LFA‐1 Antagonism Inhibits Early Infiltration of Endogenous Memory CD8 T Cells into Cardiac Allografts and Donor‐Reactive T Cell Priming |
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Authors: | K Setoguchi A D Schenk D Ishii Y Hattori W M Baldwin III K Tanabe R L Fairchild |
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Institution: | 1. Glickman Urological and Kidney Institute;2. Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH;3. Department of Urology, Tokyo Women's Medical University, Tokyo, Japan;4. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH |
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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‐2b) recipients of A/J (H‐2a) 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. |
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Keywords: | Acute cellular rejection acute allograft rejection adhesion molecules alloreactive T cells leukocyte infiltration memory CD8+ T cells |
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