Transplantation

Oral

interleukin-34, a New and Potent Regulatory Cytokine Involved in Treg Function and Transplant Tolerance

Thursday, June 15
5:45 PM - 7:00 PM

Cytokines are powerful tools to regulate immune responses. Interleukin-34 (IL-34) is a cytokine that binds to CSF1R (the MCSF receptor) and PTPz and involved in differentiation and survival of myeloid cells. Until recently, no link with T cell biology or transplantation had ever been reported for IL-34.
We showed that IL-34 was expressed by rodent CD8+CD45RClowTregs and human FOXP3+CD45RClowCD8+ and CD4+ Tregs and we demonstrated that IL-34 was involved in the suppressive function of both CD8+ and CD4+Tregs and markedly inhibited alloreactive immune responses. We demonstrated that rat IL34 overexpression associated with a suboptimal dose of rapamycin potently induced tolerance to cardiac allograft in rat with a total inhibition of alloantibody production. In this model, IL-34 promoted allograft tolerance through modulation of macrophages that migrated early into the graft and induced CD8+ and CD4+ Tregs. We demonstrated that human IL-34 protein administration into NSG mice infused with human PBMCs efficiently delayed in a dose dependent-manner the xenogeneic GVHD when associated with a suboptimal 10-days dose of rapamycin. In vitro, we characterized a subpopulation of macrophages more efficiently differenciated by IL-34 and showed that human macrophages cultured in the presence of IL-34 for 6 days more efficiently expanded both CD8+ and CD4+ FOXP3+ Tregs compared to allogeneic APCs or anti-CD3/CD28, with a potentiation of suppressive activity since lower ratios of IL-34-expanded Tregs were sufficient to delay GVHD development in humanized mice compared to polyclonally expanded Tregs.
We demonstrate here the clinical relevance of IL-34 in transplantation as a potent tolerance inducer.

Séverine Bézie

INSERM UMR 1064-CRTI

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    Antoine Freuchet

    INSERM 1064

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      Véronique Daguin

      INSERM UMR 1064-CRTI and Nantes University

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        Claire Usal

        Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France

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          Ignacio Anegon

          Head of laboratory
          INSERM UMR 1064-CRTI and Nantes University

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            Carole Guillonneau

            CNRS
            Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France

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