Potential role of host effector memory CD8+ T cells in marrow rejection after mixed chimerism induction in cynomolgus monkeys.
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.
Setoguchi
Kiyoshi
K
Department of Urology, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan. setoguchi-jua@umin.ac.jp
Kishimoto
Hidehiro
H
Kobayashi
Sakiko
S
Shimmura
Hiroaki
H
Ishida
Hideki
H
Toki
Daisuke
D
Suzuki
Toshihiro
T
Ohnuki
Kazunobu
K
Tate
Yoshiki
Y
Fujioka
Shigeru
S
Abe
Ryo
R
Tanabe
Kazunari
K
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
D019138:Antibodies, Blocking; D015703:Antigens, CD