regions have been spliced into a human antibody have the suffix -zumab,


Immunology_Janeway

Immunology_Janeway. antibody approved for the treatment of transplantation rejection. Humanized antibodies in which the murine hypervariable regions have been spliced into a human antibody have the suffix -zumab, as in alemtuzumab and natalizumab (Tysabri). The latter is directed against the α4 integrin subunit, and is used to treat multiple sclerosis and Crohn’s disease. Antibodies derived entirely from human sequences have the suffix -umab, as in adalimumab, an antibody derived from phage display that binds TNF-α; it is used to treat several autoimmune diseases.


Immunology_Janeway

Immunology_Janeway. 16-6 Monoclonal antibodies can be used to prevent allograft rejection.


Immunology_Janeway

Immunology_Janeway. Antibodies specific for various physiological targets are being used, or are under investigation, to prevent the rejection of transplanted organs by inhibiting the development of harmful inflammatory and cytotoxic responses. For example, alemtuzumab, discussed in Section 16-4, is licensed for the treatment of certain leukemias but is also used in both solid-organ and bone marrow transplantation. In solid-organ transplantation, alemtuzumab may be given to the recipient around the time of transplantation to remove mature T lymphocytes from the circulation. In bone marrow transplantation, alemtuzumab can be used in vitro to deplete donor bone marrow of mature T cells before its infusion into a recipient, or used in vivo to treat the recipient following infusion. Elimination of mature T cells from donor bone marrow is very effective at reducing the incidence of graft-versus-host disease (see Section 15-36). In this disease, the T lymphocytes in the donor bone marrow recognize the


Immunology_Janeway

Immunology_Janeway. T cells from donor bone marrow is very effective at reducing the incidence of graft-versus-host disease (see Section 15-36). In this disease, the T lymphocytes in the donor bone marrow recognize the recipient as foreign and mount a damaging response, causing rashes, diarrhea, and hepatitis, which can occasionally be fatal. Bone marrow transplantation is also used as a treatment for leukemia, as T cells in the graft can have a so-called graft-versus-leukemia effect where they recognize the leukemic cells as foreign and destroy them. It was originally thought that elimination of mature donor


Immunology_Janeway

Immunology_Janeway. Fig. 16.8 Monoclonal antibodies developed for immunotherapy. A substantial fraction of pharmaceuticals currently under development are antibodies, and additions to this list, current as of this writing, are under development and in clinical trials. T cells during such procedures would be disadvantageous, as the antileukemic action of the donor T cells could be lost, but this seems to not be the case when alemtuzumab is used as the depleting agent. Specific antibodies directed against T cells have been used to treat episodes of graft rejection that occur after transplantation. The murine antibody muromomab (OKT3) targets the CD3 complex and leads to T-cell immunosuppression by inhibiting signaling through the T-cell receptor. It has been used clinically in solid-organ transplantation but is often associated with a dangerous side-effect, namely, the stimulation of pro-inflammatory cytokine release, and its use is declining. This cytokine release is related to muromomab’s intact


Immunology_Janeway

Immunology_Janeway. Fc region, which can activate Fc receptors via cross-linking and activate the cells that bear these receptors. In the antibody called teplizumab, or OKT3γ1 (Ala-Ala), amino acids 234 and 235 in the human IgG1 Fc region have been changed to alanines, and this antibody no longer stimulates cytokine release. Two other antibodies, daclizumab and basiliximab, approved for treating kidney transplant rejection, are directed against CD25 (a subunit of the IL-2 receptor) and reduce T-cell activation, presumably by blocking the growth-promoting signals delivered by IL-2.


Immunology_Janeway

Immunology_Janeway. A primate model of kidney transplant rejection showed promising effects for a humanized monoclonal antibody against the CD40 ligand expressed by T cells (see Section 9-17). A possible mechanism of protection by this antibody is blockade of the activation of dendritic cells by helper T cells that recognize donor antigens. Only preliminary studies of anti-CD40 ligand antibodies have been performed in humans. One antibody was associated with thromboembolic complications and was withdrawn; a different anti-CD40 ligand antibody was administered to patients with the autoimmune disease systemic lupus erythematosus (SLE) without significant complications, but also with little evidence of efficacy.


