title: Memory CD4 T Cells Induce Antibody-Mediated Rejection of Renal Allografts.
abstract: Despite advances in immunosuppression, antibody-mediated rejection is a serious threat to allograft survival. Alloreactive memory helper T cells can induce potent alloantibody responses and often associate with poor graft outcome. Nevertheless, the ability of memory T cells to elicit well characterized manifestations of antibody-mediated rejection has not been tested. We investigated helper functions of memory CD4 T cells in a mouse model of renal transplantation. Whereas the majority of unsensitized C57Bl/6 recipients spontaneously accepted fully MHC-mismatched A/J renal allografts, recipients containing donor-reactive memory CD4 T cells rapidly lost allograft function. Increased serum creatinine levels, high serum titers of donor-specific alloantibody, minimal T cell infiltration, and intense C4d deposition in the grafts of sensitized recipients fulfilled all diagnostic criteria for acute renal antibody-mediated rejection in humans. IFNγ neutralization did not prevent the renal allograft rejection induced by memory helper T cells, and CD8 T cell depletion at the time of transplantation or depletion of both CD4 and CD8 T cells also did not prevent the renal allograft rejection induced by memory helper T cells starting at day 4 after transplantation. However, B cell depletion inhibited alloantibody generation and significantly extended allograft survival, indicating that donor-specific alloantibodies (not T cells) were the critical effector mechanism of renal allograft rejection induced by memory CD4 T cells. Our studies provide direct evidence that recipient T cell sensitization may result in antibody-mediated rejection of renal allografts and introduce a physiologically relevant animal model with which to investigate mechanisms of antibody-mediated rejection and novel therapeutic approaches for its prevention and treatment.
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gorbacheva
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Ran
authors.initials: R
authors.lastname: Fan
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fairchild
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: William M
authors.initials: WM
authors.lastname: Baldwin
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio valujsa@ccf.org.
authors.forename: Anna
authors.initials: A
authors.lastname: Valujskikh
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D007156:Immunologic Memory; D007518:Isoantibodies / Q000276:immunology*; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D007518:Isoantibodies
keywords: immunology; lymphocytes; transplantation