Inulin Advax poly fructo furanosyl glucose is a plant derived

Inulin (Advax™, β–[2→1] poly(fructo-furanosyl) α–glucose) is a plant-derived carbohydrate. It has no immunological activity in soluble form; however, once it is formulated into delta inulin microparticles, its adjuvanting activity is widely acknowledged (). Inulin was applied to enhance vaccine efficacy against influenza, hepatitis B, West Nile virus, Japanese encephalitis, human immunodeficiency virus, SARS, and anthrax, amongst others. The carbohydrate was effective and safe in both experimental animals, as well as in humans. Yet, despite the large number of studies performed, its mechanism of action is still unclear. This prompted Ishii and coworkers to investigate the potential mode of action of inulin microparticles. At first, they investigated its adjuvanting capacity when administered together with cp-690550 already bearing danger signals. It has been reported that influenza split vaccine (SV) elicits Th2, while whole virion influenza vaccine (WV) triggers a Th1 response. When antigens were delivered with inulin, immune responses were significantly increased and the Th1/Th2 direction remained unchanged. And when inulin was delivered with “danger signal free” ovalbumin as an antigen, nothing happened. No antibody production against ovalbumin was detected. Moreover, inulin on its own was not able to stimulate dendritic cell (DC) maturation . Maturation of DCs is the crucial step before adaptive immunity can be activated. Just taking into account these observations, it might be assumed that inulin acts as a delivery system, possibly by preventive antigen degradation or through improved delivery to APCs, but without its own immune stimulating abilities.
Is inulin really just a delivery platform for vaccines, without adjuvanting properties? The answer is no. In contrast to testing, DC maturation experiments showed that inulin acted as an adjuvant and enhanced the expression of maturation markers on these cells. The reason for such unique behavior of inulin is yet to be determined. In addition, Ishii and coworkers demonstrated that DCs and phagocytic macrophages, as well as tumor necrosis factor (TNF)-α played a crucial role in the adjuvanting ability of inulin. It is of note that the ability of inulin to enhance adaptive immune responses when injected a day earlier than an antigen was reported previously (). Thus, inulin acts as an unusual adjuvant, as it did not force the direction of immune response (Th1 Th2), as typical adjuvants do. For example, commercially-approved alum is a well-known Th-2 pathway stimulator, while CpG-ODN triggers Th1 response ().

Primary biliary cholangitis, formerly designated primary biliary cirrhosis, represents a model cholestatic liver disease characterized by chronic, progressive immune-mediated bile duct destruction mainly affecting middle-aged women. Though its distinct pathogenesis remains to be fully defined, complex environmental-host immunogenic interactions have been highlighted by large-scale genome-wide association studies (GWAS) identifying a total of at least 27 disease-associated human leukocyte antigen (HLA) and non-HLA risk loci (). The diagnosis can be firmly assumed in the presence of at least two of three criteria including biochemical evidence of chronic cholestasis, presence of pathognomonic anti-mitochondrial antibodies (AMA, targeting the E2 and/or E3BP subunits of the pyruvate dehydrogenase complex) and/or supportive liver histology including florid bile duct lesions. The well-established standard of care consists of the oral hydrophilic bile acid (BA) ursodeoxycholic acid (UDCA), the hitherto only Food and Drug Administration (FDA)-approved agent for PBC treatment, with proven beneficial effects on disease progression as well as transplant-free survival and liver-related mortality. A convincing long-term response to UDCA identifies a low-risk subgroup without disease progression and survival rates comparable to the general population. By contrast, an estimated one in three PBC individuals reveals UDCA suboptimal or non-response as assessed by variable biochemical surrogate endpoints with a special emphasis on serum alkaline phosphatase (ALP) activity (e.g. or criteria), thus conferring high risk of continued disease progression despite treatment (“”). Novel prognostic tools, such as the score, predictive of transplant-free survival in a large cohort of 4119 UDCA-treated individuals, or the score have recently been reported (). The major drawback, however, remains the nature of determining UDCA response, traditionally after one year, although smaller studies reported adequate reflection of long-term prognosis assessing UDCA response as early as after six months (). Therefore, an unmet clinical need in PBC research lies in the identification of adequate biomarkers for high-risk disease at diagnosis and prediction criteria of UDCA response applicable early on or even before treatment (). The reliable identification of non-responders represents an opportunity to actively alter future disease trajectories and may be of key importance in prioritizing patients for novel and/or re-purposed second-line treatments. The changing and vital landscape of second-line options in PBC treatment is underscored by the recent conditional FDA licensing of obeticholic acid (OCA) as the first-in-class farnesoid X receptor (FXR) agonist, regulating BA synthesis and transport, after phase III randomized data () demonstrated biochemical improvement in approximately 40% of UDCA non-responders ().