Requirements for the promotion of allogeneic engraftment by anti-CD154 (anti-CD40L) monoclonal antibody under nonmyeloablative conditions.
The promotion of alloengraftment in the absence of global immune suppression and multiorgan toxicity is a major goal of transplantation. It is demonstrated that the infusion of a single modest bone marrow dosage in 200 cGy-irradiated recipients treated with anti-CD154 (anti-CD40L) monoclonal antibody (mAb) resulted in chimerism levels of 48%. Reducing irradiation to 100 or 50 cGy permitted 24% and 10% chimerism, respectively. In contrast, pan-T-cell depletion resulted in only transient engraftment in 200 cGy-irradiated recipients. Host CD4(+) cells were essential for alloengraftment as depletion of CD4(+) cells abrogated engraftment in anti-CD154-treated recipients. Strikingly, the depletion of CD8(+) cells did not further enhance engraftment in anti-CD154 mAb-treated recipients in a model in which rejection is mediated by both CD4(+) and CD8(+) T cells. However, anti-CD154 mAb did facilitate engraftment in a model in which only CD8(+) T cells mediate rejection. Furthermore, CD154 deletional mice irradiated with 200 cGy irradiation were not tolerant of grafts, suggesting that engraftment promotion by anti-CD154 mAb may not simply be the result of CD154:CD40 blockade. Together, these data suggest that a CD4(+) regulatory T cell may be induced by anti-CD154 mAb. In contrast to anti-CD154 mAb, anti-B7 mAb did not promote donor engraftment. Additionally, the administration of either anti-CD28 mAb or anti-CD152 (anti-CTLA-4) mAb or the use of CD28 deletional recipients abrogated engraftment in anti-CD154 mAb-treated mice, suggesting that balanced CD28/CD152:B7 interactions are required for the engraftment-promoting capacity of anti-CD154 mAb. These data have important ramifications for the design of clinical nonmyeloablative regimens based on anti-CD154 mAb administration.
Taylor
P A
PA
Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, USA.
Lees
C J
CJ
Waldmann
H
H
Noelle
R J
RJ
Blazar
B R
BR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D023201:CD40 Ligand / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D005434:Flow Cytometry; D006085:Graft Survival; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D023201:CD40 Ligand