Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Transplantation. 2010 Nov 15;90(9):951-7. doi: 10.1097/TP.0b013e3181f54728.
Immunosuppression focused at or near the graft site would reduce the need for systemic immunosuppression thus educing fewer side effects. We investigated whether locally produced CTLA4Ig, mediated by adenovirus (Adv) transduction of mouse islets, would protect allografts and whether such immunosuppression would remain localized.
Adv-CTLA4Ig- or Adv-control-transduced islets were grafted under the kidney capsule of fully allogeneic diabetic mice. CTLA4Ig secreted from the grafted islets was detected by enzyme immunoassay of blood or immunohistochemistry of graft sections. Graft survival was monitored by blood glucose measurement. Histologic scores of graft sections stained with Gomori aldehyde fuchsin to detect insulin granules or hematoxylin-eosin to detect inflammation were used to compare grafts placed at different sites within the same mouse.
Adv-CTLA4Ig-transduced islet grafts secreted CTLA4Ig that was detected transiently in the circulation but persistently at the graft site. Survival of these grafts was significantly enhanced compared with control Adv-transduced and untransduced grafts. The kidney graft site availed elucidation of the site of action of CTLA4Ig. Histologic scores indicated that CTLA4Ig-producing grafts were protected by comparison with control grafts on the contralateral kidney. Hence, graft protection was not attributable to general systemic immunosuppression. Indeed, survival of CTLA4Ig-producing grafts was enhanced over control grafts placed at the opposite pole of the same kidney, indicating that graft protection was not solely due to inhibition of priming in the common draining lymph nodes.
Islet allografts are protected by locally produced CTLA4Ig-disrupting immune interactions at the effector site.
在移植物部位或其附近进行免疫抑制治疗，可以减少对全身免疫抑制的需求，从而减少副作用。我们研究了局部产生 CTLA4Ig （通过腺病毒转导小鼠胰岛实现）是否可以保护同种异体移植物，以及这种免疫抑制是否仍然局限于局部。
将 Adv-CTLA4Ig-或 Adv-对照转导的胰岛移植到完全同种异体糖尿病小鼠的肾包膜下。通过检测血液中的 CTLA4Ig 或移植组织切片的免疫组化，来检测从移植胰岛中分泌的 CTLA4Ig。通过监测血糖测量来监测移植物的存活情况。用 Gomori 醛固酮-复红检测胰岛素颗粒或苏木精-伊红检测炎症来对移植组织切片进行组织学评分，以比较同一小鼠体内不同部位的移植组织。
Adv-CTLA4Ig 转导的胰岛移植物分泌 CTLA4Ig，在循环中短暂检测到，但在移植物部位持续存在。与对照 Adv 转导和未转导的移植物相比，这些移植物的存活时间显著延长。肾脏移植物部位有助于阐明 CTLA4Ig 的作用部位。组织学评分表明，与对照移植物相比，产生 CTLA4Ig 的移植物受到保护。因此，移植物的保护不能归因于全身免疫抑制。事实上，与放置在同一肾脏相对侧的对照移植物相比，产生 CTLA4Ig 的移植物的存活时间延长，表明移植物的保护不仅是由于抑制共同引流淋巴结中的初始免疫反应。
局部产生 CTLA4Ig 可破坏效应部位的免疫相互作用，从而保护胰岛同种异体移植物。
