Blocking cell microtubule assembly inhibits the alloimmune response in vitro and prolongs renal allograft survival by inhibition of Th1 and sparing of Th2 cell function in vivo.
Colchicine inhibits cell microtubule assembly by binding to and preventing the polymerization of tubulin monomers. Although there are data to indicate that colchicine inhibits a variety of cell-mediated immune responses, the effects and mechanisms of inhibiting cell microtubule assembly on the alloimmune response have not been thoroughly investigated. It has recently been shown that colchicine prevents acute rejection and promotes the long-term survival of rat renal allografts. In this study, the effects and mechanisms of inhibiting cell microtubule assembly by colchicine on the alloimmune response in vitro and in vivo were examined. First, the effects of colchicine on T lymphocyte response to alloantigen in vitro were tested. In the standard one-way mixed lymphocyte response (MLR), responder Lewis rat lymph node cells were cultured with irradiated Brown-Norway stimulators. Colchicine inhibited the MLR in a dose-dependent manner, with 100% inhibition at a concentration of 25 ng/mL (6.25 x 10(-8) M) and 50% inhibition at a concentration of approximately 5 to 10 ng/mL. Colchicine also inhibited the generation of cytotoxic T lymphocytes as well as cytotoxic T cell effector function in vitro in a dose-dependent fashion. Second, detailed immunohistologic studies of renal allografts harvested from unmodified control (acutely rejecting) and colchicine-treated rats (Day 15 or 30) were performed. These studies showed that grafts from colchicine-treated animals had significantly fewer mononuclear cell infiltrates and less edema, and moderately decreased deposition of immunoglobulin M, C3, and fibrin, as compared with acutely rejecting control grafts.(ABSTRACT TRUNCATED AT 250 WORDS)
Akalin
E
E
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Hancock
W W
WW
Perico
N
N
Remuzzi
G
G
Imberti
O
O
Carpenter
C B
CB
Sayegh
M H
MH
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects; D007107:Immune System / Q000187:drug effects; D007519:Isoantigens / Q000276:immunology*; D016030:Kidney Transplantation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*
D016207:Cytokines; D007519:Isoantigens; D003078:Colchicine