Immunology_Janeway

Immunology_Janeway. In experimental models, monoclonal antibodies against other targets have also had some success in preventing graft rejection, including nondepleting antibodies that bind the CD4 co-receptor or the co-stimulatory receptor CD28 on lymphocytes. Similarly, abatacept, a soluble recombinant CTLA-4–Ig fusion protein which binds to the co-stimulatory B7 molecules on antigen-presenting cells and prevents their interaction with CD28 on T cells, is approved for the treatment of rheumatoid arthritis. 16-7 Depletion of autoreactive lymphocytes can treat autoimmune disease.


Immunology_Janeway

Immunology_Janeway. In addition to their use in preventing transplantation rejection, monoclonal antibodies can be used to treat certain autoimmune diseases, and the different immune mechanisms targeted are discussed in the next few sections. We start by discussing the use of depleting and nondepleting antibodies to remove lymphocytes nonspecifically. The anti-CD20 monoclonal antibody rituximab was originally developed to treat B-cell lymphomas, but has also been tried in treating certain autoimmune diseases. By ligating CD20, rituximab (Rituxan, MabThera) transduces a signal that induces lymphocyte apoptosis and depletes B cells for several months. Certain autoimmune diseases are believed to involve autoantibody-mediated pathogenesis. There is evidence for the efficacy of rituximab in some patients with autoimmune hemolytic anemia, SLE, rheumatoid arthritis, or type II mixed cryoglobulinemia, all of which have autoantibodies as a part of their clinical presentation. Although CD20 is not expressed on


Immunology_Janeway

Immunology_Janeway. autoimmune hemolytic anemia, SLE, rheumatoid arthritis, or type II mixed cryoglobulinemia, all of which have autoantibodies as a part of their clinical presentation. Although CD20 is not expressed on antibody-producing plasma cells, their B-cell precursors are targeted by anti-CD20, resulting in a substantial reduction in the short-lived, but not the long-lived, plasma-cell population.


Immunology_Janeway

Immunology_Janeway. Alemtuzumab, discussed above for its use in treating leukemia and in transplant rejection, has shown some beneficial effect in studies of small numbers of patients with multiple sclerosis. However, immediately after its infusion, most multiple sclerosis patients suffered a frightening, although fortunately brief, flare-up of their illness, illustrating another potential complication of antibody therapy. Alemtuzumab was acting as intended, killing cells by complementand Fc-dependent mechanisms. However, it also stimulated the release of cytokines, including TNF-α, interferon (IFN)-γ, and IL-6, which transiently block nerve conduction in nerve fibers previously affected by demyelination. This caused the transient but dramatic exacerbation of symptoms. Nevertheless, alemtuzumab may be useful at early stages of the disease, when the inflammatory response is maximal, but this has yet to be determined.


Immunology_Janeway

Immunology_Janeway. Fig. 16.9 Anti-inflammatory effects of anti-TNF-α therapy and objective parameters of disease activity (as measured by pain in rheumatoid arthritis. The clinical course of 24 patients was score and swollen-joint count, respectively) and in the systemic followed for 4 weeks after treatment with either a placebo or a inflammatory acute-phase response, measured as a fall in the monoclonal antibody against TNF-α at a dose of 10 mg • kg–1. The concentration of the acute-phase C-reactive protein. Data courtesy antibody therapy was associated with a reduction in both subjective of R.N. Maini.


Immunology_Janeway

Immunology_Janeway. Treating patients suffering from rheumatoid arthritis or multiple sclerosis by using anti-CD4 antibodies has been tried, but with disappointing results. In controlled studies, the antibodies showed only small therapeutic effects but caused depletion of T lymphocytes from peripheral blood for more than 6 years after treatment. The likely explanation for the failure seems to be that these antibodies failed to delete already primed CD4 T cells secreting pro-inflammatory cytokines, and may thus have missed their target. This cautionary tale shows that it is possible to deplete large numbers of lymphocytes and yet completely fail to kill the cells that matter. 16-8 Biologics that block TNF-α, IL-1, or IL-6 can alleviate autoimmune diseases.


Immunology_Janeway

Immunology_Janeway. 16-8 Biologics that block TNF-α, IL-1, or IL-6 can alleviate autoimmune diseases. Anti-inflammatory therapy either can attempt to eliminate an autoimmune response altogether, as with immunosuppressive drugs or depleting antibodies, or it can try to reduce the tissue injury caused by the immune response. This second category of treatment is called immunomodulatory therapy, and is illustrated by the use of conventional anti-inflammatory agents such as aspirin, nonsteroidal anti-inflammatory drugs, or low-dose corticosteroids. A newer avenue of immunomodulatory therapy using biologics is illustrated by several FDA-approved antibodies that block the activity of powerful pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6.


