Antibody‐Mediated Rejection of Single Class I MHC‐Disparate Cardiac Allografts |
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Authors: | Y Hattori R P Bucy Y Kubota W M Baldwin III R L Fairchild |
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Institution: | 1. Glickman Urological and Kidney Institute;2. Department of Immunology, Cleveland Clinic, Cleveland, OH;3. Department of Urology, Yokohama City University, Kanagawa, Japan;4. Department of Pathology, University of Alabama‐Birmingham, Birmingham, AL;5. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH |
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Abstract: | Murine CCR5?/? recipients produce high titers of antibody to complete MHC‐mismatched heart and renal allografts. To study mechanisms of class I MHC antibody‐mediated allograft injury, we tested the rejection of heart allografts transgenically expressing a single class I MHC disparity in wild‐type C57BL/6 (H‐2b) and B6.CCR5?/? recipients. Donor‐specific antibody titers in CCR5?/? recipients were 30‐fold higher than in wild‐type recipients. B6.Kd allografts survived longer than 60 days in wild‐type recipients whereas CCR5?/? recipients rejected all allografts within 14 days. Rejection was accompanied by infiltration of CD8 T cells, neutrophils and macrophages, and C4d deposition in the graft capillaries. B6.Kd allografts were rejected by CD8?/?/CCR5?/?, but not μMT?/?/CCR5?/?, recipients indicating the need for antibody but not CD8 T cells. Grafts recovered at day 10 from CCR5?/? and CD8?/?/CCR5?/? recipients and from RAG‐1?/? allograft recipients injected with anti‐Kd antibodies expressed high levels of perforin, myeloperoxidase and CCL5 mRNA. These studies indicate that the continual production of antidonor class I MHC antibody can mediate allograft rejection, that donor‐reactive CD8 T cells synergize with the antibody to contribute to rejection, and that expression of three biomarkers during rejection can occur in the absence of this CD8 T cell activity. |
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Keywords: | Antibody‐mediated rejection animal models basic science biomarker cardiac transplant graft rejection leukocyte infiltration neutrophils |
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