sirolimus and Hepatitis--Autoimmune

Corticosteroids alone or in combination with azathioprine are the mainstay therapies of autoimmune hepatitis. Suboptimal responses (treatment failure, partial response, drug toxicity), frequent relapse after drug withdrawal, and the emergence of alternative immunosuppressive medications have fueled the pursuit of new treatments. The goals of this review are to present current management strategies and evolving interventions.. PubMed searches from 1970 - 2014 provide the bases for this review. Corticosteroid regimens should be administered until resolution of symptoms, laboratory tests, and liver tissue abnormalities. Treatment failure warrants high doses of the original regimen, and relapse warrants re-treatment followed by long-term maintenance with azathioprine. The calcineurin inhibitors, budesonide, and mycophenolate mofetil are evolving as frontline therapies, and they may be considered as salvage therapies with the exception of budesonide. Rapamycin, rituximab, and infliximab have also rescued refractory patients but experiences are limited. Anti-oxidants, recombinant molecules, mAbs, and modulators of critical cell populations are key prospects.. Autoimmune hepatitis must be managed by multiple medications that supplement or supplant current regimens depending on the clinical situation. Rescue therapies will emerge as adjunctive interventions to minimize tissue damage (prevent fibrosis and hepatocyte apoptosis) and improve immune tolerance (regulatory T cell manipulations).

Topics: Adrenal Cortex Hormones; Animals; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Budesonide; Hepatitis, Autoimmune; Humans; Immunologic Factors; Immunosuppressive Agents; Liver; Mycophenolic Acid; Rituximab; Salvage Therapy; Sirolimus

Nonsteroidal medications, previously unfamiliar in the management of autoimmune hepatitis, can supplement or replace conventional corticosteroid regimens, especially in problematic patients. Mycophenolate mofetil is a next-generation purine antagonist that has been useful in treating patients with azathioprine intolerance. It has been less effective in salvaging patients with steroid-refractory disease. Azathioprine is the choice as a corticosteroid-sparing agent in treatment-naive patients and in individuals with corticosteroid intolerance, incomplete response and relapse after drug withdrawal. Tacrolimus is preferred over cyclosporine for recalcitrant disease because of its established preference in organ transplantation, but replacement with cyclosporine should be considered if the disease worsens on treatment. Rapamycin has antiproliferative and proapoptotic actions that warrant further study in autoimmune hepatitis. The nonstandard, nonsteroidal medications are mainly salvage therapies with off-label indications that must be used in highly individualized and well-monitored clinical situations.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Sirolimus

Imbalance between effector and regulatory T-cells (Treg) underlies the loss of immune-tolerance to self-antigens in autoimmune disease. In autoimmune hepatitis type 2 (AIH-2), effector CD4 T-cell immune responses to cytochrome P450IID6 (CYP2D6) are permitted by numerically and functionally impaired Treg. Restoration of CYP2D6-specific Treg in AIH-2 would enable control over effectors sharing the same antigen specificity, leading to re-establishment of immune-tolerance. We have previously developed a protocol for generating antigen-specific Treg through co-culture with semi-mature dendritic cells presenting CYP2D6 peptides. In this study, we aimed to explore phenotypic and functional features of patient Treg compared to health, to test Treg stability under pro-inflammatory conditions, and to investigate the potential benefit of supplementation with all-trans-retinoic acid (RA) or rapamycin (RP), agents proven to enhance Treg function. We show that antigen-specific Treg from patients have comparable phenotypic and functional features to those from healthy controls, suppressing both proliferation and pro-inflammatory cytokine production by effector cells. Treg exposure to inflammatory challenge results in decreased suppressive function and up-regulation of Th1/Th2/Th17 transcription factors both in health and AIH-2. The increase of Th1 and Th17 transcription factors is limited by addition of RA in controls and Th1 expression is decreased by RP in patients. Importantly, inflammation-induced decrease in Treg function is also abrogated by RA/RP in health and RA in patients. Our data provide important information for the optimization of protocols aiming at generating antigen-specific Treg for treatment of autoimmune disease and for understanding their biology upon pro-inflammatory challenge and RP/RA supplementation.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Cytochrome P-450 CYP2D6; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Sirolimus; T-Lymphocytes, Regulatory; Th17 Cells; Tretinoin

The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct innate and adaptive immune responses. Myeloid-derived suppressive cells (MDSCs) are a heterogeneous cell population that plays a crucial regulatory effect in immune-related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unexplored. Here, we show that mTOR signaling is a pivotal, negative determinant of MDSC function in immune-mediated hepatic injury (IMH) diseases. In the context of IMH, the blocking of mTOR with rapamycin or mTOR-deficient CD11b

Topics: Adoptive Transfer; Animals; Concanavalin A; Dose-Response Relationship, Immunologic; Female; Glycolysis; Hepatitis, Autoimmune; Hypoxia-Inducible Factor 1, alpha Subunit; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Nitric Oxide; Recombinant Fusion Proteins; RNA Interference; Signal Transduction; Sirolimus; Specific Pathogen-Free Organisms; T-Lymphocyte Subsets; TOR Serine-Threonine Kinases

