Guiding postablative lymphocyte reconstitution as a route toward transplantation tolerance.
Anti-lymphocyte-depleting antibodies have increasingly been utilized in the clinic as induction therapy aiming to improve transplantation outcomes by reducing the need for long-term immunosuppression. However, maintenance immunosuppression is still required as lymphocyte reconstitution through homeostatic proliferation, partially driven by IL-7, continues to replenish tolerance-refractory immune cells capable of rejection. In murine models of MHC mismatched skin grafting, we investigated whether it is feasible to control the lymphocyte reconstitution process to delay rejection and favor tolerance processes. We found that a short course of anti-IL-7 receptor blocking antibody following T cell depletion, combined with the mammalian target of rapamycin inhibitor Rapamycin, could significantly delay graft rejection in one mouse strain, and achieve transplantation tolerance in another. The combination treatment was found to delay T cell reconstitution and, in the short term, enriched for Foxp3+ regulatory T cells (Tregs), at the expense of effector cells. Extended graft survival and tolerance were dependent on TGF-ß, indicating a role for induced Tregs. These findings point to the feasibility of building on lympholytic induction by guiding early lymphocyte reconstitution to favor endogenous regulatory mechanisms.
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
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Piotti
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Ma
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E
Adams
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Cobbold
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Waldmann
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000502:physiology; D000951:Antigens, Neoplasm / Q000502:physiology; D000074301:CD52 Antigen; D005260:Female; D006023:Glycoproteins / Q000502:physiology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors* / Q000276:immunology; D020123:Sirolimus / Q000627:therapeutic use; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023001:Transplantation Tolerance
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000074301:CD52 Antigen; D006023:Glycoproteins; D007166:Immunosuppressive Agents; D020395:Receptors, Interleukin-7; D016212:Transforming Growth Factor beta; D020123:Sirolimus
Campath; IL-7; homeostatic proliferation; rapamycin; transplantation tolerance