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Antibody-Induced Transplantation Tolerance That Is Dependent on Thymus-Derived Regulatory T Cells¹

Shaoping Deng^*, Daniel J. Moore, Xiaolun Huang^*, Mohammad Mohiuddin^*, Major K. Lee, IV^*, Ergun Velidedeoglu^*, Moh-Moh Lian^*, Meredith Chiaccio^*, Samsher Sonawane^*, Anton Orlin^*, Jing Wang^*, Haiying Chen^*, Andrew Caton, Robert Zhong and James F. Markmann^2,*

^* Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104; Department of Pediatrics, Vanderbilt Children’s Hospital, Nashville, TN 37232; The Wistar Institute, Philadelphia, PA; and Department of Surgery, University of Western Ontario, London, Ontario, Canada

Targeting of the CD45RB isoform by mAb (anti-CD45RB) effectively induces donor-specific tolerance to allografts. The immunological mechanisms underlying the tolerant state remain unclear although some studies have suggested the involvement of regulatory T cells (T-regs). Although their generative pathway remains undefined, tolerance promoting T-regs induced by systemic anti-CD45RB treatment have been assumed to originate in the peripheral immune system. We demonstrate herein that separable effects on the peripheral and central immune compartments mediate graft survival induced by anti-CD45RB administration. In the absence of the thymus, anti-CD45RB therapy is not tolerogenic though it retains peripheral immunosuppressive activity. The thymus is required for anti-CD45RB to produce indefinite graft survival and donor-specific tolerance, and this effect is accomplished through thymic production of donor-specific T-regs. These data reveal for the first time an Ab-based tolerance regimen that relies on the central tolerance pathway.

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