Angiotensin Receptors, Non-Selective

These results suggest that inhibiting the Notch pathway may be effective in treating additional autoimmune and lymphoproliferative conditions

These results suggest that inhibiting the Notch pathway may be effective in treating additional autoimmune and lymphoproliferative conditions. we avoided the reported toxicities of gamma-secretase inhibitors. Inhibiting the Notch signaling pathway may therefore present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases. Intro The pathophysiology of a number of autoimmune and lymphoproliferative diseases is related to T-cell dysregulation. Individuals and mice with 2 of these diseases, autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE), produce both abnormal, triggered T lymphocytes and a designated development of a usually very small T-cell human population, double bad T cells (DNTs; cell Macitentan phenotype: CD3+, CD4?, CD8?, T-cell receptor [TCR]+).1C3 These abnormalities in T-cell regulation are caused in part by problems in the Fas apoptotic pathway, leading to irregular lymphocyte survival with subsequent autoimmunity.4,5 The essential role of the Fas apoptotic pathway in lymphocyte homeostasis was first elucidated in studies in Fas-deficient MRL-mice.6 Mice homozygous for Fas mutations develop hypergammaglobulinemia, glomerulonephritis, massive lymphadenopathy, and expansion of DNTs.6,7 This discovery offered insights into the pathophysiology of a similar syndrome observed in humans, ALPS. Individuals with ALPS usually present at a young age with lymphadenopathy and splenomegaly.8 A high percentage of individuals develop autoimmunity, most commonly with autoimmune Macitentan cytopenias.9 ALPS is often associated with heterozygous mutations in the genes encoding the Fas protein, (tumor necrosis factor receptor superfamily 6), and related proteins that regulate lymphocyte survival.10 These mutations are usually inherited in an autosomal dominant fashion with variable penetrance.10 In contrast to ALPS, the defective apoptosis in SLE is caused by factors extrinsic to the Fas pathway that interfere with its activation, including excess soluble Fas protein.4,11 Systemic manifestations in SLE individuals are heterogeneous, frequently including autoimmunity, vasculitis, arthritis, and glomerulonephritis.12 While many individuals with ALPS and SLE respond to conventional therapies, some individuals are refractory and new treatments are needed. The Macitentan majority of treatment modalities for individuals with ALPS and SLE focus on use of nonspecific immunosuppressants, regularly with significant toxicity profiles and limited effectiveness. Because these treatment modalities are nonspecific, development of target-specific treatment methods may be beneficial. One candidate for targeted treatment is the Notch signaling pathway, because it offers several critical tasks in T-cell function, including DNT transition in T-cell development and T-cell activation.13 Notch signaling is mediated through a pathway of 4 mammalian transmembrane Notch receptors (Notch1-4).13 After ligand binding, 2 cleavages of the Notch receptors occur, 1st by a metalloprotease and subsequently by gamma-secretase, releasing the intracellular website of Notch1 (ICN) that translocates to the nucleus and binds to the transcription element CSL (RBP-Jk), activating transcription of a number of key intracellular proteins.13 Gamma-secretase inhibitors (GSIs) block the second cleavage, preventing the launch of ICN and transcriptional activation. We hypothesized that inhibiting Notch signaling would be effective in reducing symptoms and treating LATS1 antibody the disease in individuals with ALPS and SLE both by reducing the production of irregular DNTs and by obstructing aberrant T cell activation. We tested this hypothesis using 2 murine models of defective lymphocyte apoptosis, CBA-and MRL-has a phenotype much like human ALPS, as these mice develop massive lymphadenopathy and splenomegaly with DNT infiltration of these organs. While there are a number of mouse models that mimic human being ALPS, CBA-mice have been shown to be the most similar to the majority of ALPS individuals.11 While the MRL-mouse model has been used to study ALPS, this model has phenotypic features very similar to human being SLE: these mice develop autoantibodies, glomerulonephritis, and a vasculitic dermatitis. The MRL-mouse model is definitely a well-studied model of SLE and is used regularly for preclinical screening of new providers for this disease.15C18 GSIs are in clinical development for treatment of other disorders, including Alzheimer disease and T-cell leukemia. We tested one of these inhibitors, N-S-phenyl-glycine-t-butyl ester (DAPT), in the 2 2 mouse models.19,20 Early reports using GSIs in additional disease models delivered drugs at high doses for any short-duration and mice developed thymic hypoplasia and intestinal goblet cell hyperplasia within 7 days.21,22 These effects were clearly dose and time dependent.23,24 To reduce toxicity, we used a lower potency GSI and treated mice daily for 5 days a week. Using this approach, we found that inhibiting the Notch pathway was effective and safe in both mouse models, suggesting that titration.

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