A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 9; pp. 2253 - 2264
• Main Authors: Vergani, Andrea, D'Addio, Francesca, Jurewicz, Mollie, Petrelli, Alessandra, Watanabe, Toshihiko, Liu, Kaifeng, Law, Kenneth, Schuetz, Christian, Carvello, Michele, Orsenigo, Elena, Deng, Shaoping, Rodig, Scott J, Ansari, Javeed M, Staudacher, Carlo, Abdi, Reza, Williams, John, Markmann, James, Atkinson, Mark, Sayegh, Mohamed H, Fiorina, Paolo
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.09.2010
• Subjects: Abatacept; Animals; Antibodies, Monoclonal - therapeutic use; Antilymphocyte Serum; Autoimmunity; Autoimmunity - immunology; Care and treatment; Cell Division - immunology; Cytokines - blood; Diabetes; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - surgery; Enzyme-Linked Immunosorbent Assay; Glucose; Graft Rejection - prevention & control; Health aspects; Humans; Immunoconjugates - therapeutic use; Immunology and Transplantation; Immunosuppressive Agents - therapeutic use; Inflammation; Islets of Langerhans Transplantation - immunology; Islets of Langerhans Transplantation - pathology; Lymphocytes; Mice; Mice, Inbred NOD; Ovalbumin - immunology; Research design; Skin Transplantation - immunology; Transplantation, Homologous; Transplants & implants; Type 1 diabetes
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-1264

To investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent allo- and autoimmune activation using a stringent model of islet transplantation and diabetes reversal. 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 immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig. 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). Immunologic 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 syngeneic islet transplantation (NOD.SCID into NOD mice). 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.