sirolimus and Immune-System-Diseases

Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes for recycling. Accumulating evidence suggests that autophagy plays vital roles in determining pathological outcomes of immune responses and tumorigenesis. Autophagy regulates innate and adaptive immunity affecting the pathologies of infectious, inflammatory, and autoimmune diseases. In cancer, autophagy appears to play distinct roles depending on the context of the malignancy by either promoting or suppressing key determinants of cancer cell survival. This review covers recent developments in the understanding of autophagy and discusses potential therapeutic interventions that may alter the outcomes of certain diseases.

Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Autophagy; Benzylisoquinolines; Cholecalciferol; Humans; Immune System Diseases; Immunity, Innate; Indoles; Infections; Isoquinolines; Lysosomes; Maprotiline; Metformin; Neoplasms; Phenols; Pyrroles; Resveratrol; Sirolimus; Spermidine; Stilbenes; Tetrahydroisoquinolines; Trehalose

FOXP3 deficiency results in severe multisystem autoimmunity in both mice and humans, driven by the absence of functional regulatory T cells. Patients typically present with early and severe autoimmune polyendocrinopathy, dermatitis, and severe inflammation of the gut, leading to villous atrophy and ultimately malabsorption, wasting, and failure to thrive. In the absence of successful treatment, FOXP3-deficient patients usually die within the first 2 years of life. Hematopoietic stem cell transplantation provides a curative option but first requires adequate control over the inflammatory condition. Due to the rarity of the condition, no clinical trials have been conducted, with widely unstandardized therapeutic approaches. We sought to compare the efficacy of lead therapeutic candidates rapamycin, anti-CD4 antibody, and CTLA4-Ig in controlling the physiological and immunological manifestations of Foxp3 deficiency in mice.. We generated Foxp3-deficient mice and an appropriate clinical scoring system to enable direct comparison of lead therapeutic candidates rapamycin, nondepleting anti-CD4 antibody, and CTLA4-Ig.. We found distinct immunosuppressive profiles induced by each treatment, leading to unique protective combinations over distinct clinical manifestations. CTLA4-Ig provided superior breadth of protective outcomes, including highly efficient protection during the transplantation process.. These results highlight the mechanistic diversity of pathogenic pathways initiated by regulatory T cell loss and suggest CTLA4-Ig as a potentially superior therapeutic option for FOXP3-deficient patients.

Topics: Abatacept; Animals; Clinical Deterioration; CTLA-4 Antigen; Disease Models, Animal; Forkhead Transcription Factors; Humans; Immune System Diseases; Mice; Sirolimus; T-Lymphocytes, Regulatory

Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear.. We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations.. Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR.. Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells.. Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.

Topics: Cell Movement; Cells, Cultured; Child; Diabetes Mellitus, Type 1; Diarrhea; Forkhead Transcription Factors; Gene Expression Regulation; Genetic Diseases, X-Linked; Glucocorticoid-Induced TNFR-Related Protein; Humans; Immune System Diseases; Immune Tolerance; Immunosuppressive Agents; Interleukins; Lymphocyte Activation; Male; Minor Histocompatibility Antigens; Mutation; Sirolimus; T-Lymphocytes, Regulatory