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

Rats receiving syngeneic marrow transplants and treated with either the control diluent or CsA were followed for cytotoxic T cell activity at various intervals after cessation of CsA therapy. Results are presented in Fig. 2 . Within the first 8 d after withdrawal of CsA therapy, 5 of 10 animals exhibited cytotoxic T cell activity. Of the five animals who showed cytotoxic T cell activity, two animals had evidence of clinically significant syngeneic GVHD, as manifested by erythroderma of the ears, and dermatitis. The diagnosis was confirmed histologically. The remaining three animals had histological evidence of syngeneic GVHD. No evidence of the syngeneic GVHD syndrome was present in the five animals that did not exhibit spleen cell-mediated lysis of the test target cells. Among animals tested 14-28 d after cessation of CsA therapy, 15 of 19 animals had demonstrated this cytotoxic activity against Lewis, ACI, and BN blast cells. 12 of the 15 animals had clinical and histological evidence of syngeneic GVHD, the remaining 3 had minimal GVHD-like histological changes. Of the 4 of 19 animals that did not demonstrate any significant spleen cell-mediated cytotoxic activity, two showed no histological evidence of syngeneic GVHD, while the remaining two had histological evidence compatible with mild GVHD. The spleens from these two animals were very fibrotic, with limited cell recovery. In the animals that were tested 32-44 d after CsA therapy was stopped, five of eight animals exhibited cytotoxic T cell activity and also showed histological evidence of syngeneic GVHD. Of the remaining three animals, which did not exhibit significant cytotoxic activity, only one showed histological evidence of syngeneic GVHD. In all, 28 of 37 animals treated with CsA following a syngeneic marrow transplant exhibited clinical and/or histologic evidence of the syngeneic GVHD-iike syndrome. Of the 28 animals with this syndrome, 25 demonstrated cytotoxic activity to Lewis, ACI, and/or BN target cells. The remaining nine CsA-treated syngeneic marrow recipients, without the syndrome, did not have this activity. The presence of the cytotoxic activity was significantly (P < 0.001) associated with the incidence of the GVHD-Iike syndrome. Spleen cell-mediated cytotoxic activity from nontransplanted animals that had been treated wtih CsA, and nontransplanted animals treated with the control diluent was assessed. The regimen of CsA or control diluent therapy was identical to that for the syngeneic marrow recipients. Table I demonstrates that the nylon wool-nonadherent spleen cells from these two groups were not capable of mediating significant lysis of ACI, Lewis, or BN target cells. Table II summarizes the results of NK activity for the four experimental groups. NK activity in animals receiving syngeneic transplants and treated with CsA was significantly (P <0.01) elevated compared to the syngeneic marrow transplant recipient not treated with CsA. Animals that received syngeneic marrow transplants, were treated with CsA, and later exhibited histological evidence of syngeneic GVH D had no significantly different N K activity compared to animals that received the same treatments, but showed no histological signs of GVHD. In comparison, nontransplanted animals that received either the control diluent or CsA had levels of NK activity comparable to the control non-CsA-treated syngeneic marrow recipients.