Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia

We demonstrate an increase in graft-versus-host disease (GVHD) after experi mental bone marrow transplant (BMT) when cyclophosphamide (Cy) is added to an otherwise well-tolerated dose (900 cGy) of total body irradiation (TBI). Donor T cell expansion on day +13 was increased after conditioning with Cy /TBI compared with Cy or TBI alone, although cytotoxic T lymphocyte (CTL) f unction was not altered. Histological analysis of the gastrointestinal trac t demonstrated synergistic damage by Cy/TBI and allogeneic donor cells, whi ch permitted increased translocation of LPS into the systemic circulation. TNF-alpha and IL-1 production in response to LIPS was increased in BMT reci pients after Cy/TBI conditioning. Neutralization of IL-1 significantly redu ced serum LPS levels and GVHD mortality, but it did not affect donor CTL ac tivity. By contrast, neutralization of TNF-alpha did not prevent GVHD morta lity but did impair CTL activity after BMT. When P815 leukemia cells were a dded to the bone marrow inoculum, allogeneic BMT recipients given the TNF-a lpha inhibitor relapsed at a significantly faster rate than those given the IL-1 inhibitor. To confirm that the role of TNF-alpha in graft versus leuk emia (GVL) was due to effects on donor T cells, cohorts of animals were tra nsplanted with T cells from either wild-type mice or p55 TNF-alpha receptor -deficient mice. Recipients of TNF-alpha p55 receptor-deficient T cells dem onstrated a significant impairment in donor CTL activity after BMT and an i ncreased rate of leukemic relapse compared with recipients of wild-type T c ells. These data highlight the importance of conditioning in GVHD pathophys iology, and demonstrate that TNF-alpha is critical to GVL mediated by donor T cells, whereas IL-1 is not.