Antibody-mediated targeting of CD45 isoforms: A novel immunotherapeutic strategy
Antibody-mediated targeting of CD45 isoforms: A novel immunotherapeutic strategy
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DOI：
10.1073/pnas.95.7.3821
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发表时间：
1998-03-31
影响因子：
11.1
通讯作者：
Rothstein, DM
中科院分区：
文献类型：
--
作者：
Basadonna, GP;Auersvald, L;Rothstein, DM
CD45是一个跨膜蛋白酪氨酸磷酸酶家族，仅由造血细胞表达，并参与T细胞激活信号的调节。我们现在证明，三次100 μ g剂量的antid45rb mAb MB23G2可以诱导胰岛长期移植到主要组织相容性复合物-不同化学的糖尿病小鼠中，长期移植幸存者（bb0 120天）对来自原始供体株的新胰岛异体移植具有耐受性。MB23G2诱导循环白细胞数量暂时减少，但对其他淋巴细胞室的白细胞数量没有影响，对接受治疗和未接受治疗的同种异体移植物的组织学检查显示，在第6天，胰岛周围浸润相似，移植后11天，治疗动物的胰岛周围浸润持续存在，但与未接受治疗的对照动物相比，没有胰岛炎，胰岛完整性得以保留。治疗动物胰岛周围浸润显示CD4细胞轻度增加，CD8细胞减少，CD45RB表达强度降低。用抗CD45RB （MB23G2）治疗初始动物导致T细胞上CD45异构体表达发生变化，高分子量异构体缺失，低分子量（CD45R0）异构体表达增加。CD45亚型表达从CD45RBH（Hi）到CD45RB（Lo）的转变与白细胞介素（IL） 4和IL-10转录本的转染量增加有关，这与这种独特的免疫调节T细胞亚群的预期活性一致。抗体介导的靶向CD45可能通过新机制诱导耐受性，并直接适用于人类临床移植。
CD45 is a family of transmembrane protein tyrosine phosphatases exclusively expressed by hematopoietic cells and critically involved in the regulation of T cell activation signals, We now demonstrate that three 100-mu g doses of antiCD45RB mAb MB23G2 can induce long-term engraftment of islets into major histcompatibility complex-disparate chemically diabetic mice, Long-term graft survivors (>120 days) were tolerant to new islet allografts from the original donor strain, MB23G2 induced a temporary decrease in number circulating leukocytes but had no effect on leukocyte number in other lymphoid compartments, Histologic examination of allografts from treated and untreated recipients revealed a similar peri-islet infiltration on day 6, Eleven days after transplant, the peri islet infiltrate in treated animals persisted, but in marked contrast to untreated control animals, there was no insulitis and islet integrity was preserved, The peri-islet infiltrate from treated animals showed a mild increase in CD4 cells, a decrease in CD8 cells, and decreased intensity of CD45RB expression, Treatment of naive animals with anti-CD45RB (MB23G2) resulted in a shift in CD45 isoform expression on T cells with a loss of higher molecular weight isoforms and increased expression of lower molecular weight (CD45R0) isoform, This shift in CD45 isoform expression from CD45RBH(Hi) to CD45RB(Lo) was associated with an increase in the intragraft expression of transcripts for interleukin (IL) 4 and IL-10, consistent with the expected activity of this distinct immunoregulatory T cell subset, Antibody-mediated targeting of CD45 may induce tolerance through novel mechanisms and have direct applicability to clinical transplantation in humans.