Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance

T Wekerle, MH Sayegh, J Hill, Y Zhao… - The Journal of …, 1998 - rupress.org
T Wekerle, MH Sayegh, J Hill, Y Zhao, A Chandraker, KG Swenson, G Zhao, M Sykes
The Journal of experimental medicine, 1998rupress.org
A reliable, nontoxic method of inducing transplantation tolerance is needed to overcome the
problems of chronic organ graft rejection and immunosuppression-related toxicity. Treatment
of mice with single injections of an anti-CD40 ligand antibody and CTLA4Ig, a low dose (3
Gy) of whole body irradiation, plus fully major histocompatibility complex–mismatched
allogeneic bone marrow transplantation (BMT) reliably induced high levels (> 40%) of stable
(> 8 mo) multilineage donor hematopoiesis. Chimeric mice permanently accepted donor …
A reliable, nontoxic method of inducing transplantation tolerance is needed to overcome the problems of chronic organ graft rejection and immunosuppression-related toxicity. Treatment of mice with single injections of an anti-CD40 ligand antibody and CTLA4Ig, a low dose (3 Gy) of whole body irradiation, plus fully major histocompatibility complex–mismatched allogeneic bone marrow transplantation (BMT) reliably induced high levels (>40%) of stable (>8 mo) multilineage donor hematopoiesis. Chimeric mice permanently accepted donor skin grafts (>100 d), and rapidly rejected third party grafts. Progressive deletion of donor-reactive host T cells occurred among peripheral CD4+ lymphocytes, beginning as early as 1 wk after bone marrow transplantation. Early deletion of peripheral donor-reactive host CD4 cells also occurred in thymectomized, similarly treated marrow recipients, demonstrating a role for peripheral clonal deletion of donor-reactive T cells after allogeneic BMT in the presence of costimulatory blockade. Central intrathymic deletion of newly developing T cells ensued after donor stem cell engraftment had occurred. Thus, we have shown that high levels of chimerism and systemic T cell tolerance can be reliably achieved without myeloablation or T cell depletion of the host. Chronic immunosuppression and rejection are avoided with this powerful, nontoxic approach to inducing tolerance.
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