SUPPRESSION OF B-CELL PROLIFERATION TO LIPOPOLYSACCHARIDE IS MEDIATEDTHROUGH INDUCTION OF THE NITRIC-OXIDE PATHWAY BY TUMOR-NECROSIS-FACTOR-ALPHA IN MICE WITH ACUTE GRAFT-VERSUS-HOST DISEASE

Graft-versus-host disease (GVHD) is associated with impaired B-cell re sponses. We investigated the mechanism of impaired proliferation of B cells in response to the mitogen lipopolysaccharide (LPS) by analyzing the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), both of which have independently been described as importa nt effector mechanisms in the pathogenesis of acute GVHD. A threefold decrease of mature surface Ig-positive (sIg(+)) B cells was observed i n GVHD spleens isolated 2 weeks after transplant. However, proliferati on of these cells in response to LPS was suppressed by more than 35-fo ld. Activated GVHD splenocytes secreted large amounts of TNF-alpha and NO in culture, Neutralization of TNF-alpha with anti-TNF-alpha antibo dy (Ab) both abrogated NO production and restored LPS-induced prolifer ation of B cells to levels found in non-GVHD control mice. The specifi c inhibition of NO synthesis with L(G)-monomethyl-arginine (NNMA) rest ored splenocyte responses but did not significantly reduce TNF-alpha l evels, showing that TNF-alpha per se did not cause immunosuppression. These data show that, during GVHD, induction of the MO pathway is an i mportant mechanism that mediates B-cell hyporesponsiveness to LPS and that this pathway is induced by TNF-alpha. (C) 1996 by The American So ciety of Hematology.