TNF enhances CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease by IL-12-independent mechanisms.
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-2(bm12) (bm12) x B6 F(1) recipients. The present studies examined whether these effects of TNF are IL-12 dependent. T cell proliferative responses of B6.129S1-IL-12rb2(tm1Jm) (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-gamma 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-gamma (16 vs 6%). These findings indicate that TNF promotes CD4(+) T cell alloproliferation, IFN-gamma responses, and intestinal GVHD by IL-12-independent mechanisms.
Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, and Dallas Veterans Affairs Medical Center, Dallas, TX, USA. gbrow1@mednet.swmed.edu
Geri R
GR
Brown
Edward L
EL
Lee
Dwain L
DL
Thiele
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002478:Cells, Cultured; D003108:Colonic Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000502:physiology*; D020382:Interleukin-18 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D053707:Receptors, Interleukin-12; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D000949:Histocompatibility Antigens Class II; D007143:Immunoglobulin Heavy Chains; D020382:Interleukin-18; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma