title: Potential role of host effector memory CD8+ T cells in marrow rejection after mixed chimerism induction in cynomolgus monkeys.
abstract: Mixed hematopoietic chimerism provides a powerful means of achieving transplantation tolerance. We investigated the efficacy of combined blockade of the CD40/CD154 and CD28/B7 costimulation pathways to induce sustained mixed chimerism in cynomolgus monkeys following major histocompatibility complex-mismatched bone marrow (BM) transplants. A nonmyeloablative conditioning regimen of busulfan, intravenous and intraosseous ifosfamide, and anti-thymocyte globulin was used. BM transplantation was followed by a one-week course of CTLA4-Ig/anti-CD154 monoclonal antibodies. Three recipients achieved a wide range of transient chimerism (10.8-79.8%). A rapid proliferation of host effector memory (CD28(low)CD95(high)) CD8(+) T cells was observed in conditioned animals whether or not they received allogeneic BM, and this expansion occurred concurrently with the loss of chimerism in BM recipients. CD8(+) T cells from the recipients had increased reactivity to donor stimulators vs. third-party stimulators. Additional immunosuppression with tacrolimus or deoxyspergualin after transplantation delayed post-transplant proliferation of effector memory CD8(+) T cells but did not promote chimerism. A one-month course of costimulatory blockade also did not prevent marrow rejection. These studies demonstrate that combined CD40/CD154 and CD28/B7 costimulatory blockade supports transient mixed chimerism induction following nonmyeloablative conditioning in primates, but is insufficient to overcome host immune resistance likely mediated by effector memory CD8(+) T cells.
authors.affiliation: Department of Urology, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan. setoguchi-jua@umin.ac.jp
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Setoguchi
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Sakiko
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimmura
authors.forename: Hideki
authors.initials: H
authors.lastname: Ishida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Toki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Ohnuki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tate
authors.forename: Shigeru
authors.initials: S
authors.lastname: Fujioka
authors.forename: Ryo
authors.initials: R
authors.lastname: Abe
authors.forename: Kazunari
authors.initials: K
authors.lastname: Tanabe
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000378:metabolism*; D015703:Antigens, CD / Q000276:immunology; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D046528:Chimerism / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007156:Immunologic Memory; D008252:Macaca fascicularis / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD