sirolimus and Hepatitis

ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to induce a durable tolerogenic immune response to co-administered biologics and gene therapy vectors. Prior mechanism of action studies have demonstrated selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration. In the spleen, ImmTOR has been shown to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomy of mice resulted in partial but incomplete abrogation of the tolerogenic immune response induced by ImmTOR. Here we investigated the ability of ImmTOR to enhance the tolerogenic environment in the liver. All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. LSEC isolated from ImmTOR treated mice inhibited antigen-specific activation of ovalbumin-specific OT-II T cells. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4

Topics: Animals; B-Lymphocytes; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Cells, Cultured; CTLA-4 Antigen; Dendritic Cells; Endothelial Cells; Female; Hepatic Stellate Cells; Hepatitis; Hepatocytes; Histocompatibility Antigens Class II; Immune Tolerance; Kupffer Cells; Liver; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Nanoparticles; Ovalbumin; Polyesters; Programmed Cell Death 1 Receptor; Sirolimus; T-Lymphocytes, Regulatory

AIE is a rare disorder in children that presents with severe diarrhea and malabsorption, caused by immune-mediated damage to intestinal mucosa. AIE is often associated with various syndromes of immunodeficiency including IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X-linked). Dysfunctional T regulatory cells are the source of pathology in both IPEX syndrome and AIE as they are essential in maintaining tolerance to self-antigens and eliminating autoreactive B cells. This case report describes a 10-year-old cardiac transplant and total thymectomy patient on chronic immunosuppression with tacrolimus that presented with AIE and extraintestinal manifestations of cyclical hepatitis. Transition from tacrolimus to sirolimus successfully increased T regulatory cells and resolved enteritis and hepatitis symptoms. Data support that thymectomy at <1 year of age increases risk of autoimmune disease due to abnormal immune maturation. Studies suggest that the sirolimus promotes the upregulation of the FoxP3 protein that is classically associated with Tregs. In turn, Tregs prevent the maturation of autoreactive B cells that lead to autoimmune reactions.

Topics: B-Lymphocytes; Child; Female; Forkhead Transcription Factors; Heart Failure; Heart Transplantation; Hepatitis; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Intestinal Mucosa; Polyendocrinopathies, Autoimmune; Sirolimus; T-Lymphocytes; Tacrolimus; Thymectomy; Up-Regulation

This retrospective case series reviews our center's experience with sirolimus and a CNI as alternative therapy for the treatment of PTAH. It also characterizes regulatory T cells (Tregs) in PTAH. LT recipients with PTAH who had received or were receiving treatment with sirolimus were retrospectively identified (n = 12). Liver enzymes, immunohistochemistry, and histology were compared in all 12 patients. Immunophenotyping for Tregs in peripheral blood mononuclear cells was performed on LT recipients with PTAH on conventional therapy with CNI, azathioprine ± prednisone (CT) (n = 11), recipients with PTAH on sirolimus, CNI ± prednisone (n = 8), recipients without PTAH (n = 25), and pre-transplant patients (n = 5). Severity of necro-inflammatory changes markedly improved with sirolimus. Treg frequency and number were significantly lower in recipients with PTAH on CT compared to (i) those on sirolimus (p = 0.002 and p = 0.01, respectively), and (ii) recipients without PTAH (p = 0.07 and p = 0.009, respectively). Treg frequency was significantly higher in recipients with PTAH on sirolimus compared to recipients without PTAH under CNI therapy (p = 0.027). Sirolimus in addition to a CNI is successful in reversing inflammation in LT recipients with PTAH. This is associated with significantly higher circulating Tregs.

