title: Prolonged allograft survival in TNF receptor 1-deficient recipients is due to immunoregulatory effects, not to inhibition of direct antigraft cytotoxicity.
abstract: TNF-alpha and lymphotoxin (LT)alpha 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-alpha and LTalpha 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-alpha and LTalpha exert profound immunoregulatory effects through TNF-R1.
authors.affiliation: Laboratory of Molecular Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: McKee
authors.forename: Rachel
authors.initials: R
authors.lastname: Defina
authors.forename: Hongzhen
authors.initials: H
authors.lastname: He
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Haley
authors.forename: James R
authors.initials: JR
authors.lastname: Stone
authors.forename: David L
authors.initials: DL
authors.lastname: Perkins
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology*; D016827:CD8 Antigens / Q000096:biosynthesis / Q000235:genetics; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D016827:CD8 Antigens; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I