Kato Y, Yamataka A, Yagita H, Okumura K, Fujiwara T, Miyano T
Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan.
Ann Surg. 1996 Jan;223(1):94-100. doi: 10.1097/00000658-199601000-00013.
The aim of this study was to see whether tolerance could be induced by simultaneous administration of monoclonal antibodies (MoAbs) to intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-1 (LFA-1) after transplantation of fetal small bowel between fully incompatible mice strains.
Fetal small bowel from either BALB/c (H-2d) or C3H/He (H-2k) mice was transplanted into the space between the peritoneum and rectus abdominis of adult C3H/He recipient mice. Syngeneic (n = 6) and two allogeneic transplant groups were made. In one of the allogeneic groups (n = 8), no immunosuppressant was given. In the other allogeneic group (n = 13), both anti-LFA-1 and anti-ICAM-1 MoAbs (50 micrograms each/mouse/day) were given intraperitoneally after transplantation for the first 4 weeks. In the syngeneic and untreated allogeneic groups, all mice were killed 4 weeks after transplantation. In the treated allogeneic group, eight mice were killed 6 weeks after cessation of the MoAb treatment. At the time the mice were killed, the bowel graft as well as the recipient spleen were taken for histologic analysis and cytotoxic T-lymphocyte (CTL) assay, respectively. Each mouse in the remaining treated five mice was transplanted with BALB/c and C57BL/6 (as third-party) full-thickness skin simultaneously 8 weeks after cessation of the MoAb treatment.
All grafts in the syngeneic group survived with normally developing villi, whereas all grafts in the untreated allogeneic group disappeared. In the treated allogeneic group, all allografts developed normal mucosa without any sign of rejection. Splenocytes from the recipient mice in the untreated allogeneic group showed increased CTL induction against donor-type alloantigen (p < 0.005), compared with that in the syngeneic group. Suppressed CTL induction against donor-type alloantigen was observed in the treated allografted recipient (p < 0.001), whereas CTL induction against third-party alloantigen was intact (p = NS). Third-party skin graft was normally rejected within 10 days, whereas donor-type skin graft was accepted in all mice tested.
Specific tolerance for fetal bowel allografts could be induced by a relatively short-term treatment with anti-ICAM-1 and anti-LFA-1 MoAbs. This mode of immunointervention could perhaps be applied to humans undergoing small-bowel transplantation.
本研究旨在观察在完全不相容的小鼠品系间进行胎鼠小肠移植后，同时给予抗细胞间黏附分子-1（ICAM-1）和抗白细胞功能相关抗原-1（LFA-1）单克隆抗体（MoAbs）是否能诱导耐受。
将来自BALB/c（H-2d）或C3H/He（H-2k）小鼠的胎鼠小肠移植到成年C3H/He受体小鼠的腹膜与腹直肌之间的间隙。设立同基因移植组（n = 6）和两个异基因移植组。在其中一个异基因移植组（n = 8）中，未给予免疫抑制剂。在另一个异基因移植组（n = 13）中，移植后前4周每天腹腔内给予抗LFA-1和抗ICAM-1 MoAbs（各50微克/只小鼠）。在同基因移植组和未处理的异基因移植组中，所有小鼠在移植后4周处死。在处理过的异基因移植组中，8只小鼠在MoAb治疗停止后6周处死。在处死小鼠时，分别取肠移植物和受体脾脏进行组织学分析和细胞毒性T淋巴细胞（CTL）检测。在MoAb治疗停止8周后，将剩余5只处理过的小鼠中的每只同时移植BALB/c和C57BL/6（作为第三方）的全层皮肤。
同基因移植组的所有移植物均存活，绒毛发育正常，而未处理的异基因移植组的所有移植物均消失。在处理过的异基因移植组中，所有同种异体移植物均发育出正常黏膜，无任何排斥迹象。与同基因移植组相比，未处理的异基因移植组受体小鼠的脾细胞对供体型同种异体抗原的CTL诱导增加（p < 0.005）。在处理过的同种异体移植受体中观察到对供体型同种异体抗原的CTL诱导受到抑制（p < 0.001），而对第三方同种异体抗原的CTL诱导未受影响（p = 无显著性差异）。第三方皮肤移植物在10天内正常排斥，而供体型皮肤移植物在所有受试小鼠中均被接受。
用抗ICAM-1和抗LFA-1 MoAbs进行相对短期的治疗可诱导对胎鼠小肠同种异体移植物的特异性耐受。这种免疫干预方式或许可应用于接受小肠移植的人类患者。
