LFA-1 Antagonism Inhibits Early Infiltration of Endogenous Memory CD8 T Cells into Cardiac Allografts and Donor-Reactive T Cell Priming

Authors

  • K. Setoguchi,

    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
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  • A. D. Schenk,

    1. Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH
    2. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
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  • D. Ishii,

    1. Glickman Urological and Kidney Institute
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  • Y. Hattori,

    1. Glickman Urological and Kidney Institute
    2. Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH
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  • W. M. Baldwin III,

    1. Glickman Urological and Kidney Institute
    2. Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH
    3. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
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  • K. Tanabe,

    1. Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
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  • R. L. Fairchild

    Corresponding author
    1. Glickman Urological and Kidney Institute
    2. Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH
    3. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
      Corresponding author: Robert L. Fairchild, fairchr@ccf.org
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Corresponding author: Robert L. Fairchild, fairchr@ccf.org

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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