Immunology_Janeway

Immunology_Janeway. Anti-TNF therapy was the first specific biological therapeutic to enter the clinic. Anti-TNF-α antibodies induced striking remissions in rheumatoid arthritis (Fig. 16.9) and reduced inflammation in Crohn’s disease, an inflammatory bowel disease (see Section 15-23). Two types of established biologics are used to antagonize TNF-α in clinical practice. The first type comprises the antiTNF-α antibodies, such as infliximab and adalimumab, which bind to TNF-α and block its activity. The second type is a recombinant human TNF receptor (TNFR) subunit p75–Fc fusion protein called etanercept, which also binds TNF-α, neutralizing its activity. These are extremely potent anti-inflammatory agents, and the number of diseases in which they have been shown to be effective is growing as further clinical trials are performed. In addition to rheumatoid arthritis, the rheumatic diseases ankylosing spondylitis, psoriatic arthropathy, and juvenile idiopathic arthritis (other than the systemic-onset subset)


Immunology_Janeway

Immunology_Janeway. are performed. In addition to rheumatoid arthritis, the rheumatic diseases ankylosing spondylitis, psoriatic arthropathy, and juvenile idiopathic arthritis (other than the systemic-onset subset) respond well to blockade of TNF-α, and this treatment is now routine in many cases.


Immunology_Janeway

Immunology_Janeway. An illustration of the importance of TNF-α in defending against infection is the observation that TNF-α blockade carries a small but increased risk of patients developing serious infections, including tuberculosis (see Section 3-20). AntiTNF-α therapy has not been successful in all diseases. TNF-α blockade as a treatment for experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, led to amelioration of the disease, but in human patients with multiple sclerosis treated with anti-TNF-α, relapses became more frequent, possibly because of an increase in T-cell activation.


Immunology_Janeway

Immunology_Janeway. Antibodies and recombinant proteins against the pro-inflammatory cytokine IL-1 and its receptor have not proved as effective as TNF-α blockade for treating rheumatoid arthritis in humans, despite being equally powerful in animal models of arthritis. An antibody against the cytokine IL-1 has been licensed for clinical use against the hereditary autoinflammatory disease Muckle– Wells syndrome (see Section 13-9), and blockade of the IL-1β receptor by the recombinant protein anakinra (Kineret) has also proven useful in adults with moderate to severe rheumatoid arthritis. Another cytokine antagonist in clinical use is the humanized antibody tocilizumab; by virtue of being directed against the IL-6 receptor, it blocks the effects of the pro-inflammatory cytokine IL-6. This seems to be as effective as anti-TNF-α in patients with rheumatoid arthritis and also shows promise in treating systemic-onset juvenile idiopathic arthritis, an autoinflammatory condition.


Immunology_Janeway

Immunology_Janeway. Interferon (IFN)-β (Avonex) is used to treat diseases of viral origin based on its ability to enhance immunity, but is also effective in treating multiple sclerosis, attenuating its course and severity and reducing the occurrence of relapses. Until recently, it was unclear how IFN-β could reduce rather than enhance immunity. In Section 3-9, we described the inflammasome, in which innate sensors of the NLR family activate caspase 1 to cleave the IL-1 pro-protein into the active form of the cytokine (see Fig. 3.19). We now know that IFN-β acts at two levels to reduce IL-1 production. It inhibits the activity of the NALP3 (NLRP3) and NLRP1 inflammasomes and also reduces expression of the IL-1 pro-protein, reducing the substrate available to caspase 1. Thus, IFN-β limits the production of a powerful pro-inflammatory cytokine, which may explain its observed effects on the symptoms of multiple sclerosis.


Immunology_Janeway

Immunology_Janeway. 16-9 Biologic agents can block cell migration to sites of inflammation and reduce immune responses.


