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

Andrea Vergani, Francesca D'Addio, Mollie Jurewicz, Alessandra Petrelli, Toshihiko Watanabe, Kaifeng Liu, Kenneth Law, Christian Schuetz, Michele Carvello, Elena Orsenigo, Shaoping Deng, Scott J. Rodig, Javeed M. Ansari, Carlo Staudacher, Reza Abdi, John Williams, James Markmann, Mark Atkinson, Mohamed H. Sayegh, Paolo Fiorina*

*Corresponding author for this work

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

OBJECTIVE - To investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent alloand autoimmune activation using a stringent model of islet transplantation and diabetes reversal. RESEARCH 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 immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig. RESULTS - 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). CONCLUSIONS - 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.

Original languageEnglish (US)
Pages (from-to)2253-2264
Number of pages12
JournalDiabetes
Volume59
Issue number9
DOIs
Publication statusPublished - Sep 2010

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Vergani, A., D'Addio, F., Jurewicz, M., Petrelli, A., Watanabe, T., Liu, K., ... Fiorina, P. (2010). A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice. Diabetes, 59(9), 2253-2264. https://doi.org/10.2337/db09-1264