Umesue M, Mayumi H, Nishimura Y, Kong Y Y, Omoto K, Murakami Y, Nomoto K
Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Transplantation. 1996 Jan 15;61(1):116-24. doi: 10.1097/00007890-199601150-00023.
Because of the recent interest in human xenotransplantation, we investigated the possibility of inducing tolerance in a xenogeneic combination using cyclophosphamide (CP). Donor-specific prolongation of xenogeneic Fisher 344 (F344) rat skin graft survival for up to 60 days was induced in C57BL/6 (B6) mice by giving F344 bone marrow cells and spleen cells on day 0, CP on day 2, and monoclonal antibodies against murine TCR-alpha beta and NK1.1 on days--1 and 3. The inoculation of the xenogeneic cells brought accelerated repopulation of TCR-alpha beta+ T cells, even under the administration of anti-TCR-alpha beta mAb. The quick increase of the host TCR-alpha beta+ T cells caused by the xenogeneic cell injection was deeply suppressed by CP. Mixed lymphocyte reaction, CTL activity, and antibody production against donor F344 were profoundly suppressed for 50 days. Mixed xenogeneic chimerism was observed for 1 month after the inoculation of donor cells in the spleen and peripheral blood of the recipient B6 mice, but was never observed in the thymus. Moreover, when irradiated F344 cells were used in place of viable cells, chimerism was never detected and graft survival was only slightly prolonged. Clonal deletion of V beta 5- or V beta 11-bearing murine T cells was not observed on day 50 in the thymus or spleen of the recipient B6 mice. These results suggest that treatment with viable xenogeneic donor cells, CP, and mAbs against T and NK cells can induce a temporary peripheral mixed chimerism and donor-specific prolongation of xenogeneic skin graft survival. The destruction with CP of T and B cells that are xenoreactive and thus proliferating after antigen stimulation, followed by mechanism other than intrathymic clonal deletion, may be the mechanism of the hyporesponsiveness in the present system.
由于近期对人类异种移植的关注，我们研究了使用环磷酰胺（CP）在异种组合中诱导免疫耐受的可能性。通过在第0天给予F344大鼠骨髓细胞和脾细胞、第2天给予CP以及在第 - 1天和第3天给予抗小鼠TCR - αβ和NK1.1单克隆抗体，在C57BL / 6（B6）小鼠中诱导了供体特异性的异种Fisher 344（F344）大鼠皮肤移植存活期延长至60天。异种细胞的接种带来了TCR - αβ + T细胞的加速再填充，即使在给予抗TCR - αβ单克隆抗体的情况下也是如此。CP深度抑制了异种细胞注射引起的宿主TCR - αβ + T细胞的快速增加。混合淋巴细胞反应、CTL活性以及针对供体F344的抗体产生在50天内受到了显著抑制。在受体B6小鼠的脾脏和外周血中接种供体细胞后1个月观察到了混合异种嵌合体，但在胸腺中从未观察到。此外，当使用经照射的F344细胞代替活细胞时，未检测到嵌合体，移植存活期仅略有延长。在受体B6小鼠的胸腺或脾脏中，第50天时未观察到携带Vβ5或Vβ11的小鼠T细胞的克隆缺失。这些结果表明，用活的异种供体细胞、CP以及抗T和NK细胞的单克隆抗体进行治疗可以诱导暂时的外周混合嵌合体以及异种皮肤移植存活期的供体特异性延长。CP对抗原刺激后增殖的异种反应性T和B细胞的破坏，随后通过胸腺内克隆缺失以外的机制，可能是本系统中低反应性的机制。
