Costimulatory blockade with anti-CD154 monoclonal antibody (aCD154) prolongs allograft survival in nonhuman primates, but has not reliably induced tolerance when used alone. In the current studies, we evaluated the effect of adding CD154 blockade to a chimerism inducing nonmyeloablative regimen in primates. We observed a significant improvement of donor bone marrow (DBM) engraftment, which has been associated with a lower incidence of acute rejection and long-term survival of renal allografts without the need for previously required splenectomy. Among the long-term survivors, four never showed evidence of rejection, with the longest survival exceeding 1700 days following discontinuation of immunosuppression. Nevertheless, late chronic rejection was observed in three of eight recipients, indicating the necessity of further modifications of the regimen. Control recipients receiving no DBM or donor splenocytes in place of DBM rejected their allografts. Thus, DBM engraftment with, at least, transient mixed chimerism appears essential for induction of allograft tolerance using this conditioning regimen. Modification of the original mixed chimerism approach, by the addition of costimulatory blockade, has been shown to enhance mixed chimerism and induce renal allograft tolerance with less morbidity in nonhuman primates.

SummaryIn vitro studies have revealed that help for cytotoxic T lymphocyte (CTL) induction can be mediated through several pathways, including direct recognition of allogeneic class II antigens by CD4 § cells, direct recognition of altogeneic class I antigens by "CD4-independent" CD8 + cells, and "indirect" recognition of peptides of alloantigens presented in association with self class II molecules. Whereas good evidence for the two direct pathways is available in vivo, there is relatively little evidence to show that indirect recognition can initiate graft rejection. This study examined the role of indirect allorecognition during the generation of CTLs in mice as they rejected major histocompatibility complex (MHC) class II-deficient skin after depletion of CD8 + T cells in vivo. Recipients were depleted of CD8 + T cells by in vivo treatment with anti-CD8 monoclonal antibody and then grafted with allogeneic skin lacking MHC class II antigens. The mice rejected the skin grafts rapidly. Although flow cytometry showed marked depletion of CD8 + T cells in these mice, we found that (a) CD8 + CTLs were generated and sensitized to MHC class I antigens of the donor; (b) the generation of the CD8 + CTLs required the help in vivo of CD4 + cells, as well as priming with the allogeneic skin graft; and (c) the CD4 + T helper cells were sensitized indirectly to donor peptides presented in association with class II antigens on recipient antigen-presenting cells. These results provide evidence that indirect recognition can provide effective help for CTL induction during graft rejection, even when the cytotoxic T cells are sensitized by determinants expressed only on the donor graft. I~irect recognition describes the stimulation of recipient cells by allogeneic donor antigens presented in association with self MHC antigens on recipient APCs. Although indirect recognition represents the ordinary process by which T cells are sensitized during normal immune responses, its contribution to graft rejection is obscured by the powerful direct stimulation of T cells by donor APCs in allogeneic responses. Although it has been known for a long time that indirect recognition can occur during rejection of foreign tissue, and that it can play an effective role in allogeneic responses in vitro (1-3), it has not been clear whether this pathway alone can actually initiate graft rejection in vivo. This uncertainty has been especially important when the donor and recipient have been MHC mismatched, such that the determinants formed on recipient APCs would not be expressed on the cells of the donor graft.The recent availability of mice lacking MHC class II antigens has provided a new opportunity to examine the role of indirect recognition. Lacking class II antigens on their own APCs, grafts from these animals to normal recipients would be expected to stimulate CD4 + T cells only by the presentation of donor peptides in association with recipient class II molecules. However, because these grafts still express class I antigens, they can sensitize a...

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