Immunology_Janeway

Immunology_Janeway. Effector lymphocytes expressing the integrin α4:β1 (VLA-4) bind to VCAM-1 on endothelium in the central nervous system, while those expressing integrin α4:β7 (lamina propria-associated molecule 1) bind to MAdCAM-1 on the endothelium in the gut. The humanized monoclonal antibody natalizumab is specific for the α4 integrin subunit and binds both VLA-4 and α4:β7, preventing their interaction with their ligands (Fig. 16.10). This antibody has shown therapeutic benefit in placebo-controlled trials in patients with Crohn’s disease or with multiple sclerosis. The early signs that this treatment could be successful illustrate the fact that disease depends on the continuing emigration of lymphocytes, monocytes, and macrophages from the circulation into the tissues of the brain in multiple sclerosis, and into the gut wall in Crohn’s disease. However, blockade of α4:β1 integrin is not specific and, like anti-TNF therapy, could lead to reduced defense against infection. Rarely patients treated


Immunology_Janeway

Immunology_Janeway. and into the gut wall in Crohn’s disease. However, blockade of α4:β1 integrin is not specific and, like anti-TNF therapy, could lead to reduced defense against infection. Rarely patients treated with natalizumab have developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus. This led to the temporary withdrawal of natalizumab from the market in 2005, but in June 2006 it was again allowed to be prescribed for multiple sclerosis and for Crohn’s disease.


Immunology_Janeway

Immunology_Janeway. A similar problem with multifocal leukoencephalopathy led to the withdrawal from the market in the United States and Europe in 2009 of another anti-integrin antibody, efalizumab; this drug targets the αL subunit CD11a and had shown promise in treating psoriasis, an inflammatory skin disease driven primarily by T cells that produce pro-inflammatory cytokines. 16-10 Blockade of co-stimulatory pathways that activate lymphocytes can be used to treat autoimmune disease.


Immunology_Janeway

Immunology_Janeway. 16-10 Blockade of co-stimulatory pathways that activate lymphocytes can be used to treat autoimmune disease. Blocking co-stimulatory pathways, as noted above in connection with the prevention of transplantation rejection (see Section 16-6), has also been applied to autoimmune diseases. For example, CTLA-4–Ig (abatacept) blocks the interaction of the B7 expressed by antigen-presenting cells with the CD28 expressed by T cells. This drug is approved for the treatment of rheumatoid arthritis, and also seems to be beneficial in treating psoriasis. When CTLA-4–Ig was given to patients with psoriasis, there was an improvement in the psoriatic rash and histological evidence of loss of activation of keratinocytes, T cells, and dendritic cells within the damaged skin.


Immunology_Janeway

Immunology_Janeway. Another co-stimulatory pathway that has been targeted in psoriasis is the interaction between the adhesion molecule CD2 on T cells and CD58 (LFA-3) on antigen-presenting cells. A recombinant CD58–IgG1 fusion protein, called alefacept (Amevive), inhibits the interaction between CD2 and CD58, and is now a routine and effective treatment for psoriasis. Although memory T cells are targeted by this therapy, responses to vaccination such as antitetanus remain intact. 16-11 Some commonly used drugs have immunomodulatory properties.


Immunology_Janeway

Immunology_Janeway. 16-11 Some commonly used drugs have immunomodulatory properties. Certain existing medications, such as the statins and angiotensin-converting enzyme (ACE) inhibitors widely used in the prevention and treatment of cardiovascular disease, can also modulate the immune response in experimental animals. Statins are very widely prescribed drugs that block the enzyme 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase, thereby reducing cholesterol levels. They also reduce the increased level of expression of MHC class II molecules in some autoimmune diseases. These effects may be due to an alteration in the cholesterol content of membranes, thereby influencing lymphocyte signaling. In animal models, these drugs also seem to cause T cells to switch from a more pathogenic TH1 response to a more protective TH2 response, although whether this occurs in human patients is not clear.


Immunology_Janeway

Immunology_Janeway. The hormone vitamin D3, essential for bone and mineral homeostasis, also exerts immunomodulatory effects. It decreases IL-12 production by dendritic cells and leads to a decrease in IL-2 and IFN-γ production by CD4 T cells, and


Immunology_Janeway

Immunology_Janeway. Fig. 16.10 Treatment with an anti-α4 integrin humanized monoclonal antibody reduces relapses in multiple sclerosis. Left panel: interaction between α4:β1 integrin (VLA-4) on lymphocytes and macrophages and VCAM-1 expressed on endothelial cells permits the adhesion of these cells to brain endothelium. This facilitates the migration of these cells into the plaques of inflammation in multiple sclerosis. Center panel: the monoclonal antibody natalizumab (blue) binds to the α4 chain of the integrin and blocks adhesive interactions between lymphocytes and monocytes and VCAM-1 on endothelial cells, thus preventing the cells from entering the tissue and exacerbating the inflammation. The future of this treatment is unclear because of the development of a rare infection as a side-effect (see the text). Right panel: the number of new lesions detected on magnetic resonance imaging (MRI) of the brain is greatly reduced in patients treated with natalizumab compared with a placebo. Data from


