Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance.
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.
Wekerle
T
T
Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.
Sayegh
M H
MH
Hill
J
J
Zhao
Y
Y
Chandraker
A
A
Swenson
K G
KG
Zhao
G
G
Sykes
M
M
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D019070:Cell Lineage; D017637:Clonal Deletion; D006084:Graft Rejection / Q000276:immunology*; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D018796:Immunoconjugates; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D011828:Radiation Chimera / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D000069594:Abatacept