title: Low-dose cyclosporine mediates donor hyporesponsiveness in a fully mismatched rat kidney transplant model.
abstract: Tolerance induction protocols have been successfully tested in animal models, yet their compatibility with immunosuppressive drugs remains to be fully elucidated. Our own previous data have indicated that cyclosporine A (CsA) affects the balance of effector and regulatory mechanisms with low-dose CsA doses promoting hyporesponsiveness. Here, we present a fully mismatched rat kidney model in which low-dose CsA treatment induces donor hyporesponsiveness to secondary renal allografts. Lewis recipients of DA kidney grafts received low, medium or high doses of CsA × 10 days. By 30 days, the primary transplant was removed and a second transplant of donor origin was engrafted. Following low-dose CsA, but not high-dose CsA treatment of the primary recipient, secondary transplants were accepted long-term in the absence of immunosuppression. Regulatory T-cell function was unimpaired and independent of the CyA dosage. Of note, low-dose CsA significantly reduced alloantibody titers in primary recipients. Adoptive transfer of graft infiltrating cells or splenocytes from hyporesponsive recipients supported long-term acceptance of donor kidney allografts. These results demonstrate a dose-dependent and transferable "pro-tolerogenic" effect of low-dose CsA treatment. This model is of clinical relevance to test the interference of CsA with tolerance induction in the absence of additional immunosuppression.
authors.affiliation: Department of Visceral, Transplantation and Thoracic Surgery, Medizinische Universitaet Innsbruck, Austria; Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Denecke
authors.forename: Anja
authors.initials: A
authors.lastname: Reutzel-Selke
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.forename: Olaf
authors.initials: O
authors.lastname: Boenisch
authors.forename: Zain
authors.initials: Z
authors.lastname: Khalpey
authors.forename: Martina
authors.initials: M
authors.lastname: Seifert
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Tullius
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000097:blood; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D016572:Cyclosporine / Q000008:administration & dosage*; D006680:HLA Antigens / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation / Q000276:immunology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors; D019172:Transplantation Conditioning
chemical_list: D000906:Antibodies; D001897:Boronic Acids; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D016572:Cyclosporine