Immunology_Janeway

Immunology_Janeway. the text). Right panel: the number of new lesions detected on magnetic resonance imaging (MRI) of the brain is greatly reduced in patients treated with natalizumab compared with a placebo. Data from Miller, D.H., et al.:


Immunology_Janeway

Immunology_Janeway. N. Engl. J. Med. 2003, 348:15–23. protective effects have been demonstrated in a variety of animal models of autoimmunity, such as EAE (see Section 15-5) and diabetes, as well as in transplantation. The major drawback of vitamin D3 is that its immunomodulatory effects are seen only at dosages that would lead to hypercalcemia and bone resorption in humans. There is a major search under way for structural analogs of vitamin D3 that retain the immunomodulatory effects but do not cause hypercalcemia. 16-12 Controlled administration of antigen can be used to manipulate the nature of an antigen-specific response.


Immunology_Janeway

Immunology_Janeway. 16-12 Controlled administration of antigen can be used to manipulate the nature of an antigen-specific response. In some diseases, the target antigen of an unwanted immune response can be identified. It can then be possible to use the antigen itself, rather than drugs or antibodies, to treat the disease, because the manner of antigen presentation can alter the immune response and reduce or eliminate its pathogenic features. As discussed in Section 14-13, this principle has been applied with some success to the treatment of allergies caused by an IgE response to very low doses of antigen. Repeated treatment of allergic individuals with increasing doses of allergen seems to divert the allergic response to one dominated by T cells that favor the production of IgG and IgA antibodies from B cells. These antibodies are thought to desensitize the patient by binding the small amounts of allergen normally encountered and preventing it from binding to IgE.


Immunology_Janeway

Immunology_Janeway. There has been considerable interest in using peptide antigens to suppress pathogenic responses in T-cell-mediated autoimmune disease. The type of CD4 T-cell response induced by a peptide depends on the way in which it is presented to the immune system (see Section 9-18). For instance, peptides given orally tend to induce regulatory T cells through production of transforming growth factor (TGF)-β, but do not induce TH1 cells or systemic antibody production (see Section 12-14). Indeed, experiments in animals indicate that oral antigens can protect against induced autoimmune disease. Diseases resembling multiple sclerosis or rheumatoid arthritis can be induced in mice by the injection of myelin basic protein (MBP) or collagen type II, respectively, in Freund’s complete adjuvant (see Section 16-29). Oral administration of MBP or type II collagen inhibits the development of these diseases in animals, but oral administration of the whole protein in patients with multiple sclerosis or


Immunology_Janeway

Immunology_Janeway. 16-29). Oral administration of MBP or type II collagen inhibits the development of these diseases in animals, but oral administration of the whole protein in patients with multiple sclerosis or rheumatoid arthritis has had marginal therapeutic effects. Similarly, no protective effect was found in a large study that examined whether giving low-dose parenteral insulin could delay the onset of diabetes in people at high risk of developing the disease.


Immunology_Janeway

Immunology_Janeway. Other approaches using antigen to shift the autoimmune T-cell response to a less damaging TH2 response have been more effective in humans. The peptide drug glatiramer acetate (Copaxone) is approved for treating multiple sclerosis, in which it may reduce relapse rates by up to 30%. It is a polymer consisting of the four amino acids glutamic acid, alanine, tyrosine, and lysine in ratios that mimic their composition in MBP, and it induces a TH2-type protective response. A more refined strategy uses altered peptide ligands (APLs), in which amino acid substitutions have been made in specific amino acids in an antigenic peptide that are at the T-cell receptor contact positions. APLs can be designed to act as partial agonists or antagonists, or to induce regulatory T cells. But despite the success of APLs in treating EAE in mice, a trial of these peptides for multiple sclerosis in some patients led to exacerbated disease or to allergic reaction associated with a vigorous TH2 response, and


Immunology_Janeway

Immunology_Janeway. of APLs in treating EAE in mice, a trial of these peptides for multiple sclerosis in some patients led to exacerbated disease or to allergic reaction associated with a vigorous TH2 response, and their value in humans remains to be seen.


