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 mechanism by which CsA leads to syngeneic GVHD and allows for the development of polycional or self-anti-Ia-reactive T cells remains unknown. The integrity of thymic tissue appears to be a critical factor. The importance of the thymus in the induction of syngeneic GVHD is supported by the results of Glazier et ai. (15, 21) . Despite comparable CsA therapy, syngeneic GVHD could not be induced if the thymus was shielded during irradiation. This is in contrast to the consistent development of GVHD seen in CsA-treated rats given total body irradiation without shielding the thymus. The development of syngeneic GVHD is not limited to CsA-treated animals, since Van Bekkum and DeVries (24) described the development of syndromes similar to syngeneic and autologous GVHD in neonatally thymectomized animals, and in animals that received additional irradiation to the thymus. Further studies implying a role for thymic integrity in the induction of syngeneic GVHD are those in which nontransplanted, nonirradiated animals treated with CsA do not develop the syndrome, and anti-Ia cytotoxic T cells cannot be found. This is in spite of the fact that CsA treatment of both transplanted and nontransplanted animals leads to remarkable thymic changes, with rapid depletion of medullary lymphocytes (21). It is tempting to speculate that CsA alters the educational process, or accentuates a maturational failure of T lymphocytes in the irradiated thymus that allows the development of polyclonal or self-anti-Ia-reactive cells. Whether radiation damage to the thymus, or depletion of normal thymocytes, in combination with CsA therapy leads directly to development of the polyclonal or self-class II-reactive cytotoxic T cells and the development of syngeneic GVHD remains unknown. It remains possible that generation of class II-reactive cytotoxic T cells is a normal part of the ongoing differentiation in the thymus, controlled by intrathymic regulatory events, and that CsA abates this regulatory influence. The syngeneic GVHD syndrome would only appear after radiation damage to the thymus or depletion of normal thymocytes, including a regulatory subset that controls the generation of autoreactive cells. The regulatory influence of the host has been shown (15, 21) . Adoptive transfer of normal syngeneic spleen cells with spleen cells from animals suffering from syngeneic GVHD into irradiated Lewis recipients did not prevent the development of syngeneic GVHD. However, transfer of spleen cells from animals with syngeneic GVHD into normal, unirradiated recipients apparently prevented the development of this syndrome, implicating some facet of host regulation that remains unidentified.