Opposing roles of CD28 : B7 and CTLA-4 : B7 pathways in regulating in vivoalloresponses in murine recipients of MHC disparate T cells

Blockade with B7 antagonists interferes with CD28:B7 and CTLA-4:B7 interact ions, which may have opposing effects, We have examined the roles of CD28:B 7 and CTLA-4:B7 on in vivo alloresponses, A critical role of B7:CD28 was de monstrated by markedly compromised expansion of CD28-deficient T cells and diminished graft-versus-host disease lethality of limited numbers of purifi ed CD4(+) or CD8(+) T cells: When high numbers of T cells were infused, the requirement for CD28:B7 interaction was lessened. In lethally irradiated r ecipients, anti-CTLA-4 mAb enhanced in vivo donor. T cell expansion, but di d not affect, on a per cell basis, anti-host proliferative or CTL responses of donor T cells. Graft-versus-host lethality was accelerated by anti-CTLA -4 mAb infusion given early post-bone marrow transplantation (BMT), mostly in a CD28-dependent fashion, Donor T cells obtained from anti-CTLA-4 mAb-tr eated recipients were skewed toward a Th2 phenotype, Enhanced T; cell expan sion in mAb-treated recipients was strikingly advantageous in the graft-ver sus-leukemia effects of delayed dongs lymphocyte infusion. In two different systems, anti-CTLA-4 mAb enhanced the rejection of allogeneic T cell-deple ted marrow infused into sublethally irradiated recipients. We conclude that blockade of the selective CD28-B7 interactions early post-BMT, which prese rve CTLA-4:B7 interactions, would be preferable to blocking both pathways. For later post-BMT, the selective blockade of CTLA-4:B7 interactions provid es a potent and previously unidentified means for augmenting the GVL effect of delayed donor lymphocyte infusion.