Transplantation tolerance by a combined therapy with sulfatide, anti-LFA-1/ICAM-1 monoclonal antibodies and FK506 in rat cardiac transplantation.
Selectins promote a rolling phenomenon of leukocytes along activated endothelial surfaces, which is the first step in the events that ultimately lead to leukocyte transmigration at acute inflammatory sites. Our previous study revealed that sulfatide, which is one of the selectin inhibitors, prolonged graft survival in rat cardiac allografts. In the present study, to obtain a longer graft acceptance, we examined a combination treatment of sulfatide, monoclonal antibodies (mAbs) against LFA-1/ICAM-1, and FK506 in a Fischer 344 (F344, RT1lvl) to Lewis (LEW, RT1l) rat heart transplantation. FK506 alone (n = 6) and FK506/sulfatide-treated LEW rats (n = 6) rejected F344 heart grafts with an MST of 49 and 55.2 days, respectively. Otherwise, four out of six heart grafts treated with sulfatide, mAbs against LFA-1/ICAM-1, and FK506 (n = 6) survived for over 100 days after transplantation. The proliferative response of alloreactive T cells obtained from tolerant rats against both F344 alloantigen and third-party alloantigen on day 104 postgrafting was significantly suppressed as compared to that from naive LEW rats. On light microscopic examination, specimens of tolerant rat on day 104 postgrafting showed an almost normal appearance. Our results suggested that blocking both each step of leukocyte entry and recognition of alloantigens by a combination treatment of sulfatide, mAbs against LFA-1/ICAM-1, and FK506 could lead to tolerance.
Horimoto
H
H
Department of Surgery, Meikai University, Saitama, Japan.
Ito
T
T
Hayashi
T
T
Miyasaka
M
M
Nozawa
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013433:Sulfoglycosphingolipids / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D013433:Sulfoglycosphingolipids; D018799:Intercellular Adhesion Molecule-1; D016559:Tacrolimus