Wang Xiaojie, Hao Jianqiang, Metzger Daniel L, Mui Alice, Ao Ziliang, Verchere C Bruce, Chen Lieping, Ou Dawei, Warnock Garth L
Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
Transplantation. 2009 Feb 27;87(4):482-90. doi: 10.1097/TP.0b013e318195e5fa.
Allogeneic pancreatic islet transplantation has the potential to cure type 1 diabetes. One of the barriers to islet transplantation is the alloreactive T-cell response between donors and recipients. Costimulatory molecules, which play a major role in the regulation of the immune response to antigens during graft rejection, may be used to inhibit allograft destruction. B7-H4 is one such member in the costimulatory family, which has established negative regulatory function of T-cell responses.
To determine whether local expression of B7-H4 protein can protect beta cells from damage in islet allotransplantation, we have constructed a recombinant adenovirus expressing a B7-H4 complementary deoxyribonucleic acid (Ad-B7-H4). To study the in vivo effects of B7-H4 expression on islet graft survival, adenovirus-transduced islets from donor Balb/c mice were transplanted into streptozotocin-diabetic C57BL/6 mice (n=12).
Expression of B7-H4 in islets by Ad-B7-H4 transduction at an optimized condition did not inhibit glucose-stimulated insulin secretion of the treated islets. The recipient mice transplanted with Ad-B7-H4-transduced islets established euglycemia for a longer time (mean 56.5 days), compared with control mice transplanted with Ad-LacZ-transduced islets (mean 14.5 days, [n=12, P<0.001]). Splenocytes isolated from the recipients of Ad-B7-H4-transduced islets showed hyporesponsiveness to alloantigenic stimulation, compared with control recipients. CD45 and insulin staining of the graft transplanted with Ad-B7-H4-transduced islets indicated the preservation of beta cells and decrease of infiltrating immune cells.
Local expression of B7-H4 prolongs islet allograft survival in vivo, suggesting translational potential for beta-cell replacement with reduced immune injury.
同种异体胰岛移植有可能治愈1型糖尿病。胰岛移植的障碍之一是供体和受体之间的同种异体反应性T细胞反应。共刺激分子在移植排斥反应中对抗抗原的免疫反应调节中起主要作用，可用于抑制同种异体移植的破坏。B7-H4是共刺激家族中的一员，已证实其对T细胞反应具有负调节功能。
为了确定B7-H4蛋白的局部表达是否能在胰岛同种异体移植中保护β细胞免受损伤，我们构建了一种表达B7-H4互补脱氧核糖核酸的重组腺病毒（Ad-B7-H4）。为了研究B7-H4表达对胰岛移植存活的体内影响，将来自供体Balb/c小鼠的腺病毒转导胰岛移植到链脲佐菌素诱导的糖尿病C57BL/6小鼠（n=12）体内。
在优化条件下通过Ad-B7-H4转导使胰岛表达B7-H4，并未抑制处理后胰岛的葡萄糖刺激胰岛素分泌。与移植Ad-LacZ转导胰岛的对照小鼠（平均14.5天，[n=12，P<0.001]）相比，移植Ad-B7-H4转导胰岛的受体小鼠维持正常血糖的时间更长（平均56.5天）。与对照受体相比，从移植Ad-B7-H4转导胰岛的受体中分离的脾细胞对同种异体抗原刺激反应低下。对移植Ad-B7-H4转导胰岛的移植物进行CD45和胰岛素染色显示β细胞得以保留，浸润的免疫细胞减少。
B7-H4的局部表达可延长体内胰岛同种异体移植的存活时间，提示其在减少免疫损伤的β细胞替代治疗方面具有转化应用潜力。
