Lu X, Schulz M, Zihlmann H R, Borel J F
Novartis Pharma, Inc., Transplantation Research, Basel, Switzerland.
Xenotransplantation. 1998 May;5(2):154-63. doi: 10.1111/j.1399-3089.1998.tb00021.x.
Xenogeneic grafts provide a potential alternative to the current shortage of human organs for transplantation. However, the prevention of rejection and tolerance induction of xenografts still remain to be further explored. Islet xenografts appear more promising than vascularized whole organ xenografts and additionally also more resistant to the recurrence of autoimmune disease than allografts. Recently, the nondepleting monoclonal antibody (mAb), which blocks the CD4 molecule on lymphocytes, was reported to be able to induce tolerance in allotransplantation and CD4 positive cells were further confirmed to be a major factor responsible for cellular xenograft rejection. Therefore, we hypothesize that anti-CD4 nondepleting mAb could also be effective in protecting cellular xenografts and inducing unresponsiveness of recipients. We studied the effect of the nondepleting anti-CD4 mAb YTS177.9 on islet xenograft survival by using the hamster-to-mouse islet transplantation model. Results were compared with that of the depleting anti-CD4 mAb GK1.5 that was shown to have similar binding sites on the CD4 molecule to mAb YTS177.9. Our data show that mAb YTS177.9 did effectively prolong the survival of islet xenografts and, in addition, also successfully did induce long-term acceptance of 40% grafts after only three perioperative injections of 0.5 mg mAb per mouse. The average survival of the graft was markedly prolonged to >66.8+/-37.1 days compared with controls (8.3+/-1.4 days) or with the depleting anti-CD4 mAb GK1.5 (25.7+/-5.5 days). However, the latter displayed a more profound inhibition in in vitro and ex vivo mixed lymphocyte xenoreaction than mAb YTS177.9. Moreover, the activity of this nondepleting mAb was found to be dose-dependent and 80% of grafts survived permanently when the dose was increased to six injections of 0.5 mg mAb. Like mAb GK1.5, mAb YTS177.9 also prevented rejection when given after a delay of two days posttransplant. In addition, we found that neither depleting nor nondepleting anti-CD8 mAb was effective in this model. Our results strongly suggest that an anti-CD4 nondepleting or blocking mAb alone is able to induce long-term acceptance of islet xenografts and that blocking the CD4 molecule is significantly superior to depleting CD4 positive cells for the protection of islet xenografts. This may indicate that CD4 cells play a major role in xenograft tolerance induction.
异种移植为当前移植用人体器官短缺提供了一种潜在的替代方案。然而，异种移植的排斥预防和耐受性诱导仍有待进一步探索。胰岛异种移植似乎比血管化的全器官异种移植更具前景，此外，与同种异体移植相比，其对自身免疫性疾病复发的抵抗力也更强。最近，有报道称，阻断淋巴细胞上CD4分子的非清除性单克隆抗体（mAb）能够在同种异体移植中诱导耐受性，并且进一步证实CD4阳性细胞是细胞异种移植排斥的主要因素。因此，我们假设抗CD4非清除性mAb在保护细胞异种移植和诱导受体无反应性方面也可能有效。我们使用仓鼠到小鼠的胰岛移植模型研究了非清除性抗CD4 mAb YTS177.9对胰岛异种移植存活的影响。将结果与清除性抗CD4 mAb GK1.5进行比较，后者在CD4分子上的结合位点与mAb YTS177.9相似。我们的数据表明，mAb YTS177.9确实有效地延长了胰岛异种移植的存活时间，此外，在每只小鼠仅进行三次围手术期注射0.5 mg mAb后，还成功诱导了40%的移植物长期存活。与对照组（8.3±1.4天）或清除性抗CD4 mAb GK1.5（25.7±5.5天）相比，移植物的平均存活时间显著延长至>66.8±37.1天。然而，后者在体外和离体混合淋巴细胞异种反应中的抑制作用比mAb YTS177.9更为显著。此外，发现这种非清除性mAb的活性呈剂量依赖性，当剂量增加到六次注射0.5 mg mAb时，80%的移植物永久存活。与mAb GK1.5一样，mAb YTS177.9在移植后延迟两天给药时也能预防排斥反应。此外，我们发现清除性和非清除性抗CD8 mAb在该模型中均无效。我们的结果强烈表明，单独使用抗CD4非清除性或阻断性mAb能够诱导胰岛异种移植的长期存活，并且对于保护胰岛异种移植而言，阻断CD4分子明显优于清除CD4阳性细胞。这可能表明CD4细胞在异种移植耐受性诱导中起主要作用。
