Cutting edge: membrane lymphotoxin regulates CD8+ T cell-mediated intestinal allograft rejection

Z Guo, J Wang, L Meng, Q Wu, O Kim… - The Journal of …, 2001 - journals.aai.org
Z Guo, J Wang, L Meng, Q Wu, O Kim, J Hart, G He, P Zhou, JR Thistlethwaite, ML Alegre
The Journal of Immunology, 2001journals.aai.org
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 …
Abstract
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-γ (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.
journals.aai.org