Londrigan Sarah L, Sutherland Robyn M, Brady Jamie L, Zhan Yifan, Li Ruili, Estella Eugene, Kay Thomas W H, Lew Andrew M
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
J Gene Med. 2006 Jan;8(1):42-52. doi: 10.1002/jgm.818.
Currently, successful transplantation of allografts requires the systemic use of immunosuppressive drugs. These can cause serious morbidity due to toxicity and increased susceptibility to cancer and infections. Local production of immunosuppressive molecules limited to the graft site would reduce the need for conventional, generalized immunosuppressive therapies and thus educe fewer side effects. This is particularly salient in a disease like type 1 diabetes, which is not immediately life-threatening yet islet allografts can effect a cure.
We studied the efficacy of locally produced anti-CD4 antibody, mediated by adenovirus (Adv-anti-CD4) transduction of islets, to enhance allograft survival. Adenovirus-transduced islets were transplanted under the kidney capsule of diabetic recipients and graft rejection determined by monitoring blood glucose levels.
Adv-anti-CD4 transduction of mouse islets afforded protection against allogeneic rejection after transplantation into fully mismatched recipients. In some recipients, the islet allograft survival was prolonged (persisting for at least 15 weeks), corresponding to the prolonged expression of the anti-CD4 antibody. The effect was local, as absence of CD4+ T lymphocytes was observed primarily at the graft site.
Immunosuppressive effects can be restricted locally by our strategy. Local production of a single antibody against one subset of T lymphocytes can protect mouse islets from allograft rejection during transplantation to treat diabetes. Our findings foreshadow that this strategy may be even more effective when a combination of antibodies are used and that similar strategies may prevent xenograft rejection.
目前，同种异体移植物的成功移植需要全身使用免疫抑制药物。这些药物可能因毒性以及癌症和感染易感性增加而导致严重的发病率。局限于移植部位的免疫抑制分子的局部产生将减少对传统的全身性免疫抑制疗法的需求，从而减少副作用。这在1型糖尿病等疾病中尤为突出，1型糖尿病不会立即危及生命，但胰岛同种异体移植可以实现治愈。
我们研究了由腺病毒（Adv-抗CD4）转导胰岛介导的局部产生的抗CD4抗体增强移植物存活的功效。将腺病毒转导的胰岛移植到糖尿病受体的肾包膜下，并通过监测血糖水平来确定移植物排斥反应。
小鼠胰岛的Adv-抗CD4转导在移植到完全不匹配的受体后提供了针对同种异体排斥的保护。在一些受体中，胰岛同种异体移植物存活时间延长（持续至少15周），这与抗CD4抗体的延长表达相对应。这种作用是局部的，因为主要在移植部位观察到CD4 + T淋巴细胞的缺失。
我们的策略可以将免疫抑制作用局限于局部。针对T淋巴细胞一个亚群的单一抗体的局部产生可以在移植治疗糖尿病期间保护小鼠胰岛免受同种异体排斥。我们的研究结果预示，当使用抗体组合时，这种策略可能会更有效，并且类似的策略可能会预防异种移植排斥。
