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

The most surprising finding of our studies was that the incidence of SGVHD was significantly associated with the age ofthe marrow donor and had an even greater effect than the age of the recipient . In addition, the age of the recipient became less important if the donor marrow was derived from the youngest animals . Marrow from animals 6 mo of age was, to a large extent, incapable ofpermitting the induction of SGVHD despite the age of the recipient . In contrast, SGVHD could be consistently induced, even in mature animals, provided that the marrow was derived from animals 4 wk of age. Furthermore, mixing marrow from donors 1 and 6 mo of age elicited a reduced incidence of SGVHD, mimicking that obtained with marrow derived from rats 6 mo of age. These data implicated a regulatory effect present in the marrow of mature animals . Further studies demonstrated that the regulatory effect in the marrow from animals 6 mo of age was due to the presence of small, mature T lym- phocytes. Depletion of the T lymphocytes eliminated the modifying influence ofmarrow derived from mature animals on the induction of SGVHD when co-infused with marrow from rats 1 mo of age. In further support of the regulatory effect of mature T lymphocytes are the findings that: (a) T cell-depleted marrow from mature animals was able to permit the development of SGVHD; and (b) addition of splenic T lymphocytes from 6-mo-old rats to the marrow from animals 1 mo old prevented the induction of SGVHD. In contrast, although slightly less in number, the mature T lymphocytes contained in marrow from the immature animals did not prevent the development ofSGVHD. Dose-response studies clearly suggested that this regulatory activity was absent in marrow from the immature animals or was present at a very low frequency. Comparatively, some regulatory activity of splenic T lymphocytes from young animals on the induction of SGVHD was observed, but only at higher concentrations of cells. Much lower numbers o£ splenic T lymphocytes from animals 6 mo of age were required to prevent the induction of SGVHD. Taken together, these data suggest that this T cell-dependent regulatory system capable of modifying the induction of SGVHD develops as the animal matures . Our data are consistent with the observations of Sakaguchi and Sakaguchi (13) , who demonstrated that administration of C&A to newborn mice induced pleiomorphic organ-specific autoimmune diseases . CsA treatment was also noted to be far more effective if started on the day of birth rather than the third to seventh day after birth. Not even higher doses or protracted periods of C&A treatment could induce autoimmunity in adult mice. Sakaguchi and Sakaguchi (13) attributed these effects to the development of an autoregulatory system that prevented the amplification and expression of autoregulatory clones . They also postulated that CsA prevented the development of this autoregulatory system and that a temporary absence of this thymic-dependent regulatory system allowed the differentiation/activation of autospecific effector cells. Some of the early studies clearly implicated the role of a host resistance mechanism involved in controlling C&Ainduced SGVHD. The primary evidence included the finding that SGVHD could only be transferred into irradiated secondary recipients, not into normal animals, and that CsA treatment of normal animals did not induce the SGVHD syndrome although adoptive transfer of these spleen cells into irradiated secon