Lin J, Qin L, Chavin K D, Ding Y, Punch J D, Yang Q, Burkly L C, Bromberg J S
Department of Surgery, University of Michigan, Ann Arbor 48109-0331, USA.
Pathobiology. 1995;63(3):119-32. doi: 10.1159/000163943.
The combination of anti-CD2 plus anti-CD3 monoclonal antibodies (mAbs) synergistically prolongs allograft survival and induces antigen-specific tolerance. Since altered expression of cell surface molecules might be important for tolerance induction, the effect of anti-CD2 and anti-CD3 mAbs on the expression of adhesion molecules was analyzed on splenic T cells with an in vitro model. The anti-CD2 mAb, 12-15, alone had no effect on the expression of integrin alpha 4-chain epitopes recognized by two anti-CD49d (VLA-4 alpha) mAbs, R1-2 and PS/2. The anti-CD3 mAb, 2C11, caused R1-2 epitope expression to decrease, while PS/2 epitope expression remained unchanged. The combination of anti-CD2 and anti-CD3 mAbs further decreased R1-2 epitope expression while preserving PS/2 epitope expression. The expression of integrin beta 1 and beta 7 chains, each of which form heterodimers with alpha 4 chains, also remained unchanged. Expression of other integrin, selectin, or immunoglobulin superfamily molecules (CD11a, CD18, CD44, CD45, CD48, CD54 and CD62L) were all significantly increased by anti-CD2 or anti-CD3 mAbs. Decreased R1-2 epitope expression was anti-CD3 dependent and specifically augmented by anti-CD2 mAb. CD2-regulated decreases in R1-2 epitope expression correlated with increased cAMP and could be prevented by addition of high doses of IL-2 but was not affected by the addition of other cytokines. R1-2 alpha 4 epitope expression could be specifically restored by the divalent cation Mn2+, which also increased functional binding to the VCAM-1 ligand. Significantly, the R1-2 but not the PS/2 mAb prolonged graft survival in a cardiac allograft model. These results show that anti-CD2 and anti-CD3 mAbs selectively decrease integrin alpha 4 chain epitope expression on T cells through conformational regulation. Decreased expression of a CD49d epitope is unique in comparison to the up-modulation of other T-cell adhesion receptors. These changes correlate with functional effects and provide an additional mechanistic explanation for the synergistic effect of anti-CD2 plus anti-CD3 in producing tolerance.
抗CD2与抗CD3单克隆抗体（mAb）联合使用可协同延长同种异体移植物的存活时间并诱导抗原特异性耐受。由于细胞表面分子表达的改变可能对耐受诱导很重要，因此利用体外模型分析了抗CD2和抗CD3单克隆抗体对脾T细胞上黏附分子表达的影响。单独使用抗CD2单克隆抗体12 - 15对两种抗CD49d（VLA - 4α）单克隆抗体R1 - 2和PS/2识别的整合素α4链表位的表达没有影响。抗CD3单克隆抗体2C11使R1 - 2表位表达降低，而PS/2表位表达保持不变。抗CD2和抗CD3单克隆抗体联合使用进一步降低了R1 - 2表位表达，同时保持PS/2表位表达。整合素β1和β7链（它们分别与α4链形成异二聚体）的表达也保持不变。抗CD2或抗CD3单克隆抗体均显著增加了其他整合素、选择素或免疫球蛋白超家族分子（CD11a、CD18、CD44、CD45、CD48、CD54和CD62L）的表达。R1 - 2表位表达的降低依赖于抗CD3，且被抗CD2单克隆抗体特异性增强。CD2调节的R1 - 2表位表达降低与cAMP增加相关，并且可以通过添加高剂量的IL - 2来预防，但不受添加其他细胞因子的影响。二价阳离子Mn2 +可以特异性恢复R1 - 2α4表位表达，Mn2 +还增加了与VCAM - 1配体的功能性结合。值得注意的是，在心脏同种异体移植模型中，R1 - 2单克隆抗体而非PS/2单克隆抗体延长了移植物存活时间。这些结果表明，抗CD2和抗CD3单克隆抗体通过构象调节选择性降低T细胞上整合素α4链表位的表达。与其他T细胞黏附受体的上调相比，CD49d表位表达的降低是独特的。这些变化与功能效应相关，并为抗CD2加抗CD3产生耐受的协同效应提供了额外的机制解释。
