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Is Critical for Long-Term Allograft Survival Induced by Blocking the CD28 and CD40 Ligand T Cell Costimulation Pathways1
The Carlos and Marguerite Mason Transplantation Research Center,
*
Renal Division, Department of Medicine and
Department of Surgery, Emory University School of Medicine and Veterans Affairs Medical Center, Atlanta, GA 30033;
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121; and
§
Pathology and Laboratory Medicine, Veterans Affairs Medical Center and State University of New York, Buffalo, NY 14215
It is postulated that IFN-
production hinders long-term
acceptance of transplanted organs. To test this hypothesis, we compared
survival of skin and heart allografts in wild-type
(IFN-+/+) mice to that in IFN- gene knockout
(IFN--/-) mice. We found that perioperative blockade
of the CD28 and/or CD40 ligand T cell costimulation pathways induces
long-term skin and heart allograft survival in IFN-+/+
recipients but fails to do so in IFN--/- mice or in
wild-type mice treated with IFN--neutralizing Ab at the time of
transplantation. In vitro studies showed that endogenously produced
IFN- down-regulates T cell proliferation and CTL generation in MLCs.
These actions of IFN- were not mediated by TNF-
production or
Fas-Fas ligand interactions. In vivo studies revealed exaggerated
expansion and, subsequently, impaired deletion of superantigen-reactive
T lymphocytes in IFN--/- mice injected with
staphylococcal enterotoxin B. Taken together, our findings indicate
that IFN- does not hinder but instead facilitates induction of
long-term allograft survival possibly by limiting expansion of
activated T cells.
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A. Schwarting, T. Wada, K. Kinoshita, G. Tesch, and V. Rubin Kelley IFN-{gamma} Receptor Signaling Is Essential for the Initiation, Acceleration, and Destruction of Autoimmune Kidney Disease in MRL-Faslpr Mice J. Immunol., July 1, 1998; 161(1): 494 - 503. [Abstract] [Full Text] [PDF]
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T. Wekerle, M. H. Sayegh, J. Hill, Y. Zhao, A. Chandraker, K. G. Swenson, G. Zhao, and M. Sykes Extrathymic T Cell Deletion and Allogeneic Stem Cell Engraftment Induced with Costimulatory Blockade Is Followed by Central T Cell Tolerance J. Exp. Med., June 15, 1998; 187(12): 2037 - 2044. [Abstract] [Full Text] [PDF]
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A. Schwarting, K. Moore, T. Wada, G. Tesch, H.-J. Yoon, and V. R. Kelley IFN-{gamma} Limits Macrophage Expansion in MRL-Faslpr Autoimmune Interstitial Nephritis: A Negative Regulatory Pathway J. Immunol., April 15, 1998; 160(8): 4074 - 4081. [Abstract] [Full Text] [PDF]
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K.-i. Seino, K. Fukao, K. Muramoto, K. Yanagisawa, Y. Takada, S. Kakuta, Y. Iwakura, L. Van Kaer, K. Takeda, T. Nakayama, et al. Requirement for natural killer T (NKT) cells in the induction of allograft tolerance PNAS, February 27, 2001; 98(5): 2577 - 2581. [Abstract] [Full Text] [PDF]
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