Specificity of Cellular Migration Into Cardiac Allografts in Rats

SUMMARY The question has not been previously investigated as to whether host lymphocytes infiltrate vascularized organ allografts in indiscriminate fashion, or whether they are retained selectively because of specific antigenic recognition sites on their surfaces. By using a dual cardiac allograft model in LEW rats, we have examined this problem by two methods: (1) detection of preferentially accumulating cells selectively cytotoxic to allografts bearing specific transplantation antigens as compared with “third-party” allografts; and (2) examination of trafficking patterns of separate radiolabeled populations of sensitized cells adoptively transferred into double heart-grafted recipients. In the first series of experiments, using BN and BUF rats as donors, differences in specific cytotoxicity mounted by infiltrating lymphocytes harvested from the appropriate and inappropriate graft were moderately significant (P < 0.05). Because the question of cross-reactivity between BUF and BN antigen was raised, lymphocytes sensitized to BN and WF donors were differentially labeled in vitro with 3H- or 14C-thymidine. After mixture and adoptive transfer, the ratio of specific to third-party labels was measured in each graft. In this second series of experiments, significant (P < 0.001) preferential accumulation of specifically sensitized cells were found in the appropriate vascularized organ allograft. These experiments confirm the results of other experimental models, and demonstrate that sensitized lymphocytes accumulate selectively in specific vascularized organ allografts. The characteristic traffic and distribution of lymphocytes in the recirculating pool and through host lymphoid tissues changes following antigenic stimulation ( 7, 24, 25). Cell subpopulations with selective antiallogeneic activity may home preferentially to particular lymphoid tissues and to the site of antigenic challenge such as an allograft, becoming selectively depleted from other lymphoid areas at the same time (10, 15, 22). Such lymphocytes, bearing specific alloantigen recognition structures, interact with antigenic determinants on the foreign tissues and initiate graft injury. The proportion of committed cells entering the graft is small; the great bulk are probably unsensitized, appear at random from the circulation, and may be attracted into the graft by signals from the sensitized population. Some early investigators were unable to demonstrate differential localization of sensitized cells in specific antigenic sites (14, 20, 23); however, small but significant degrees of selective accumulation have been detected subsequently by several workers (17, 29, 31). The migration patterns of specifically sensitized lymphocytes into vascularized organ allografts have not been examined. In this study, we have transplanted heterotopic cardiac grafts of differing genotypes into single histoincompatible recipients, and investigated the selective accumulation of host lymphoid cells by two methods: (1) assessment of specific antiallogeneic cytotoxicity mounted by infiltrating T lymphocytes isolated from the grafts; and (2) monitoring the migratory behavior of separate radiolabeled populations of sensitized cells adoptively transferred into recipients of the double heart grafts. The data indicate significant immunospecificity among lymphocytes entering vascularized organ allografts.