Age-related factors in cyclosporine-induced syngeneic graft-versus-host disease: regulatory role of marrow-derived T lymphocytes

this autoaggression syndrome appears to be the enhanced generation of autoreactive clones that enter the periphery, and the essential elimination ofa host resistance or autoregulatory mechanism that can modify the action of the autoreactive cells (11, 19, 20) . Previous studies have clearly identified three important elements necessary for the induction of SGVHD and the resultant imbalance between autoaggression and autoregulatory suppression . First, CsA is a necessary requirement for the induction of SGVHD since this syndrome only occurs in syngeneic BMT recipients treated with this drug, although rare exceptions have been noted (6, 21) . Second, radiation also appears to play an essential role in accelerating the appearance of disease. Cheney and Sprent (10) and Glazier et al. (6, 22) reported that normal, nontransplanted animals treated with CsA do not develop this autoaggression syndrome even if treated with very high doses of CsA . This is in contrast to the routine induction of syngeneic GVHD after whole-body irradiation, syngeneic BMT, and CsA therapy. Recent data suggest that in the absence ofradiation, CsA must be administered for 6 mo to induce this autoimmune disease (23). The third essential requirement is an intact thymus, which must be included in the field of irradiation . As shown by Glazier et al. (22) , shielding of the thymus during total-body irradiation results in the failure to induce this syndrome. Further evidence for the importance and pivotal role of an intact thymus was provided by Sorokin et al. (7) . Syngeneic GVHD could not be induced in thymectomized animals but required that an intact thymus be present . Although CsA treatment, radiation, and an intact thymus are required for the successful induction of SGVHD, the present studies have demonstrated that age is also a critical variable involved in this autoaggression syndrome. Virtually a 100% incidence ofSGVHD could be induced if the animals 92 were initially transplanted and treated with CsA beginning at 4 wk of age. Thereafter, the incidence ofSGVHD decreased dramatically with the increasing age of the animals. The inverse correlation of age with the successful induction of SGVHD was surprising since in many murine autoimmune models, increasing age correlates with the onset of disease (24, 25 ). An inverse relationship of age with induction of autoimmunity with CsA mice has recently been reported (13) . Of particular importance in our studies was the finding that not only was the age of the recipient a significant variable, but that the age of the marrow donor had an even greater effect . SGVHD could be consistently induced in older animals if the marrow was derived from animals 4 wk of age, but not if the marrow donors were 6 mo of age or older.