Cutting edge: Membrane lymphotoxin regulates CD8(+) T cell-mediated intestinal allograft rejection

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 rej ection, these approaches fail, resulting in costimulation blockade-resistan t rejection. To address this problem we examined the role of lymphotoxin-re lated molecules in CD8(+) T cell-mediated rejection of murine intestinal al lografts. 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 -gamma (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 membr ane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-typ e mice. These data demonstrate that membrane lymphotoxin is an important re gulatory molecule for CD8(+) T cells mediating rejection and suggest a stra tegy to avoid costimulation blockade-resistant rejection.