Kumagai-Braesch Makiko, Ekberg Henrik, Wang Feng, Osterholm Cecilia, Ehrnfelt Cecilia, Sharma Amit, Lindeborg Ellinor, Holgersson Jan, Corbascio Matthias
Department of Transplantation Surgery, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Transplantation. 2007 May 15;83(9):1259-67. doi: 10.1097/01.tp.0000261722.02697.75.
It has been previously demonstrated that addition of anti-LFA-1 to a combination of CTLA4Ig and anti-CD40L induces the permanent acceptance of dopaminergic fetal pig xenografts when transplanted into the brain of wild-type mice. The purpose of this study was to test whether this costimulation blockade also can induce acceptance of adult pig islets transplanted to C57BL/6 mice with streptozotocin-induced diabetes.
Recipients were treated with CTLA4Ig/anti-CD40L+/-anti-LFA-1 or isotype control antibodies during the first week after transplantation. Half of the costimulation blockade-treated recipients had their grafts removed after 8 weeks. The other half was observed up to 5 months.
Recipients treated with CTLA4Ig/anti-CD40L/anti-LFA-1 had significantly lower blood glucose and gained more weight than CTLA4Ig/anti-CD40L-treated recipients. CTLA4Ig/anti-CD40L-treated recipients exhibited unstable blood glucose. IPGTT of these recipients revealed a slow recovery to normal blood glucose levels at week 4. In comparison, CTLA4Ig/anti-CD40L/anti-LFA-1 treated recipients exhibited a significantly superior glucose clearance. CTLA4Ig/anti-CD40L+/-anti-LFA-1 treated recipients did not produce anti-pig IgG, whereas control antibody-treated mice did. CD4+ T cells from costimulation blockade-treated recipients proliferated less than CD4+ T cells from control antibody-treated mice when co-cultured with syngeneic antigen presenting cells loaded with pig islet antigens.
CTLA4Ig/anti-CD40L/anti-LFA-1-treated recipients had superior islet function compared with CTLA4Ig/anti-CD40L-treated recipients. However, both costimulation blockade regimens led to islet graft acceptance up to 5 months after a 1-week treatment.
先前已有研究表明，在CTLA4Ig和抗CD40L的组合中添加抗LFA-1，可使多巴胺能胎猪异种移植物在移植到野生型小鼠脑内时被永久接受。本研究的目的是测试这种共刺激阻断是否也能诱导成年猪胰岛移植到链脲佐菌素诱导糖尿病的C57BL/6小鼠体内后被接受。
在移植后的第一周，用CTLA4Ig/抗CD40L+/-抗LFA-1或同型对照抗体治疗受体。一半接受共刺激阻断治疗的受体在8周后移除移植物。另一半观察长达5个月。
与接受CTLA4Ig/抗CD40L治疗的受体相比，接受CTLA4Ig/抗CD40L/抗LFA-1治疗的受体血糖显著降低且体重增加更多。接受CTLA4Ig/抗CD40L治疗的受体血糖不稳定。这些受体的腹腔内葡萄糖耐量试验显示在第4周时血糖缓慢恢复至正常水平。相比之下，接受CTLA4Ig/抗CD40L/抗LFA-1治疗的受体葡萄糖清除能力明显更强。接受CTLA4Ig/抗CD40L+/-抗LFA-1治疗的受体不产生抗猪IgG，而接受对照抗体治疗的小鼠则产生。与负载猪胰岛抗原的同基因抗原呈递细胞共培养时，接受共刺激阻断治疗的受体的CD4+T细胞增殖少于接受对照抗体治疗的小鼠的CD4+T细胞。
与接受CTLA4Ig/抗CD40L治疗的受体相比，接受CTLA4Ig/抗CD40L/抗LFA-1治疗的受体胰岛功能更优。然而，两种共刺激阻断方案在1周治疗后均导致胰岛移植物在长达5个月的时间内被接受。
