Rejection of primarily vascularized heart grafts. III. Depression of the interleukin 2 mechanism early after grafting.

The immunologic status of B10.A recipients of primarily vascularized B10.BR heart grafts, which undergo temporary rejection but then generally survive long term, was investigated. Generation of cytotoxicity in mixed lymphocyte culture was moderately increased soon after grafting, as compared with naive mice, while mixed lymphocyte cultures did not reveal greater lymphocyte activation after grafting. Unexpectedly, the interleukin 2 mechanism was nonspecifically depressed 1 week after placement of the heart graft. This depressed interleukin 2 activity was restored essentially to normal in splenocytes, but it remained in effect in mesenteric lymph nodes, of long-term recipients with active heart allografts.

Rejection of murine cardiac allografts. II. Evidence that splenocytes bearing Lyt2 inhibit responsiveness in long-term heart graft recipients.

Mixed lymphocyte culture--lymphocyte-mediated cytotoxicity (MLC-LMC) reactions by recipient spleen cells were strongly and specifically increased shortly after primarily vascularized heart grafts were placed in mice. Subsequently, in strain combinations in which eventual long-term graft survival occurred, the MLC-LMC became markedly suppressed, unlike the case in situations in which the recipients rejected their allografts. Unseparated spleen cells from long-term recipients are unchanged or slightly depressed in their in vitro MLC-LMC capacity. However, when splenocytes from the long-term B10.A recipients of B10.BR heart grafts were depleted of B cells and Lyt-2-positive cells, they were found to significantly enhance responses when added as third-party cells to MLC-LMC cultures. Similarly depleted splenocytes from naive mice were unaffected or depressed in their ability to contribute to this response as third-party cells. It was concluded that non-Ig-bearing, nonadherent Lyt 2+ lymphocytes from long-term heart graft recipient spleens were present that inhibited the responsiveness of other cells in these spleens.

Rejection of murine cardiac allografts. I. Relative roles of major and minor antigens.

The relative contributions of incompatibilities for class I, class II, or minor antigens to primarily vascularized graft rejection have not been previously compared in large numbers of strains. In our experiments, murine primarily vascularized heterotopic cardiac graft rejection was studied in 16 donor-recipient strain combinations, representing different precisely defined major and/or minor histoincompatibilities. Complete major incompatibilities generally produced strong graft rejection, although it was confirmed that prolonged survival occurs in certain combinations that are incompatible for class I, or class I plus class II, antigens. In addition, however, strong rejection of these grafts was produced in some recipient strains when the donor was incompatible only for minor antigens. This strong effect of minor antigens may reflect their strong stimulation of delayed-type hypersensitivity, whereas the influence of class II antigens seems more related to stimulation of mixed lymphocyte culture generation of lymphocyte-mediated cytotoxicity.

Vascularized bone allografts: in vitro assessment of cell-mediated and humoral responses.

The immunologic consequences of transplantation of vascularized bone allografts have not been previously characterized. In this study, knee allografts, both vascularized and nonvascularized, were transplanted from Lewis rats to Brown Norway rats across a strong histocompatibility barrier. A total of 66 transplants and 8 control animals were evaluated. The vascularized knee grafts consisted of 1 cm of proximal tibia and distal femur with a minimal muscular cuff isolated on the femoral vessels, and these were transplanted to a heterotopic, subcutaneous position on the abdominal wall of the recipient rat. Nonvascularized allografts (identical but without anastomoses) were transplanted for comparison. The cell-mediated response was measured by lymphocytotoxicity assay, and the humoral response was measured by cytotoxic antibody assay, both employing 51Cr-labeled target cells. The timing and intensity of the immune response differed according to the type of graft. The vascularized bone allografts generated significant cell-mediated and humoral responses as early as 5 days posttransplant. A significant humoral response in nonvascularized bone allografts was not apparent until day 14, while cell-mediated response in these grafts was variable. These findings were correlated with the histologic appearance of the grafted tissue. Cyclosporine, which was administered to one group of vascularized bone allografts, resulted in the suppression of both types of immune responses. The histologic appearance of this group resembled that of isografts transplanted as controls. The clinical application of vascularized bone allografts may offer significant advantages over nonvascularized allografts in the reconstruction of massive bone defects. Complications such as nonunion, fracture, and collapse of articular segments seen in nonvascularized allograft transplantation may be avoided by preservation of the blood supply to the graft. Characterization of the immune response to vascularized bone allografts may subsequently allow the manipulation of the host and/or graft tissue and promote graft incorporation.