title: Repeated Injections of IL-2 Break Renal Allograft Tolerance Induced via Mixed Hematopoietic Chimerism in Monkeys.
abstract: Tolerance of allografts achieved in mice via stable mixed hematopoietic chimerism relies essentially on continuous elimination of developing alloreactive T cells in the thymus (central deletion). Conversely, while only transient mixed chimerism is observed in nonhuman primates and patients, it is sufficient to ensure tolerance of kidney allografts. In this setting, it is likely that tolerance depends on peripheral regulatory mechanisms rather than thymic deletion. This implies that, in primates, upsetting the balance between inflammatory and regulatory alloimmunity could abolish tolerance and trigger the rejection of previously accepted renal allografts. In this study, six monkeys that were treated with a mixed chimerism protocol and had accepted a kidney allograft for periods of 1-10 years after withdrawal of immunosuppression received subcutaneous injections of IL-2 cytokine (0.6-3 × 10(6) IU/m(2) ). This resulted in rapid rejection of previously tolerated renal transplants and was associated with an expansion and reactivation of alloreactive pro-inflammatory memory T cells in the host's lymphoid organs and in the graft. This phenomenon was prevented by anti-CD8 antibody treatment. Finally, this process was reversible in that cessation of IL-2 administration aborted the rejection process and restored normal kidney graft function.
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Harvard Medical School, Boston, MA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Harvard Medical School, Boston, MA.
authors.forename: O
authors.initials: O
authors.lastname: Nadazdin
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Harvard Medical School, Boston, MA.
authors.forename: S
authors.initials: S
authors.lastname: Boskovic
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Harvard Medical School, Boston, MA.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Harvard Medical School, Boston, MA.
authors.forename: E
authors.initials: E
authors.lastname: Zorn
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: R N
authors.initials: RN
authors.lastname: Smith
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: R B
authors.initials: RB
authors.lastname: Colvin
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Harvard Medical School, Boston, MA.
authors.forename: J C
authors.initials: JC
authors.lastname: Madsen
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Harvard Medical School, Boston, MA.
authors.forename: A B
authors.initials: AB
authors.lastname: Cosimi
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Harvard Medical School, Boston, MA.
authors.forename: T
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Harvard Medical School, Boston, MA.
authors.forename: G
authors.initials: G
authors.lastname: Benichou
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D046528:Chimerism; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy / Q000209:etiology*; D006085:Graft Survival; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage*; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008252:Macaca fascicularis; D051379:Mice; D011183:Postoperative Complications; D012307:Risk Factors; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D007376:Interleukin-2
keywords: animal models: nonhuman primate; basic (laboratory) research/science; bone marrow/hematopoietic stem cell transplantation; immunosuppression/immune modulation; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; tolerance: chimerism; tolerance: mechanisms; translational research/science