To investigate the preventive and therapeutic effects of rapamycin (RAPA) on autoimmune hepatitis and liver fibrosis induced by concanavalin A (ConA) and possible mechanisms.. Female C57BL/6 mice aged 8 weeks were randomly divided into normal control group, ConA model group, and ConA+RAPA treatment group. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured; hematoxylin-eosin and Masson staining and Knodell HAI and Ishak scoring systems were used to evaluate the degrees of liver inflammation and fibrosis. Gradient centrifugation was used to separate mononuclear cells, flow cytometry was used to measure CD4(+)/CD8(+) ratio, and intracellular cytokine staining was performed to measure the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor β (TGF-β) in immune cells. The t-test was used for data comparison between groups.. The RAPA treatment group showed a significant reduction in serum ALT level compared with the ConA model group (P < 0.05). Liver inflammatory injury was reduced significantly, and there was no obvious fibrous tissue proliferation. The level of TGF-β in mononuclear cells was reduced significantly, and the treatment group had a significantly lower level of TGF-β than the model group (8.91%±1.25% vs 16.65%±2.05%, P < 0.05). The proportions of CD4(+) and CD8(+)T cells in the liver were reduced, and the treatment group had significantly lower proportions of CD4(+) and CD8(+)T cells than the model group (proportion of CD4(+)T cells: 4.09%±1.20% vs 8.91%±0.69%, P < 0.05; proportion of CD8(+)T cells: 3.28%±0.66% vs 9.68%±1.46%, P < 0.05). The proportion of Th1 cells was reduced, and the treatment group had a significantly lower proportion of Th1 cells than the model group (1.02%±0.06% vs 2.83%±0.21%, P < 0.05); the proportions of Th3 and Tr1 regulatory T cells were increased, and the treatment group had significantly higher proportions of Th3 and Tr1 regulatory T cells than the model group (proportion of Th3 regulatory T cells: 59.53%±9.82% vs 47.13%±4.79%, P < 0.05; proportion of Tr1 regulatory T cells: 10.63%±2.27% vs 7.09%±1.66%, P < 0.05), but the proportion of Th2 cells showed no significant difference between the two groups (P > 0.05).. RAPA can promote the differentiation of Th3/Tr1 cells, reduce the expression of TGF-β in mononuclear cells, slow down the progression of chronic hepatitis induced by ConA into liver fibrosis, and thus prevent liver fibrosis.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Concanavalin A; Female; Hepatitis, Autoimmune; Interferon-gamma; Interleukin-10; Interleukin-4; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Random Allocation; Sirolimus; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Topics: Adolescent; Child; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Sirolimus

Corticosteroids and azathioprine are widely accepted as the initial therapy for autoimmune hepatitis. However, the disease is refractory to steroids in about 10%-20% of patients, for whom currently there is no standardized treatment. Here we describe our experience with sirolimus in treatment of steroid refractory autoimmune hepatitis.. This is a longitudinal follow-up study. Between November 2007 and January 2014, 5 subjects with steroid refractory autoimmune hepatitis were treated with sirolimus at our institution.. A response, defined as a sustained >50% fall in alanine aminotransferase (ALT) levels, was achieved in 4/5 patients. A complete response, sustained normalization of ALT levels, was achieved in 2/5 patients. The need for steroids was significantly reduced in all patients (P < .05).. In this small series, sirolimus appears to be useful in the treatment of patients with steroid refractory autoimmune hepatitis.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Azathioprine; Bilirubin; Drug Resistance; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Prednisone; Sirolimus; Young Adult

Rapamycin (Rapa), one of the newer immunosuppressants has been found to control and prevent autoimmune features in animal models. This is the first report describing the successful control of post-transplant autoimmune hepatitis (AIH) with Rapa. Post-transplant AIH is diagnosed in the presence of raised transaminases, elevated immunoglobulin G, presence of autoantibodies and histologic changes consistent with AIH on liver biopsy. It may represent a recurrence of the original AIH that led to transplantation or present as a de novo AIH after liver transplant. Post-transplant AIH has conventionally been treated with Prednisolone (Pred) and Azathioprine (AZA). In this report, tailoring of immunosuppression after diagnosis of post-transplant AIH is described with special emphasis on those treated successfully with Rapa. Fifteen of 21 patients responded to treatment with an increase in dose of Pred and addition of AZA or Mycophenolate Mofetil (MMF) to calcineurin inhibitor. Five non-responders and one other patient with post-transplant AIH were treated with addition of Rapa. All six responded to treatment but drug was withdrawn in one patient. Adverse events were minimal. Rapa may prove to be an important addition in the control of autoimmune liver disease.

Topics: Autoantibodies; Azathioprine; Biopsy; Calcineurin Inhibitors; Child; Child, Preschool; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Infant, Newborn; Liver; Liver Diseases; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Sirolimus; Time Factors; Transaminases; Treatment Outcome