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Cutting Edge: Membrane Lymphotoxin Regulates CD8⁺ T Cell-Mediated Intestinal Allograft Rejection¹

Zhong Guo^2,*, Jun Wang^2,*, Lingzhong Meng, Qiang Wu, Oliver Kim, John Hart, Gang He, Ping Zhou, J. Richard Thistlethwaite, Jr., Maria-Luisa Alegre, Yang-Xin Fu^3, and Kenneth A. Newell^3,4,*

^* Emory Transplant Center and Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322; and the Departments of Surgery, Pathology, and Medicine, University of Chicago, Chicago, IL 60637

Blocking the CD28/B7 and/or CD154/CD40 costimulatory pathways promotes long-term allograft survival in many transplant models where CD4⁺ T cells are necessary for rejection. When CD8⁺ T cells are sufficient to mediate rejection, these approaches fail, resulting in costimulation blockade-resistant rejection. To address this problem we examined the role of lymphotoxin-related molecules in CD8⁺ T cell-mediated rejection of murine intestinal allografts. Targeting membrane lymphotoxin by means of a fusion protein, mAb, or genetic mutation inhibited rejection of intestinal allografts by CD8⁺ T cells. This effect was associated with decreased monokine induced by IFN- (Mig) and secondary lymphoid chemokine (SLC) gene expression within allografts and spleens respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4⁺ T cells. Combining disruption of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice. These data demonstrate that membrane lymphotoxin is an important regulatory molecule for CD8⁺ T cells mediating rejection and suggest a strategy to avoid costimulation blockade-resistant rejection.

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