The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/6/2037/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 12, June 15, 1998 2037-2044

Articles

Extrathymic T Cell Deletion and Allogeneic Stem Cell Engraftment Induced with Costimulatory Blockade Is Followed by Central T Cell Tolerance

Thomas Wekerle*, Mohamed H. Sayegh{ddagger}, Joshua Hill*, Yong Zhao*, Anil Chandraker{ddagger}, Kirsten G. Swenson*, Guiling Zhao*, and Megan Sykes*

From the * Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the {ddagger} Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115

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.

Key Words: tolerance • transplantation • costimulation • chimerism • bone marrow

Address correspondence to Megan Sykes, Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, MGH East, 13th Street, Bldg. 149-5102, Boston, MA 02129. Phone: 617-726-4070; Fax: 617-724-9892; E-mail: sykes{at}helix.mgh.harvard.edu

1 Abbreviations used in this paper: ATX, thymectomized; BM, bone marrow; BMT, bone marrow transplantation; CD40L, CD40 ligand; FCM, flow cytometric analysis; MR1, hamster anti–mouse CD40L mAb; MST, median survival time; WBI, whole body irradiation.


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