Development of graft-vs.-host disease-like syndrome in cyclosporine- treated rats after syngeneic bone marrow transplantation. I. Development of cytotoxic T lymphocytes with apparent polyclonal anti-Ia specificity, including autoreactivity

The results of our studies demonstrate that the development of cytotoxic T cells recognizing self class II or Ia histocompatibility antigens is associated with the development of this syngeneic GVHD-like syndrome. A perplexing observation is that the effector cells associated with the syngeneic GVHD are capable of lysing blast cells from several strains of rats in an apparently unrestricted fashion. The strains used here do not share class II antigens, but have distinct atlotypes with respect to both class I and class II histocompatibility antigens. Two hypotheses can be formulated to account for our results; the polyclonal activation of class II-reactive cells, including autoreactive cells; or the development of a cytotoxic effector cell with apparent multiple specificity (to "private" antigenic epitopes?). Cold target-inhibition studies support the latter hypothesis, since both ACI and Lewis cold targets were equally effective at inhibiting the lysis of either ACI or Lewis labelled target cells, although crossreactivity within the rat class II determinants cannot be totally excluded. Another hypothesis is that the effector cell is recognizing a common determinant ("public" epitope) of a class II (or related) antigen shared by many strains of rats. This hypothesis has some merit, since crossreactivity among the rat major histocompatibility antigens has been reported, including antigenic similarity of the B chain of class II molecules from independent rat haplotypes (22). However, the splenic T lymphocytes from rats with the syngeneic GVHD-iike syndrome, in the majority of instances, mediated equivalent levels of lysis regardless of the target cell used (ACI, BN, or Lewis). If crossreactivity was solely responsible for our results, it would seem likely that there would be differences in the ability of the effector cells to lyse the different targets. Further studies are needed to clarify this issue.