Anti-CD3 antibody induced immune tolerance to infused enzyme in enzyme replacement therapy for lysosomal storage disease

庞贝氏症的酶替代疗法的动物和人体研究表明，针对输注的重组人α-葡萄糖苷酶产生的抗体（Ab）可能对治疗结果产生负面影响，并引起超敏反应。我们发现，抗CD 3 Ab经肠给药可降低给予酶的野生型小鼠中抗人α-葡萄糖苷酶Ab的滴度。用抗CD 3 Ab处理然后用α-葡萄糖苷酶进行二次激发的小鼠显示Ab滴度的增加低于对照小鼠。此外，抗CD 3抗体的施用还降低了预先存在的抗体的水平。抗CD 3抗体治疗还可预防致死性超敏反应，并降低庞贝氏症小鼠模型中的抗体滴度。用抗CD 3抗体处理的小鼠显示出CD 4 ^+和CD 8 ^+细胞数量减少，CD 4 ^+ CD 25 ^+/CD 4 ^+和CD 4 ^+ CD 25 ^+ FoxP 3 ^+/CD 4 ^+细胞比例增加。当使用抗CD 25抗体去除CD 4 ^+ CD 25 ^+细胞时，观察到的抗CD 3抗体对酶的抗体减少被消除。这表明CD 4 ^+ CD 25 ^+细胞对于抗CD 3 Ab的免疫抑制活性很重要。总之，抗CD 3抗体可用于诱导对庞贝氏症的酶替代疗法的免疫耐受。

Animal and human studies of enzyme replacement therapy for Pompe disease have indicated that antibodies(Abs) generated against infused recombinant humanα-glucosidase can have a negative impact on the therapeutic outcome and cause hypersensitivity reactions. We showed that parenteral administration of anti-CD3 Abs into mice can reduce the titer of anti-humanα-glucosidase Abs in wild-type mice administered the enzyme. Mice that had been treated with anti-CD3 Abs and then subjected to a secondary challenge withα-glucosidase showed a lower increase in Ab titers than control mice. Moreover, the administration of anti-CD3 Abs also reduced the levels of pre-existing Abs. Treatment with anti-CD3 Abs also prevented a lethal hypersensitivity reaction and reduced the Ab titers in a mouse model of Pompe disease. Mice treated with anti-CD3 Abs showed reduced numbers of CD4^+and CD8^+cells, and an increased ratio of CD4^+CD25^+/CD4^+and CD4^+CD25^+FoxP3^+/CD4^+cells. When the CD4^+CD25^+cells were depleted using anti-CD25 Abs, the observed reduction in Abs against the enzyme by anti-CD3 Abs was abrogated. This suggests that CD4^+CD25^+cells are important for the immune suppressive activity of anti-CD3 Abs. In summary, anti-CD3 Abs are useful for inducing immune tolerance to enzyme replacement therapy for Pompe disease.