Cyclosporine immunosuppression does not prevent the production of donor-specific antibody capable of mediating allograft vasculopathy

• Published in: The Journal of heart and lung transplantation Vol. 31; no. 8; pp. 874 - 880
• Main Authors: Gareau, Alison J., MSc, Nashan, Bjorn, MD, PhD, Hirsch, Gregory M., MD, Lee, Timothy D.G., PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-08-2012; Elsevier
• Subjects: allograft vasculopathy; Animals; antibody; Antibody Specificity - immunology; Biological and medical sciences; Calcineurin Inhibitors; Cardiology. Vascular system; complement; Cyclosporine - therapeutic use; cyclosporine A; Graft Rejection - etiology; Graft Rejection - immunology; Heart Transplantation; immunosuppression; Immunosuppressive Agents - therapeutic use; Isoantibodies - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Models, Animal; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; T-Lymphocytes - metabolism; Tissue Donors; transplantation; Transplantation, Homologous; Vascular Diseases - complications; Vascular Diseases - immunology; immunosuppression; cyclosporine A; antibody; allograft vasculopathy; complement; transplantation; Suboptimal donor; Human; Calcineurin inhibitor; Antibody; Homograft; Cardiovascular disease; Phlebology; Vascular disease; Prevention; Immunosuppression; Production; Graft; Ciclosporin; Circulatory system; Immunosuppressive agent; Cardiology
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2012.03.017

Background Late cardiac graft rejection, primarily mediated by allograft vasculopathy (AV), remains a major limitation to cardiac transplantation, even in the face of significant calcineurin inhibitor (CNI) immunosuppression. The role played by alloantibody in AV is unclear. Evidence that CNI immunosuppression suppresses CD4+ T-cell function would suggest that antibody production and effector function would be severely limited in CNI-treated patients. In this study we examine the capacity of CNI-treated animals to develop effective alloantibody that can mediate AV. Methods Wild-type (WT) B6 mice were alloimmunized using donor splenocytes or a fully major histocompatibility complex-mismatched allogeneic abdominal aortic graft in the presence of CNI immunosuppression (30 or 50 mg/kg/day cyclosporine A). Anti-serum was harvested and tested using complement-dependent in vitro cytotoxicity assays. Anti-serum was passively transferred to immunodeficient RAG1−/− recipients of allogeneic grafts. C4d deposition was quantified in the allografts from WT recipients. Results CNI immunosuppression did not prevent the development of alloantibody in response to either immunization method ( p < 0.05). Passive transfer of anti-serum generated AV lesions in immunodeficient graft recipients and mediated complement-dependent destruction of donor cells ( p < 0.05). C4d deposition was localized to the media of grafts of CNI treated animals. Conclusions CNI therapy does not prevent the production of alloantibody with the capacity to mediate AV. C4d deposition in the media suggests a role for medial smooth muscle cell loss in antibody-mediated AV lesion development in our model.