Ardjomand Navid, McAlister James C, Rogers Nicola J, Tan Peng H, George Andrew J T, Larkin Daniel F P
Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom.
Invest Ophthalmol Vis Sci. 2003 Sep;44(9):3899-905. doi: 10.1167/iovs.03-0084.
To examine the effect of modulating the lymphocyte costimulation pathways through CD28 and CD154 (CD40 ligand) in a model of corneal allograft rejection, with particular interest in changes in the observed features of rejection.
CD28 knock-out (CD28KO) and wild-type BALB/c control mice received corneal grafts from fully major histocompatibility complex (MHC)-mismatched C3H donors and were treated with CTLA4-Ig and/or anti-CD154 Ab on days 0, 2, and 4 after transplantation. Proliferation of BALB/c and CD28KO T cells in response to C3H stimulators was examined in a mixed lymphocyte reaction (MLR) in the presence of CTLA4-Ig or anti-CD154 Ab.
Corneal allograft survival in wild-type BALB/c mice (median survival time [MST] 14 days) was significantly prolonged by blockade of the costimulatory pathways with CTLA4-Ig or anti-CD154 Ab (MST 21 days and 25 days respectively). MST in recipients treated with CTLA4-Ig and anti-CD154 Ab in combination was 29 days, not significantly longer than graft survival in single-treatment groups. MST in CD28KO recipients was 46 days and was not prolonged after treatment with anti-CD154 Ab (MST, 43 days). A similar result was found in the MLR, in which anti-CD154 Ab had no effect on proliferation of CD28KO compared with wild-type T cells. In CTLA4-Ig-treated CD28KO, grafts were rejected at an accelerated tempo, similar to that in wild-type BALB/c recipients (MST 16 days). More severe graft injury after the onset of rejection in untreated allograft recipients was accompanied by a higher number of graft-infiltrating CD45(+) cells, but similar proportions of CD4(+) and CD8(+) cells.
CD28- and CD154-mediated costimulation have significant functional roles in corneal allograft rejection. Agents that modulate CD28 and CD154 pathways delay onset and reduce the severity of observed allograft rejection. However, their use in combination did not have an additive effect, MLR data indicating that the CD40-CD154 system depends on a functioning CD28 costimulatory pathway.
通过CD28和CD154（CD40配体）调节淋巴细胞共刺激途径，研究其在角膜移植排斥反应模型中的作用，尤其关注排斥反应观察特征的变化。
CD28基因敲除（CD28KO）小鼠和野生型BALB/c对照小鼠接受来自完全主要组织相容性复合体（MHC）不匹配的C3H供体的角膜移植，并在移植后第0、2和4天用CTLA4-Ig和/或抗CD154抗体进行治疗。在存在CTLA4-Ig或抗CD154抗体的混合淋巴细胞反应（MLR）中，检测BALB/c和CD28KO T细胞对C3H刺激物的增殖反应。
用CTLA4-Ig或抗CD154抗体阻断共刺激途径可显著延长野生型BALB/c小鼠角膜移植的存活时间（中位存活时间[MST]14天）（分别为MST 21天和25天）。联合使用CTLA4-Ig和抗CD154抗体治疗的受体的MST为29天，不比单治疗组的移植物存活时间显著延长。CD28KO受体的MST为46天，用抗CD154抗体治疗后未延长（MST，43天）。在MLR中也发现了类似的结果，其中与野生型T细胞相比，抗CD154抗体对CD28KO的增殖没有影响。在CTLA4-Ig治疗的CD28KO中，移植物以加速的速度被排斥，类似于野生型BALB/c受体（MST 16天）。未治疗的同种异体移植受体排斥反应开始后更严重的移植物损伤伴随着更多的移植物浸润CD45(+)细胞，但CD4(+)和CD8(+)细胞的比例相似。
CD28和CD154介导的共刺激在角膜移植排斥反应中具有重要的功能作用。调节CD28和CD154途径的药物可延迟同种异体移植排斥反应的发生并降低其严重程度。然而，它们联合使用没有相加作用，MLR数据表明CD40-CD154系统依赖于正常运作的CD28共刺激途径。
