Chosa Eiichi, Hara Masaki, Watanabe Akira, Matsuzaki Yasunori, Nakamura Kunihide, Hamano Kimikazu, Wood Kathryn J, Onitsuka Toshio
Department of Surgery II, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Transplantation. 2007 May 15;83(9):1226-33. doi: 10.1097/01.tp.0000259928.16003.aa.
This study addresses the question of the mechanism for maintaining tolerance to donor alloantigen in the absence of antigen and the role of secondary lymphoid tissues.
Depleting anti-CD4 antibody administration in conjunction with allogeneic heart transplantation generates donor-specific operational tolerance. Primary C57BL/6 heart grafts were transplanted into the neck cavity of the anti-CD4 antibody pretreated C3H/He mice. At day 50, functioning heart grafts were removed from tolerant mice. At day 100, a secondary C57BL/6 or a third-party heart was transplanted into the abdomen.
Anti-CD4 antibody therapy induced CD4CD25 regulatory T cells by 50 days after transplantation, as depleting anti-CD25 treatment in tolerant mice abrogated graft prolongation when spleen leukocytes were adoptively transferred to syngeneic mice. Tolerance was maintained by CD4CD25 regulatory T cells via a CTLA-4 signal at 100 days, even after removal of the primary graft at day 50. Administration of anti-CD25 antibody immediately after removal of the primary graft did not break tolerance, as five out of six second allografts transplanted at day 100 were accepted. Anti-CD25 antibody therapy in conjunction with splenectomy, but not thymectomy, immediately after removal of primary heart grafts at day 50 broke tolerance at day 100; all allografts were rejected.
The spleen is important in maintaining CD4CD25 regulatory T cells after primary allograft removal.
本研究探讨了在无抗原情况下维持对供体同种异体抗原耐受性的机制问题以及二级淋巴组织的作用。
在同种异体心脏移植的同时给予抗CD4抗体耗竭疗法可产生供体特异性操作性耐受。将原代C57BL/6心脏移植物移植到经抗CD4抗体预处理的C3H/He小鼠的颈部腔隙。在第50天，从耐受小鼠体内取出功能正常的心脏移植物。在第100天，将第二个C57BL/6或第三方心脏移植到腹部。
抗CD4抗体治疗在移植后50天诱导产生CD4CD25调节性T细胞，因为当将耐受小鼠的脾脏白细胞过继转移到同基因小鼠时，在耐受小鼠中进行抗CD25耗竭治疗可消除移植物延长。即使在第50天切除原代移植物后，CD4CD25调节性T细胞在第100天仍通过CTLA-4信号维持耐受性。在切除原代移植物后立即给予抗CD25抗体并未打破耐受性，因为在第100天移植的六个二次同种异体移植物中有五个被接受。在第50天切除原代心脏移植物后立即进行抗CD25抗体治疗并联合脾切除术而非胸腺切除术，在第100天打破了耐受性；所有同种异体移植物均被排斥。
脾脏在原代同种异体移植物切除后维持CD4CD25调节性T细胞方面很重要。
