Kakkis E, Lester T, Yang R, Tanaka C, Anand V, Lemontt J, Peinovich M, Passage M
Division of Medical Genetics, Department of Pediatrics, Harbor-University of California at Los Angeles Research and Education Institute, Torrance, CA 90502, USA.
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):829-34. doi: 10.1073/pnas.0305480101. Epub 2004 Jan 8.
Immune responses can interfere with the effective use of therapeutic proteins to treat genetic deficiencies and have been challenging to manage. To address this problem, we adapted and studied methods of immune tolerance used in canine organ transplantation research to soluble protein therapeutics. A tolerization regimen was developed that prevents a strong antibody response to the enzyme alpha-l-iduronidase during enzyme replacement therapy of a canine model of the lysosomal storage disorder mucopolysaccharidosis I. The tolerizing regimen consists of a limited 60-day course of cyclosporin A and azathioprine combined with weekly i.v. infusions of low-dose recombinant human alpha-l-iduronidase. The canines tolerized with this regimen maintain a reduced immune response for up to 6 months despite weekly therapeutic doses of enzyme in the absence of immunosuppressive drugs. Successful tolerization depended on high plasma levels of cyclosporin A combined with azathioprine. In addition, the induction of tolerance may require mannose 6-phosphate receptor-mediated uptake because alpha-l-iduronidase and alpha-glucosidase induced tolerance with the drug regimen whereas ovalbumin and dephosphorylated alpha-l-iduronidase did not. This tolerization method should be applicable to the treatment of other lysosomal storage disorders and provides a strategy to consider for other nontoleragenic therapeutic proteins and autoimmune diseases.
免疫反应会干扰治疗性蛋白质用于治疗基因缺陷的有效性，并且一直难以控制。为了解决这个问题，我们将犬类器官移植研究中使用的免疫耐受方法应用于可溶性蛋白质治疗药物并进行了研究。我们制定了一种耐受方案，在溶酶体贮积症I型的犬类模型进行酶替代治疗期间，可防止对α-L-艾杜糖醛酸酶产生强烈的抗体反应。该耐受方案包括为期60天的环孢素A和硫唑嘌呤有限疗程，并结合每周一次静脉注射低剂量重组人α-L-艾杜糖醛酸酶。尽管在没有免疫抑制药物的情况下每周给予治疗剂量的酶，但用该方案耐受的犬类在长达6个月的时间内免疫反应都有所降低。成功的耐受取决于环孢素A与硫唑嘌呤的高血浆水平。此外，耐受的诱导可能需要甘露糖6-磷酸受体介导的摄取，因为α-L-艾杜糖醛酸酶和α-葡萄糖苷酶通过药物方案诱导了耐受，而卵清蛋白和去磷酸化的α-L-艾杜糖醛酸酶则没有。这种耐受方法应该适用于其他溶酶体贮积症的治疗，并为其他非致耐受性治疗性蛋白质和自身免疫性疾病提供了一种可考虑的策略。
