2011 - CTS-IXA
Parallel Session 8- Immunology (Immunoisolation) (Cell Track)
14.206 - Transplanted donor Treg cells can stably engraft leading to tolerance to allogeneic bone marrow cells in NOD mice
Presenter: Allison, Bayer, Miami, United States
Authors: Cecilia Cabello2, Jackeline Chirinos1, Robert Levy1, Thomas Malek1, Allison L. Bayer1,2
Transplanted donor Treg cells can stably engraft leading to tolerance to allogeneic bone marrow cells in NOD mice
Cecilia Cabello2, Jackeline Chirinos1, Robert Levy1, Thomas Malek1, Allison L. Bayer1,2
1Department of Microbiology and Immunology; 2Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
There is increasing interest in the use of naturally occurring CD4+Foxp3+ regulatory T cells (Treg) in their application for adoptive immunotherapy in the treatment of autoimmune diseases, including type 1 diabetes (T1D). Studies have shown Treg cells have therapeutic effects on the course of autoimmunity in NOD mouse, a model of human T1D. However, Treg immunotherapy is hindered by the inability to generate sufficient cell number to inhibit the desired immune response(s) and achieve stable donor Treg engraftment. In the present study, we examined the in vivo biological environment necessary to promote stable donor Treg engraftment and induce tolerance to allogeneic (allo) BM cells. We describe that not only is peripheral space required, but competition from endogenous Treg cells needs to be overcome for successful engraftment of transplanted donor Treg cells together with IL-2, which is critically important for driving their proliferation and survival. We found that conditioning prediabetic NOD mice with varying amounts of total body irradiation resulted in a dose-dependent level of donor Thy1.1+ NOD Treg engraftment. Furthermore, treatment with busulfan and cyclophosphamide (Bus+CyP) leads to significant engraftment of transplanted donor Treg cells compared to unmanipulated mice or mice treated with Bus or CyP alone. Importantly, adoptive transfer of syngeneic or allo-Treg cells together with short course of anti-IL-2 (clone JES6)/IL-2 complex and rapamycin, which favors Treg expansion, induces tolerance to small numbers (10x106) of allo-BM cells resulting in mixed chimerism and prevention of diabetes in these recipients. Importantly, donor Treg cells were readily detected 48 weeks post-transfer. Collectively, our findings indicate that some level of manipulation of the recipient’s immune system greatly facilitated long-term donor Treg cell engraftment and therapeutic efficacy. Thus, Treg immunotherapy can lead to alloantigen tolerance even in NOD mice, which are highly resistant to tolerance induction (Supported by ADA Junior Faculty Award 7-09-JF-06 and Diabetes Research Institute Foundation)
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