Immunology_Janeway

Immunology_Janeway. Summary. Treatments for unwanted immune responses, such as graft rejection, autoimmunity, or allergic reactions, include conventional drugs—anti-inflammatory, cytotoxic, and immunosuppressive drugs—as well as biologic agents such as monoclonal antibodies and immunomodulatory proteins. Anti-inflammatory drugs, of which the most potent are the corticosteroids, have a broad spectrum of actions and a wide range of toxic side-effects. Their dose must be carefully controlled, and they are normally used in combination with either cytotoxic or immunosuppressive drugs. The cytotoxic drugs work by killing dividing cells and thereby prevent lymphocyte proliferation, but they suppress all immune responses indiscriminately and also kill other types of dividing cells. The immunosuppressive drugs, such as cyclosporin A and rapamycin, interfere in specific signaling pathways and are generally less toxic, but are more expensive and still suppress the immune response somewhat indiscriminately.


Immunology_Janeway

Immunology_Janeway. Several types of biologic agents are now established in the clinic for treating transplant rejection and autoimmune diseases (Fig. 16.11). Many monoclonal antibodies have been approved for human use that deplete lymphocytes either generally or selectively, or inhibit lymphocyte activation through receptor blockade, or prevent lymphocyte migration into tissues. Immunomodulatory agents also include monoclonal antibodies or fusion proteins that inhibit the inflammatory actions of TNF-α, a triumph of immunotherapy. 16.2 and 16.8 can act in one of three general ways. First (red), they can act by depleting cells from inflammatory sites, causing global cell-specific depletion, or blocking integrin interactions, thereby inhibiting lymphocyte trafficking. Second (blue), agents may block specific cellular interactions or inhibit various co-stimulatory pathways. Third (green), agents may target the terminal effector mechanisms, such as the neutralization of various pro-inflammatory cytokines.


Immunology_Janeway

Immunology_Janeway. Fig. 16.12 Tumor rejection antigens are specific to individual tumors. Mice immunized with irradiated tumor cells and challenged with viable cells of the same tumor can, in some cases, reject a lethal dose of that tumor (left panels). This is the result of an immune response to tumor rejection antigens. If the immunized mice are challenged with viable cells of a different tumor, there is no protection and the mice die (right panels). Using the immune response to attack tumors.


Immunology_Janeway

Immunology_Janeway. Cancer is one of the three leading causes of death in industrialized nations, the others being infectious disease and cardiovascular disease. As treatments for infectious diseases and the prevention of cardiovascular disease continue to improve, and the average life expectancy increases, cancer is likely to become the most common fatal disease in these countries. Cancers are caused by the uncontrolled growth of the progeny of transformed cells. A major problem in treating cancer is controlling metastasis, or the spread of cancerous cells from one part of the body to unconnected parts. Curing cancer therefore requires that all the malignant cells be removed or destroyed without killing the patient. An attractive way of achieving this would be to induce an immune response against the tumor that would discriminate between the cells of the tumor and their normal-cell counterparts, in the same way that vaccination against a viral or bacterial pathogen induces a specific immune response


Immunology_Janeway

Immunology_Janeway. that would discriminate between the cells of the tumor and their normal-cell counterparts, in the same way that vaccination against a viral or bacterial pathogen induces a specific immune response that provides protection only against that pathogen. Immunological approaches to the treatment of cancer have been attempted for more than a century, but it is only in the past decade that immunotherapy of cancer has shown real promise. An important conceptual advance has been the integration of conventional approaches such as surgery or chemotherapy, which substantially reduce tumor load, with immunotherapy.


Immunology_Janeway

Immunology_Janeway. 16-13 The development of transplantable tumors in mice led to the discovery of protective immune responses to tumors. The finding that tumors could be induced in mice after treatment with chemical carcinogens or irradiation, coupled with the development of inbred strains of mice, made it possible to undertake the key experiments that led to the discovery of immune responses to tumors. These tumors could be transplanted between mice, and the experimental study of tumor rejection has generally been based on the use of such tumors. If they bear MHC molecules foreign to the mice into which they are transplanted, the tumor cells are readily recognized and destroyed by the immune system, a fact that was exploited to develop the first MHC-congenic strains of mice. Specific immunity to tumors must therefore be studied within inbred strains, so that host and tumor can be matched for their MHC type.