TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION TO LIPOPOLYSACCHARIDE STIMULATION BY DONOR CELLS PREDICTS THE SEVERITY OF EXPERIMENTAL ACUTE GRAFT-VERSUS-HOST DISEASE

Donor T cell responses to host alloantigen are known predictors for gr aft-versus-host disease (GVHD); however, the effect of donor responsiv eness to an inflammatory stimulus such as lipopolysaccharide (LPS) on GVHD severity has not been investigated. To examine this, we used mous e strains that differ in their sensitivity to LPS as donors in an expe rimental bone marrow transplant (BMT) system. Lethally irradiated (C3F eB6)F1 hosts received BMT from either LPS-sensitive (LPS-s) C3Heb/Fej, or LPS-resistant (LPS-r) C3H/Hej donors. Mice receiving LPS-r BMT dev eloped significantly less GVHD as measured by mortality and clinical s core compared with recipients of LPS-s BMT, a finding that was associa ted with significant decreases in intestinal histopathology and serum LPS and TNF-alpha levels. When donor T cell responses to host antigens were measured, no differences in proliferation, serum IFN-gamma level s, splenic T cell expansion, or CTL activity were observed after LPS-r or LPS-s BMT. Systemic neutralization of TNF-alpha from day -2 to +6 resulted in decreased intestinal pathology, and serum LPS levels and i ncreased survival after BMT compared with control mice receiving Ig. W e conclude that donor resistance to endotoxin reduces the development of acute GVHD by attenuating early intestinal damage mediated by TNF a lpha. These data suggest that the responsiveness of donor accessory ce lls to LPS may be an important risk factor for acute GVHD severity ind ependent of T cell responses to host antigens.