CD4+ T-cell-dependent immune damage of liver parenchymal cells is mediated by alloantibody.
BACKGROUND
Allogeneic hepatocytes initiate both CD4- and CD8-dependent rejection responses. The current studies address the hypothesis that acute damage of allogeneic liver parenchymal cells by the CD4-dependent pathway is alloantibody-mediated and examines immune conditions which promote activation of this pathway.


METHODS
The role of alloantibody in CD4-dependent hepatocyte rejection was evaluated by assessing hepatocyte (FVB/N, H-2q) survival in CD8-depleted B-cell knockout (KO) (H-2b) recipients and by monitoring hepatocyte survival in C57BL/6.SCID (H-2b) recipients transfused with donor-reactive alloantibody. The development of donor-reactive alloantibody in C57BL/6 (H-2b), CD8-depleted C57BL/6, CD8 KO (H-2b), IFN-gamma KO (H-2b), perforin KO (H-2b), and FasL mutant gld/gld (H-2b) hepatocyte recipients was assessed.


RESULTS
Hepatocyte rejection in B-cell KO mice was significantly delayed by CD8+ T-cell depletion (median survival time [MST], 35 days) when compared to untreated (MST, 8 days) and CD4-depleted (MST, 10 days) recipient mice. Transfusion of donor-reactive alloantibody into SCID recipients with functional hepatocellular allografts was sufficient to precipitate rejection in a dose-dependent fashion. Donor-reactive alloantibody was minimal in the serum of C57BL/6 hepatocyte recipients, but was produced in significant quantities in hepatocyte recipients genetically deficient in or depleted of CD8+ T cells and in recipients with impaired cytotoxic effector mechanisms. In addition, recipients with defects in Th1 immunity, such as IFN-gamma KO recipients, also produced readily detectable alloantibody.


CONCLUSIONS
Collectively, these data support the hypothesis that acute immune damage of allogeneic hepatocytes by the CD4-dependent pathway is mediated by alloantibody and that this pathway is favored when Th1- or cell-mediated cytotoxic effector immune mechanisms are impaired.
Horne
Phillip H
PH
Integrated Biomedical Science Graduate Program, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210-1250, USA.
Lunsford
Keri E
KE
Eiring
Anna M
AM
Wang
Yue
Y
Gao
Donghong
D
Bumgardner
Ginny L
GL
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D007518:Isoantibodies / Q000276:immunology / Q000494:pharmacology; D016031:Liver Transplantation / Q000276:immunology / Q000379:methods / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
D015704:CD4 Antigens; D016827:CD8 Antigens; D007518:Isoantibodies