Assessing the efficacy and safety of mycophenolate mofetil versus azathioprine in patients with autoimmune hepatitis (CAMARO trial): study protocol for a randomised controlled trial

Background: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. Method:s: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. Discussion: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology characterized by injury of the intrahepatic bile ducts that may eventually lead to liver failure. Affected individuals are usually in their fifth to seventh decades of life at time of diagnosis, and 90% are women. Annual incidence is estimated between 0.7 and 49 cases per million-population and prevalence between 6.7 and 940 cases per million-population (depending on age and sex). The majority of patients are asymptomatic at diagnosis, however, some patients present with symptoms of fatigue and/or pruritus. Patients may even present with ascites, hepatic encephalopathy and/or esophageal variceal hemorrhage. PBC is associated with other autoimmune diseases such as Sjogren's syndrome, scleroderma, Raynaud's phenomenon and CREST syndrome and is regarded as an organ specific autoimmune disease. Genetic susceptibility as a predisposing factor for PBC has been suggested. Environmental factors may have potential causative role (infection, chemicals, smoking). Diagnosis is based on a combination of clinical features, abnormal liver biochemical pattern in a cholestatic picture persisting for more than six months and presence of detectable antimitochondrial antibodies (AMA) in serum. All AMA negative patients with cholestatic liver disease should be carefully evaluated with cholangiography and liver biopsy. Ursodeoxycholic acid (UDCA) is the only currently known medication that can slow the disease progression. Patients, particularly those who start UDCA treatment at early-stage disease and who respond in terms of improvement of the liver biochemistry, have a good prognosis. Liver transplantation is usually an option for patients with liver failure and the outcome is 70% survival at 7 years. Recently, animal models have been discovered that may provide a new insight into the pathogenesis of this disease and facilitate appreciation for novel treatment in PBC

Targeting inflammation with autoantigen-specific T cells.

Chronic autoimmune diseases are driven by cells that respond to tissue components of the body. Inflammation in diseases like rheumatoid arthritis, diabetes or multiple sclerosis, can be suppressed by drug therapy. However, the broad range of immunosuppressive action of these drugs often does not restrict to the autoimmune response, but increases the risk of serious infection. Therefore, therapies that restrict to suppression of only the auto-immune response need to be developed. CD4+ T cells that recognize cartilage are responsible for induction of arthritis because they direct their actions to cartilage in the joints. Such T cells are present in the joints of arthritis patients. Therefore, we hypothesized that T cells specific for the cartilage-derived antigen proteoglycan can be used to target arthritis with suppressive agents after introduction of genes that express suppressive agents in these T cells. For our studies we used cartilage proteoglycan-induced arthritis, which is a chronic arthritis in mice. This arthritis represents many features of rheumatoid arthritis, and is mediated by Th1 cells, B cells and antibodies. To enable studies on cartilage-specific T cells, we generated a transgenic mouse expressing a proteoglycan-specific T cell receptor on its T cells. Due to the high number of cartilage-specific T cells, transgenic mice were highly susceptible for arthritis. Moreover, the T cell response of transgenic mice with arthritis shifted to an excessive Th1-phenotype. Therefore, these transgenic mice were useful donors for arthritogenic CD4+ T cells. To explore gene therapy of inflammation with T cells, we provided proteoglycan-specific T cells with different genes encoding immunosuppressive proteins. The genes were isolated from mouse cells and inserted into T cells by retroviruses. Retroviral transduction of T cells resulted in up to 80% of cells expressing the transgenes (IL-4, IL-10, TNF-alpha-Receptor-Ig, IL-1 receptor antagonist). T cells expressing the inserted genes were sorted by flow cytometry and transferred to mice with arthritis. Especially T cells that were manipulated to express IL-10 were able to induce significant suppression of joint inflammation. Moreover, only the IL-10-producing T cells that expressed the cartilage-specific T cell receptor suppressed arthritis, indicating specificity of therapy. In addition, manipulated T cells suppressed production of pro-inflammatory proteins like TNF-alpha, IL-17, IL-2 and PG-specific IgG2a antibodies. Strikingly, we discovered that propagation of IL-10 production in cells of the treated recipient was the mechanism that was used by the transferred IL-10-producing T cells to suppress arthritis. Among the recipient’s cells, T cells and B cells were found to express increased levels of IL-10. Because interleukin-10 is an immunomodulatory cytokine expressed by cells in order to naturally prevent exacerbation of inflammation in healthy individuals, these results indicate that T cells producing IL-10 restore natural immunosuppressive immune responses in arthritis. In conclusion, manipulation of pro-inflammatory T cells that recognize tissue components is a powerful approach to specifically target inflammation in chronic autoimmune diseases. In addition, moving focus from suppression of pro-inflammatory mediators to propagation of immunosuppressive functions of cells may provide a more comprehensive insight in mechanisms that support specific regulatory capacities of the immune system

Increased efficacy of immersion vaccination in fish with hyperosmotic pretreatment

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Heat shock proteins induce T cell regulation of chronic inflammation

The significance of immune responses to certain heat shock proteins (HSPs) that develop in virtually all inflammatory diseases is only now becoming clear. In experimental models, HSPs prevent or arrest inflammatory damage, and initial clinical trials in chronic inflammatory disease have shown HSP peptides to promote production of anti‐inflammatory cytokines—indicating immunoregulatory potential. HSPs are ubiquitous self‐antigens that are highly expressed in inflamed tissues. The prokaryotic homologous proteins, present in every bacterial species, are dominantly immunogenic. This is striking, especially as these proteins have large areas of sequence homologies with the host (mammalian) counterparts. In several experimental models of autoimmune diseases, immunisation with bacterial HSPs inhibited disease development, as did oral/nasal administration. Based on the experimental evidence so far, it is tempting to speculate that: firstly, exposure to homologues of these self‐antigens, as present in, for instance, the bacterial intestinal flora, has a decisive impact on the regulation of self‐tolerance at the level of T cells; and secondly, such proteins or their derivative peptides may have a role in an antigen specific immunotherapy approach involving modulation of relevant T cells, without the immediate necessity of defining disease specific autoantigens. Recent findings in experimental asthma and atherosclerosis have indicated that the field of application of such immunotherapy can be broader than just autoimmunity

Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization.

Regulatory T cells (Tregs) are a specific subset of lymphocytes that are critical for the maintenance of self-tolerance. Expression levels of the transcription factor Foxp3 have been causally associated with Treg differentiation and function. Recent studies show that Foxp3 can also be transiently expressed in effector T cells; however, stable Foxp3 expression is required for development of a functional Treg suppressor phenotype. Here, we demonstrate that Foxp3 is acetylated, and this can be reciprocally regulated by the histone acetyltransferase p300 and the histone deacetylase SIRT1. Hyperacetylation of Foxp3 prevented polyubiquitination and proteasomal degradation, therefore dramatically increasing stable Foxp3 protein levels. Moreover, using mouse splenocytes, human peripheral blood mononuclear cells, T cell clones, and skin-derived T cells, we demonstrate that treatment with histone deacetylase inhibitors resulted in significantly increased numbers of functional Treg cells. Taken together, our data demonstrate that modulation of the acetylation state of Foxp3 provides a novel molecular mechanism for assuring rapid temporal control of Foxp3 levels in T cells, thereby regulating Treg numbers and functionality. Manipulating Foxp3 acetylation levels could therefore provide a new therapeutic strategy to control inappropriate (auto)immune responses