Topics: Azathioprine; CD4 Lymphocyte Count; Child; Child, Preschool; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis; Humans; Immunosuppressive Agents; Infant; Liver; Liver Transplantation; Male; Postoperative Complications; Prednisone; Retrospective Studies; Single-Blind Method; Sirolimus; T-Lymphocytes, Regulatory; Tacrolimus; Treatment Outcome

Calcineurin inhibitors have dramatically improved the outcomes of pediatric liver transplantation. However, calcineurin inhibitor use is associated with a 50% reduction in glomerular filtration rate in the first year post-transplant. Nephrotoxicity can be difficult to manage, especially in the pediatric population. We hypothesized that the addition of an mTOR inhibitor with decreased calcineurin inhibitor levels might improve or prevent renal insufficiency and improve control of rejection. A retrospective chart review was performed on the patients treated with sirolimus who had undergone an orthotopic liver transplant between January 2000 and February 2003. Thirty-eight patients were identified. Mean age was 8.6 yr. Fourteen patients were male and 24 were female. Mean weight was 30.3 kg. The most common indications for starting sirolimus were rejection (42%) and renal impairment (29%). Seventy-three percent of patients begun on sirolimus remain on the medication. Those with renal impairment (11 patients) showed improvement in their creatinine levels from a mean baseline of 1.3 to 0.8 mg/dL. Their calculated creatinine clearance (Schwartz formula) improved from 63.7 to 84.8 mL/min (p = 0.03). Patients started on sirolimus for rejection showed significant improvement in hepatocellular enzymes despite a reduction in the tacrolimus level from 12.2 to 7.5 ng/mL. The mean alanine aminotransferase level improved from 221 to 100 units/L (p = 0.02), and the mean aspartate aminotransferase improved from 121 to 99 units/L (p = 0.59). Addition of sirolimus to a tacrolimus-based regimen with lower target tacrolimus levels improved liver function in patients with rejection. Addition of sirolimus significantly improved renal function as shown by creatinine level and calculated creatinine clearance in those children with renal impairment. The effect of combined immunosuppressant treatment with tacrolimus and sirolimus on long-term renal function needs to be evaluated.

Topics: Adolescent; Adult; Child; Child, Preschool; Creatinine; Drug Therapy, Combination; Female; Hepatitis; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Neutropenia; Oral Ulcer; Postoperative Care; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

mTOR and P70 S6 kinase (S6K) play a key role in regulating protein translation. The role of mTOR and S6K in hepatocellular carcinoma has not been investigated, but this pathway is of particular interest because an effective inhibitor, rapamycin, is available. This study was undertaken to determine the prevalence and clinicopathological correlates of mTOR pathway activation in hepatocellular carcinoma and to determine whether rapamycin inhibits the pathway in cell culture.. Total and phosphorylated mTOR and S6K protein expression were studied by immunohistochemistry in hepatocellular carcinomas (n = 73), fibrolamellar carcinomas (n = 13), and hepatic adenomas (n = 15). Results were correlated with tumor growth pattern as defined by the WHO (trabecular, pseudoglandular/acinar, compact, and scirrhous), tumor size, Ki-67 proliferation index, and the modified Edmondson nuclear grade, which has a scale of 1 to 4. HepG2 and Hep3B cell lines were treated with rapamycin to see the effect on proliferation and S6K phosphorylation.. Increased expression of total mTOR was seen in 5% of hepatocellular carcinoma, whereas overexpression of phospho-mTOR was evident in 15% of hepatocellular carcinoma. Phospho-mTOR positivity correlated with increased expression of total S6K, which was found in 45% of cases. Total S6K overexpression was positively correlated with tumor nuclear grade, inversely with tumor size, and was unassociated with the proliferation index or WHO growth pattern. Rapamycin treatment of HepG2 and Hep3B cell lines markedly inhibited cell proliferation and reduced S6K phosphorylation in both cell lines.. The mTOR pathway is activated in a subset of hepatocellular carcinoma. Rapamycin can inhibit proliferation of neoplastic hepatocytes in cell culture.

Topics: Adenoma; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Cell Proliferation; Female; Genetic Heterogeneity; Hepatitis; Humans; Immunoenzyme Techniques; Ki-67 Antigen; Liver Neoplasms; Male; Middle Aged; Phosphorylation; Protein Kinases; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured