HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McKee, C. M. Articles by Perkins, D. L. Search for Related Content PubMed PubMed Citation Articles by McKee, C. M. Articles by Perkins, D. L.

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.

This article has been cited by other articles:

				M. Shukla, S. Yang, C. Milla, A. Panoskaltsis-Mortari, B. R. Blazar, and I. Y. Haddad Absence of host tumor necrosis factor receptor 1 attenuates manifestations of idiopathic pneumonia syndrome Am J Physiol Lung Cell Mol Physiol, May 1, 2005; 288(5): L942 - L949. [Abstract] [Full Text] [PDF]