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

' Abbreviations used in this paper: BMT, bone marrow transplantation; CCE, counterflow centrifugation elutriation ; CsA, cyclosporine ; GVHD, graft-versus-host disease; R/O, rotor-off; SGVHD, syngeneic GVHD . This autoimmune disease, which occurs 14-21 d after cessation of CsA therapy, is mediated by T lymphocytes (6, 7) and is intimately associated with the appearance of OX8+ (CD8) autocytotoxic T cells that recognize a public epitope on class II major histocompatibility antigens (8) . A W3/25+ (CD4) Th cell subset also plays an essential role in disease manifestation (7) . Further studies have suggested that a T lymphocyte-dependent host resistance mechanism must be eliminated before the development of this autoaggression syndrome can occur (11, 12) . Of additional importance are the recent findings that indicate that in addition to thymic irradiation and CsA treatment, age is a critical variable for the induction of SGVHD (13) ; animals >3 mo of age are much more resistant to the induction of autoimmunity with CsA . The mechanism accounting for the resistance of mature animals is unknown, but it may be related to the lack ofa pronounced effect of CsA on the thymic medulla, as postulated by Beschorner et al. (14) . On the other hand, recent evidence suggests that there are increased numbers ofautoregulatory cells in older animals, thus preventing the clonal amplification of autoreactive cells (13) .