TRANSPLANTATION TOLERANCE TO RAT PANCREATIC ALLOGRAFTS BY BLOCKING INTERCELLULAR SIGNALS VIA ADHESION MOLECULES

1996 Fiscal Year Final Research Report Summary

• Project/Area Number: 07671324
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Meikai University
• Principal Investigator: NOZAWA Masumi MEIKAI UNIVERSITY,SCHOOL OF DENTISTRY,PROFESSOR, 歯学部, 教授 (00084880)
• Co-Investigator(Kenkyū-buntansha): ITO Toshinori OSAKA UNIVERSITY,SCHOOL OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 講師 (20231152)
• Project Period (FY): 1995 – 1996
• Keywords: PANCREAS TRANSPLANTATION / BLOCKING INTERCELLULAR SIGNALS / TRANSPLANTATION TOLELANCE / SUFATIDE / ICAM-1 / LFA-1

Research Abstract

Acute allograft rejection is characterized by a heavy infiltration of lymphocyte. Lymphocyte extravasation is intiated by the interaction of menbers of the selectin family and the oligosaccharide-containing counterreceptors before adhering with integrins. To prevent graft rejection, it is necessary to inhibit L-selectin-dependent lymphocyte adhesion to endothelium. Previous study revealed that sulfatide, which was a ligand for L-selectin and P-selectin, had significant in vivo blocking activity in L-selectin and P-selectin-dependent acute lung injury. Taken together, sulfatides, competing oligosaccharide constructs, are expected to prevent rejection by inhibiting leukocyte entry into allografts. In the following studies, We investigated in vivo ability to protect against graft rejection and also tried immunoregulation by clocking each molecules in various steps of leukocyte-endothelium adhesion in rat pancreatic allografts. Fischer (RT1^<lvl>) to Lewis (RT1^l) combination was used as e xperimental models. Rejection was defined as hyperglycemia. The experimental groupe were devided as follows : (1) no treatment (2) sulfatide (1mg/rat), (day-1,0), (3) anti-ratICAM-1/LFA-1mAbs (2.5mg/kg), (day+1,3), (4) anti-ratICAM-1/LFA-1mAbs and dulfatide.
The mean survival times of pancreatic allografts with no treatment, of grafts treated with sulfatide were 14 or 18.6 days respectively. The mean survival times of allografts treated with mAbs or treated with mAbs and sulfatide were 18.1 or 133.3 days. On immunological examination, significant suppression of the proliferative response of alloreactive T cells obtained from rats treated with sukfatide solely or with sulfatide in combination with mAbs were observed on day 105 after transplantation, Our results indicates that blocking both the leukocyte recruitment and alloantigens recognition by the combination treatment of sulfatide, monoclonal antibodies against LFA-1/ICAM-1 (mAbs) is useful to induce a long-term acceptance of pancreatic allografts.