Abstract
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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bone Marrow Transplantation / immunology
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Bone Marrow Transplantation / pathology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / transplantation
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Cells, Cultured
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Colonic Diseases / genetics
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Colonic Diseases / immunology*
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Colonic Diseases / pathology
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Colonic Diseases / prevention & control
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Down-Regulation / genetics
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Down-Regulation / immunology
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Female
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Graft vs Host Disease / genetics
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Graft vs Host Disease / immunology*
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Graft vs Host Disease / pathology
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Graft vs Host Disease / prevention & control
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Histocompatibility Antigens Class II / genetics
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Humans
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Immunoglobulin Heavy Chains / genetics
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Immunoglobulin Heavy Chains / pharmacology
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis*
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Interleukin-12 / physiology*
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Interleukin-18 / biosynthesis
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Lymphocyte Activation / genetics
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Lymphocyte Culture Test, Mixed / methods
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Receptors, Interleukin / deficiency
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Receptors, Interleukin / genetics
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Receptors, Interleukin / physiology
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Receptors, Interleukin-12
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / physiology
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Recombinant Fusion Proteins / pharmacology
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / physiology*
Substances
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Histocompatibility Antigens Class II
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Immunoglobulin Heavy Chains
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Interleukin-18
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Receptors, Interleukin
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Receptors, Interleukin-12
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Receptors, Tumor Necrosis Factor
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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Interleukin-12
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Interferon-gamma