Evidence for involvement of clonal anergy in MHC class I and class II disparate skin allograft tolerance after the termination of intrathymic clonal deletion
Tomita, Y.; Nishimura, Y.; Harada, N.; Eto, M.; Ayukawa, K.; Yoshikai, Y.; Nomoto, K.
Journal of Immunology 145(12): 4026-4036
1990
ISSN/ISBN: 0022-1767 PMID: 2147933 Document Number: 360857
Mechanisms of cyclophosphamide (CP)-induced tolerance to class I (D) and class II (IE) alloantigens were studied. Transplantation tolerance across H-2D plsu IE Ag-barriers has been achieved when B10.Thy-1.1 (Kb,IAb,IE-,Db; Thy-1.1) mice were primed i.v. with 9 .times. 107 spleen cells plus 3 .times. 107 bone marrow cells from B10.A(5R) mice (5R;kb,IAb,IEb,Dd; Thy-1.2) and treated i.p. with 200 mg/kg of CP 2 days later. The tolerant state in the early and the late stage was confirmed by prolonged acceptance of donor-type skin grafts, and in vitro unresponsiveness to donor Ag. In the tolerant B10.Thy-1.1 mice treated with 5R cells 28 days earlier and followed by CP, intrathymic clonal deletion of V.beta.11+ T cells reactive to IE-encoded antigens was observed in association with intrathymic mixed chimerism. 5R skin survived, however, even after the clonal deletion of V.beta.11+ T cells terminated by 180 days after tolerance induction. V.beta.11+ T cells, which reappeared in the periphery of the recipient B10.Thy-1.1 mice bearing 5R skin at this stage, were not capable of proliferating in response to receptor cross-linkeing with V.beta.11-specific mAb. Furthermore, the CTL activity against class I (Dd) alloantigens of spleen cells from these tolerant mice was restored by the addition of Il-2 to MLC. Thus, our experiments provide direct evidence that tolerance to both class I (Dd) and class II (IE(b) alloantigens by clonal allergy occurs during the termination of intrathymic clonal deletion. These results clearly show practical hierarchy of the mechanisms of transplantation tolerance.