Blood transfusions exert a powerful and long lasting immunosuppressive effect in both man and experimental animals which is both donor specific and non-specific. This immunosuppressive effect occurs as early as 24 hours after blood administration, thus making donor specific transfusions useful in both cadaveric and living related donor transplants. Graft tolerance associated with the administration of blood is an active immunologic process involving the development of both specific and non- specific macrophage and T lymphocyte suppressor cell networks. The transfusion effect is mediated in part by eicosanoids released from the macrophages and can be augmented by low doses of cyclosporine, the administration of linoleic acid, the prostacyclin analogue Iloprost, the stable prostaglandin analogue 16, 16 dimethyl PGE2, and the lipoxgenase pathway inhibitor NDGA. Conversely, the transfusion effect is reduced or eliminated by the administration of indomethacin (a cyclooxygenase pathway inhibitor) anti-CD4 monoclonal antibodies (which eliminates a subset of suppressor inducer cells), high doses of cyclosporin and high doses of steroids. The long-term goal of the proposed studies is to further refine methodologies to augment the donor specific transfusion effect in animals which can be applied to man to achieve permanent or long-lasting tolerance to an allograft with minimal or no long-term immunosuppression. Specific components of the proposed studies include optimization of multi-modality therapy, first by defining optimal dose responses for anti-CD3 antibodies, Iloprost, NDGA, 16, 16 dimethyl PGE2, and linoleic acid alone and in combination, first in a screening model in rats and then in verification models in rats and dogs. The investigator's previous laboratory studies have led to the development of a clinical protocol for both living related donor and cadaveric renal transplants which involves the administration of donor specific transfusions, cyclosporine and ketoconazole beginning one day prior to transplant. This clinical trial will be performed concurrently and should lead to more effective, safer and less costly modes of immunosuppression in man.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Cincinnati
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Gibson, S W; Valente, J F; Alexander, J W et al. (2000) Nutritional immunomodulation leads to enhanced allograft survival in combination with cyclosporine A and rapamycin, but not FK506. Transplantation 69:2034-8
Gibson, S W; Valente, J F; Alexander, J W et al. (1999) The effect of nutritional immunomodulation on cardiac allograft survival in rats receiving mycophenolate mofetil, cyclosporine A, and donor-specific transfusion. J Heart Lung Transplant 18:185-9
Alexander, J W; Levy, A; Custer, D et al. (1998) Arginine, fish oil, and donor-specific transfusions independently improve cardiac allograft survival in rats given subtherapeutic doses of cyclosporin. JPEN J Parenter Enteral Nutr 22:152-5
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Levy, A E; Alexander, J W; Babcock, G F (1997) A strategy for generating consistent long-term donor-specific tolerance to solid organ allografts. Transpl Immunol 5:83-8
Levy, A E; Alexander, J W (1996) The significance of timing of additional short-term immunosuppression in the donor-specific transfusion/cyclosporine-treated rat. Transplantation 62:262-6
Frede, S E; Levy, A E; Alexander, J W et al. (1996) An examination of tissue chimerism in the ACI to Lewis rat cardiac transplant model. Transpl Immunol 4:227-31
Tchervenkov, J I; Cofer, B R; Davies, C et al. (1995) Indefinite allograft survival induced by the combination of multiple donor-specific transfusions, cyclosporine, and an anti-T cell monoclonal antibody in a protocol relevant to cadaveric organ transplantation. The importance of prolonged posttransplant cy Transplantation 59:821-4
Levy, A E; Alexander, J W (1995) Nutritional immunomodulation enhances cardiac allograft survival in rats treated with donor-specific transfusion and cyclosporine. Transplantation 60:812-5

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