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Responses, and Intestinal Graft-Versus-Host Disease by IL-12-Independent Mechanisms1
,
* Division of Digestive and Liver Diseases, Department of Internal Medicine, and
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235; and
Dallas Veterans Affairs Medical Center, Dallas, TX 75216
Inhibition of TNF/TNFR2 interactions ameliorates intestinal graft-vs-host disease (GVHD) and Th1 cytokine responses induced by transfer of B6 CD4+ spleen cells into irradiated MHC class II disparate B6.C-H-2bm12 (bm12) x B6 F1 recipients. The present studies examined whether these effects of TNF are IL-12 dependent. T cell proliferative responses of B6.129S1-IL-12rb2tm1Jm (B6.IL-12R-/-) responder spleen cells were found to be comparable to those of control B6 spleen cells. TNF inhibition reduced T cell proliferation and IFN-
production in supernatants of MLC using either B6.IL-12R-/- or control B6 responder cells. GVHD induced wasting disease in recipients of B6.IL-12R-/- CD4+ spleen cells that received a TNF inhibitor-encoding adenovirus (5.4 ± 6.5% weight loss (n = 7)) was significantly reduced compared with levels of weight loss observed in recipients that had received a control adenovirus (25.7 ± 12.2% weight loss (n = 11), p = 0.001). Furthermore, TNF inhibition was associated with a reduction in colonic GVHD scores (p = 0.039) and in the percentage of the splenic CD4+ T cells that expressed IFN- (16 vs 6%). These findings indicate that TNF promotes CD4+ T cell alloproliferation, IFN- responses, and intestinal GVHD by IL-12-independent mechanisms.
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