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Direct allorecognition: a mechanism in intrathymic tolerance induction
Direct Allorecognition: A Mechanism in Intrathymic Tolerance Induction S.E. Turvey, M. Hara, P.J. Morris, and K.J. Wood
I
NTRATHYMIC (IT) islet transplantation has the potential to address two of the major challenges facing clinical islet transplantation: rejection and recurrent autoimmune b-cell destruction. The versatility of the IT route for tolerance induction is well established and interest has now turned to understanding the mechanisms involved in successful IT tolerance induction protocols. RESULTS
To elucidate the fate of alloreactive thymocytes following IT islet injection we used a TCR transgenic recipient strain (BM3 (H2k)) in which there are large numbers of thymocytes and T cells that recognise the class I molecule H2Kb via the direct pathway. IT injection of allogeneic islets into BM3 recipients resulted in an initial marked thymic involution that was not dependent on allorecognition. If the islets injected into the thymus did not express the specific alloantigen Kb, (ie, were of BALB/c (H2d) or CBA (H2k) origin), thymocyte numbers were fully recovered by day 28 after IT injection. In contrast, following injection of Kb1 islets (BL10 (H2b)) thymocyte recovery was significantly
0041-1345/99/$–see front matter PII S0041-1345(98)01798-9
delayed (P 5 .002) due to ongoing deletion of directly alloreactive thymocytes. This difference was not due to differential survival of the allogeneic islets as viable islets were long lived within the recipient thymus irrespective of donor strain. DISCUSSION
This experimental system provides a unique opportunity to examine the fate of alloreactive thymocytes following IT alloantigen injection. We have clearly demonstrated that clonal deletion of thymocytes that recognise alloantigen via the direct pathway is one of the mechanisms involved in tolerance induction following IT islet injection. From the Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. Supported by The Wellcome Trust and The Allison Foundation. S.E.T. was supported by The Rhodes Trust. Address reprint requests to Dr S.E. Turvey, John Radcliffe Hospital, Nuffield Department of Surgery, Oxford OX3 9DU, UK.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
844
Transplantation Proceedings, 31, 844 (1999)
I
NTRATHYMIC (IT) islet transplantation has the potential to address two of the major challenges facing clinical islet transplantation: rejection and recurrent autoimmune b-cell destruction. The versatility of the IT route for tolerance induction is well established and interest has now turned to understanding the mechanisms involved in successful IT tolerance induction protocols. RESULTS
To elucidate the fate of alloreactive thymocytes following IT islet injection we used a TCR transgenic recipient strain (BM3 (H2k)) in which there are large numbers of thymocytes and T cells that recognise the class I molecule H2Kb via the direct pathway. IT injection of allogeneic islets into BM3 recipients resulted in an initial marked thymic involution that was not dependent on allorecognition. If the islets injected into the thymus did not express the specific alloantigen Kb, (ie, were of BALB/c (H2d) or CBA (H2k) origin), thymocyte numbers were fully recovered by day 28 after IT injection. In contrast, following injection of Kb1 islets (BL10 (H2b)) thymocyte recovery was significantly
0041-1345/99/$–see front matter PII S0041-1345(98)01798-9
delayed (P 5 .002) due to ongoing deletion of directly alloreactive thymocytes. This difference was not due to differential survival of the allogeneic islets as viable islets were long lived within the recipient thymus irrespective of donor strain. DISCUSSION
This experimental system provides a unique opportunity to examine the fate of alloreactive thymocytes following IT alloantigen injection. We have clearly demonstrated that clonal deletion of thymocytes that recognise alloantigen via the direct pathway is one of the mechanisms involved in tolerance induction following IT islet injection. From the Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. Supported by The Wellcome Trust and The Allison Foundation. S.E.T. was supported by The Rhodes Trust. Address reprint requests to Dr S.E. Turvey, John Radcliffe Hospital, Nuffield Department of Surgery, Oxford OX3 9DU, UK.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
844
Transplantation Proceedings, 31, 844 (1999)