A novel clinically relevant approach to tip the balance toward regulation in stringent transplant model

Francesca D'Addio, Xueli Yuan, Antje Habicht, John Williams, Melanie Ruzek, John Iacomini, Laurence A. Turka, Mohamed H. Sayegh, Nader Najafian, Mohammed Javeed I Ansari

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34 Scopus citations

Abstract

Background: Regulatory T cells (Tregs) actively regulate alloimmune responses and promote transplantation tolerance. Thymoglobulin, a rabbit polyclonal antithymocyte globulin (ATG), is a widely used induction therapy in clinical organ transplantation that depletes peripheral T cells. However, resistance to tolerance induction is seen with certain T-cell depleting strategies and is attributed to alterations in the balance of naïve, memory and Tregs. The exact mechanism of action of ATG and its effects on the homeostasis and balance between Tregs and T-effector-memory cells (Tem) are unknown. Methods: A novel antibody reagent, rabbit polyclonal anti-murine thymocyte globulin (mATG), generated by the same process used to manufacture Thymoglobulin, was used alone or in combination with CTLA4Ig or sirolimus (SRL) in a stringent fully major histocompatibility complex-mismatched murine skin allograft model to study graft survival and mechanisms involved. Results: mATG depletes T cells but preferentially spares CD25+ natural Tregs which limit skewing of T-cell repertoire toward Tem phenotype among the recovering T cells. T-cell depletion with mATG combined with CTLA4Ig and SRL synergize to prolong graft survival by tipping the Treg/T em balance further in favor of Tregs by preserving T regs, facilitating generation of new Tregs by a conversion mechanism and limiting Tem expansion in response to alloantigen and homeostatic proliferation. CONCLUSIONS.: Simultaneous T-cell depletion with ATG and costimulatory blockade, combined with SRL, synergizes to promote regulation and prolong allograft survival in a stringent transplant model. These results provide the rationale for translating such novel combination therapy to promote regulation in primate and human organ transplantation.

Original languageEnglish (US)
Pages (from-to)260-269
Number of pages10
JournalTransplantation
Volume90
Issue number3
DOIs
StatePublished - Aug 15 2010

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Keywords

  • Costimulation
  • Homeostatic proliferation
  • Regulation
  • Sirolimus
  • T-cell depletion
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

Cite this

D'Addio, F., Yuan, X., Habicht, A., Williams, J., Ruzek, M., Iacomini, J., Turka, L. A., Sayegh, M. H., Najafian, N., & Ansari, M. J. I. (2010). A novel clinically relevant approach to tip the balance toward regulation in stringent transplant model. Transplantation, 90(3), 260-269. https://doi.org/10.1097/TP.0b013e3181e64217