Targeting LFA-1 synergizes with CD40/CD40L blockade for suppression of both CD4-dependent and CD8-dependent rejection.
Allogeneic hepatocytes elicit CD4-dependent and (CD4-independent) CD8+ T-cell-initiated graft rejection. The (CD4-independent) CD8+ T-cell pathway is resistant to immunosuppressive strategies that readily and indefinitely suppress CD4+ T-cell-dependent rejection responses. Consequently, successful immunoregulation of hepatocyte-initiated immune responses requires a strategy which regulates both CD4-dependent and CD8-dependent rejection responses. Interference with CD40/CD40 ligand (CD40L) costimulation only transiently suppresses CD4- and CD8-dependent hepatocyte rejection. Interference with CD28/B7 costimulation transiently suppresses CD4-dependent hepatocyte rejection, but is ineffective for suppression of CD8-dependent hepatocyte rejection. To date, hepatocyte survival > 60 days post-transplant has not been achieved by any immunotherapeutic strategy. In the current study, we evaluated a novel immunosuppressive strategy which targets both LFA-1 and CD40L-mediated signals. Targeting LFA-1 suppressed (CD4-independent) CD8+ T-cell-initiated hepatocyte rejection such that allogeneic hepatocyte survival > 60 days was achieved in 70% of CD4 KO mice. Targeting both LFA-1-mediated signals and CD40/CD40L costimulation resulted in synergistic effects, such that hepatocellular survival > 60 days was achieved in 100% of C57BL/6 mice (which have both CD4- and CD8-dependent T-cell pathways available).
D000818:Animals; D018106:CD28 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D019013:CD40 Antigens / Q000096:biosynthesis*; D023201:CD40 Ligand / Q000096:biosynthesis*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002470:Cell Survival; D017690:Cell Transplantation; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control*; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016031:Liver Transplantation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors
D018106:CD28 Antigens; D019013:CD40 Antigens; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand