A Novel Clinically Relevant Strategy to Abrogate Autoimmunity and Regulate Alloimmunity in NOD Mice

摘要

OBJECTIVE-To investigate a new clinically relevant immuno-regulatory strategy based on treatment with murine Thymoglobu-lin mATG Genzyme and CTLA4-Ig in NOD mice to prevent allo-and autoimmune activation using a stringent model of islet transplantation and diabetes reversal.rnRESEARCH DESIGN AND METHODS-Using allogeneic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, we addressed the therapeutic efficacy and immunomodulatory mechanisms associated with a new immu-noregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig.rnRESULTS-BALB/c islets transplanted into hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time: 54 vs. 8 days, P < 0.0001). Immuno-logic analysis of mice receiving transplants revealed a complete abrogation of autoimmune responses and severe downregulation of alloimmunity in response to treatment. The striking effect on autoimmunity was confirmed by 100% diabetes reversal in newly hyperglycemic NOD mice and 100% indefinite survival of synge-neic islet transplantation (NOD.SCID into NOD mice).rnCONCLUSIONS-The capacity to regulate alloimmunity and to abrogate the autoimmune response in NOD mice in different settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to translate to humans with type 1 diabetes.