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Type 1 Regulatory T Cells in the Control of Immune Pathology: Induction of Tolerance By Targeting CD45

Posted on: Thursday, 17 June 2004, 06:00 CDT

CD45 is a family of transmembrane protein tyrosine phosphatases expressed exclusively by hematopoietic cells, which plays a critical role in regulating T-cell activation. Multiple CD45 isoforms are generated by alternative splicing which can be simultaneously expressed by lymphocytes. In mice antibodies recognizing the CD45RB isoform are used to divide CD4^sup +^ T cells into two population: CIM^sup +^ T cells expressing high levels of CD45RB (CD45RB^sup hi^) and CD4^sup +^ T cells exhibiting low levels (CD45RBlow) These two subsets of CD4^sup +^ T cells secrete different cytokines and have a distinct functional properties: CD4^sup +^CD45RB^sup high^ cells are effector T cells which induce autoimmunity or inflammatory bowel diseases, whereas CD4^sup +^CD45RB^sup low^ cells are regulatory T cells which prevent the induction of T-cell mediate diseases including acute allograft rejection. Several studies demonstrated that anti-CD45RB mAb is a potent immunomodulant that prolong allograft survival in several murine, and non-human transplantation models. We investigated the ability of monoclonal antibodies (mAb) chA6 mAb, which has a unique specificity for both the CD45RO and CD45RB isoforms, to downregulate immune response in vitro and in vivo. We demonstrated that chA6 mAb is a potent immunosuppressant that inhibited allogeneic, polyclonal, and Ag-specific responses and induced apoptosis in CD4^sup +^A6^sup bright^ cells in vitro. ChA6 mAb also modulated antigen-specific CD4^sup +^ and CD8^sup +^ T- cell responses. Both proliferation and IFN-[gamma] production were suppressed in CD4^sup +^ T cell lines generated in the present of chA6 mAb. Interestingly, anergized CD4^sup +^ T cells display a TrI like phenotype since they produce significant amount of IL-10 and TGF-[beta], and no IL-2 and IL-4, and suppress IFN-[gamma] production and proliferation of TT-specific T cells via IL-10 and TGF-[beta]. Similarly, CDS^sup +^ T cell lines specific for the Flu peptide MP. 58-66 generated from PBMC of HLA-A*0201 normal donors in the presence of cliA6 mAb were anergic, produce IL-IO and TGF- [beta], and suppressed IFN[gamma] production by Flu-specific T cell lines. Recent data suggest that chA6 mAb also modulates the effector function of mature dendritic cells (DCs). Therefore, chA6 mAb modulates T cell responses in vitro through different mechanisms including modulation of DCs, deletion (apoptosis) of effector/ memory T cells, anergy and induction of antigen-specific regulatory T cells. ChA6 mAb has been also used in vivo in a model of human islet allograft in NOD-SCID mice. ChAo mAb treatment prevents human islet allograft rejection. Studies are in progress to determine whether chAo mAb induces Tr1 cells in vivo. Taken together, these results show that chA6 mAb is a new immunomodulant agent with multiple mechanisms of action.

S. Oregon1, P. Mangia1, E. Tresoldi1, M. Levings2, C. Traveisari3, F. Kolbinger4, G. Aversa5, J.M. Carballido5, J.E. de Vries5, U. Korthauer5, M.G. Roncarolo1

1 San Raffaele Telethon Institute for Gene Therapy (ITSR-TIGET)1 Milan, Italy; 2 Department of Surgery, University of British Colombia, Vancouver, B.C., Canada: 3 Molmed S.p.A., Milan, Italy;, 4 Novartis Institutes for Biomedical Research Basel, Basel, Switzerland; 5 Novartis Institutes for Biomedical Research Vienna, Vienna, Austria

Copyright Edizioni Minerva Medica Mar 2004

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