Gastrointestinal disease is a major cause of morbidity and mortality in human graft-versus-host disease (GVHD). Animal models of GVHD have been used in determining the pathogenesis of gut GVHD. Tumor necrosis factor (TNF)/TNF receptor (TNFR), lymphotoxin beta, LTalphabeta2/LTbeta receptor (LTbetaR) and LIGHT [(derived from homologous to lymphotoxins shows inducible expression and binds to HVEM (Herpes Virus Entry Mediator)] /LTbetaR interactions appear to be important in the development of gut GVHD. The purpose of the proposed studies is to determine the mechanisms of the effects of the TNF superfamily on murine gut GVHD. In our reports, TNF blockade ameliorates gut GVHD. TNF and its family members appear to influence GVHD mediated intestinal inflammation by augmentation of pro-inflammatory T helper 1 (Th1) cytokine production. Data from our laboratory suggest that TNF/TNFR interactions and LIGHT/LTalphabeta2/LTbetaR interactions may serve as an IL-12 and IL-18 independent Th1 augmentation signal. Enhanced Th1 cytokine levels could occur due to the engagement of TNF family members' receptors on antigen presenting cells (APC's) that affect the production of IL-12 or IL-18 which further induce Th1 cytokine production from pathogenic T cells. Alternatively, TNF receptors or members of TNF superfamily receptors could signal the T cell to directly amplify IL-12 or IL-18 independent Th-1 augmentation signals. The proposed studies will test the hypothesis that TNF/TNFR and LTalphabeta2/LIGHT/LTbetaR interactions are critical for the direct or indirect activation and differentiation of pathogenic T cells in specific models of CD4+ T cell mediated GVHD. These studies will utilize an adenoviral transduction system that generates endogenous synthesis of a chimeric TNF inhibitor or LTbeta inhibitor protein, consisting of the extracellular domain of the human 55 kDa TNF receptor (7,8) or the LTbeta receptor fused to the heavy chain of mouse immunoglobulin (Fc) (9,10). In other experiments, LIGHT antibody (11) will be used to block LIGHT/LTbetaR or LIGHT/HVEM interaction.
The specific aims are: 1) Determine whether the effect of TNF/TNFR interactions on the development of intestinal GVHD is IL-12 or IL-18 dependent. 2) Define the role of TNF/TNFR, LIGHT/HVEM, LIGHT/LTalphabeta2/LTbetaR interactions on the development of in vivo responses in gut GVHD and 3) Define whether the role of LIGHT/HVEM or LIGHT/LTalphabeta2/LTbetaR interactions on the development of intestinal GVHD is IL-12 or IL-18 dependent.
| Ali, Sabina; Starwalt, Ruth; Kreck, Jake et al. (2011) Tumor necrosis factor is critical for cytolytic T cell activity against allospecific hepatocytes and splenic targets in major histocompatibility complex class I disparate graft versus host disease. J Interferon Cytokine Res 31:423-31 |
| Brown, Geri R; Lane, George W; Whittington, Bonnie J (2010) Disparate role of LIGHT in organ-specific donor T cells activation and effector molecules in MHC class II disparate GVHD. J Clin Immunol 30:178-84 |
| Brown, Geri R; Lee, Edward L; El-Hayek, Jihad et al. (2005) IL-12-independent LIGHT signaling enhances MHC class II disparate CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease. J Immunol 174:4688-95 |
| Brown, Geri R; Lee, Edward L; Thiele, Dwain L (2003) TNF enhances CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease by IL-12-independent mechanisms. J Immunol 170:5082-8 |
