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Prolonged Allograft Survival in TNF Receptor 1-Deficient Recipients Is Due to Immunoregulatory Effects, Not to Inhibition of Direct Antigraft Cytotoxicity¹

Charlotte M. McKee^*,, Rachel Defina^*, Hongzhen He^*, Kathleen J. Haley, James R. Stone and David L. Perkins^2,*

^* Laboratory of Molecular Immunology and Pulmonary and Critical Care Division, Department of Medicine, and Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

TNF- and lymphotoxin (LT) have been shown to be important mediators of allograft rejection. TNF-R1 is the principal receptor for both molecules. Mice with targeted genetic deletions of TNF-R1 demonstrate normal development of T and B lymphocytes but exhibit functional defects in immune responses. However, the role of TNF-R1-mediated signaling in solid organ transplant rejection has not been defined. To investigate this question, we performed vascularized heterotopic allogeneic cardiac transplants in TNF-R1-deficient (TNF-R1^-/-) and wild-type mice. Because all allografts in our protocol expressed TNF-R1, direct antigraft effects of TNF- and LT were not prevented. However, immunoregulatory effects on recipient inflammatory cells by TNF-R1 engagement was eliminated in TNF-R1^-/- recipients. In our study, cardiac allograft survival was significantly prolonged in TNF-R1^-/- recipients. Despite this prolonged allograft survival, we detected increased levels of CD8 T cell markers in allografts from TNF-R1^-/- recipients, suggesting that effector functions, but not T cell recruitment, were blocked. We also demonstrated the inhibition of multiple chemokines and cytokines in allografts from TNF-R1^-/- recipients including RANTES, IFN-inducible protein-10, lymphotactin, and IL-1R antagonist, as well as altered levels of chemokine receptors. We correlated gene expression with the physiologic process of allograft rejection using self-organizing maps and identified distinct patterns of gene expression in allografts from TNF-R1^-/- recipients. These findings indicate that in our experimental system TNF- and LT exert profound immunoregulatory effects through TNF-R1.

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