title: LFA-1 antagonism inhibits early infiltration of endogenous memory CD8 T cells into cardiac allografts and donor-reactive T cell priming.
abstract: Alloreactive memory T cells are present in virtually all transplant recipients due to prior sensitization or heterologous immunity and mediate injury undermining graft outcome. In mouse models, endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts and produce IFN-γ in response to donor class I MHC within 24 h posttransplant. The current studies analyzed the efficacy of anti-LFA-1 mAb to inhibit early CD8 T cell cardiac allograft infiltration and activation. Anti-LFA-1 mAb given to C57BL/6 6 (H-2(b)) recipients of A/J (H-2(a)) heart grafts on days -1 and 0 completely inhibited CD8 T cell allograft infiltration, markedly decreased neutrophil infiltration and significantly reduced intragraft expression levels of IFN-γ-induced genes. Donor-specific T cells producing IFN-γ were at low/undetectable numbers in spleens of anti-LFA-1 mAb treated recipients until day 21. These effects combined to promote substantial prolongation (from day 8 to 27) in allograft survival. Delaying anti-LFA-1 mAb treatment until days 3 and 4 posttransplant did not inhibit early memory CD8 T cell infiltration and proliferation within the allograft. These data indicate that peritransplant anti-LFA-1 mAb inhibits early donor-reactive memory CD8 T cell allograft infiltration and inflammation suggesting an effective strategy to attenuate the negative effects of heterologous immunity in transplant recipients.
authors.affiliation: Glickman Urological and Kidney Institute Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Setoguchi
authors.forename: A D
authors.initials: AD
authors.lastname: Schenk
authors.forename: D
authors.initials: D
authors.lastname: Ishii
authors.forename: Y
authors.initials: Y
authors.lastname: Hattori
authors.forename: W M
authors.initials: WM
authors.lastname: Baldwin
authors.forename: K
authors.initials: K
authors.lastname: Tanabe
authors.forename: R L
authors.initials: RL
authors.lastname: Fairchild
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry / Q000379:methods; D016027:Heart Transplantation / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D007156:Immunologic Memory; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology*; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; C114320:anti-LFA-1 monoclonal antibody