Tankersley D L
Center for Biologics Evaluation and Research, Division of Hematology, Rockville, MD 20852-1448.
Immunol Rev. 1994 Jun;139:159-72. doi: 10.1111/j.1600-065x.1994.tb00861.x.
IgG dimers occurring in therapeutic Ig preparations have been characterized as Id-anti-Id, in that the sites of interaction are localized to the distal tips of the Fab arms. The observation that such dimers are prevalent in Ig or Igi.v. prepared from large plasma pools, but absent in preparations from a single individual, supports the notion that the individual immune repertoire is small with respect to the species repertoire. A crude mathematical model that attempts to relate Id-dimer content to the number of donors is presented. This model suggests that Id-pairs may be much more prevalent in Ig than is reflected by the Id-dimer content, inasmuch as the concentrations of the individual Ids and anti-Ids may limit the equilibrium level of dimer. The model further suggests that the antibody diversity in Ig derived from thousands of donors may be representative of the species repertoire; hence, virtually all specificities, including anti-Id specificities, will be included. Because Ig is derived from normal healthy donors, it should be relatively free of pathogenic autoantibodies. However, there is no reason to suspect that anti-Ids to such autoantibodies would not occur, and indeed the presence of such anti-Ids has been demonstrated. Several mechanisms have been proposed by which such anti-Ids might ameliorate autoimmune disease. They may directly inhibit the binding of autoantibody to its target antigen, or they may target for destruction those cells expressing or secreting autoantibody. It may well be that anti-Ids play no role in the mechanism of action of Igi.v. in autoimmune disease. Such appears to have been demonstrated, for example, in the treatment of ITP. There is an obvious need for additional studies in order to elucidate the mechanism of action of Igi.v. in various autoimmune diseases. Experimental animal models of autoimmune disease, such as the mouse model for systemic lupus erythematosus (Mozes et al. 1993), might be very useful in this regard. Finally, it needs to be emphasized that the usefulness of high doses of Igi.v. in many autoimmune diseases remains to be established by controlled clinical trials. Because Igi.v. is a limited resource, and one which cannot be produced through biotechnological advances (at least in the foreseeable future), its widespread use should be restricted to the treatment of diseases for which efficacy has been demonstrated. To do otherwise might deprive appropriate patients of a valuable therapy.
治疗性免疫球蛋白制剂中出现的IgG二聚体已被表征为独特型-抗独特型，因为相互作用位点定位于Fab臂的远端。观察到这种二聚体在从大量血浆池中制备的免疫球蛋白或静脉注射免疫球蛋白中普遍存在，但在从单个个体制备的制剂中不存在，这支持了个体免疫库相对于物种免疫库较小的观点。提出了一个试图将独特型二聚体含量与供体数量相关联的粗略数学模型。该模型表明，独特型对在免疫球蛋白中的普遍程度可能比独特型二聚体含量所反映的要高得多，因为各个独特型和抗独特型的浓度可能会限制二聚体的平衡水平。该模型进一步表明，源自数千名供体的免疫球蛋白中的抗体多样性可能代表物种免疫库；因此，几乎所有特异性，包括抗独特型特异性，都将被包括在内。由于免疫球蛋白源自正常健康供体，它应该相对不含致病性自身抗体。然而，没有理由怀疑不会出现针对此类自身抗体的抗独特型，事实上已经证明了此类抗独特型的存在。已经提出了几种机制，通过这些机制此类抗独特型可能改善自身免疫性疾病。它们可能直接抑制自身抗体与其靶抗原的结合，或者它们可能靶向破坏那些表达或分泌自身抗体的细胞。很可能抗独特型在静脉注射免疫球蛋白治疗自身免疫性疾病的作用机制中不起作用。例如，在特发性血小板减少性紫癜的治疗中似乎已经证明了这一点。显然需要进行更多研究以阐明静脉注射免疫球蛋白在各种自身免疫性疾病中的作用机制。自身免疫性疾病的实验动物模型，如系统性红斑狼疮的小鼠模型（莫泽斯等人，1993年），在这方面可能非常有用。最后，需要强调的是，高剂量静脉注射免疫球蛋白在许多自身免疫性疾病中的有效性仍有待通过对照临床试验来确定。由于静脉注射免疫球蛋白是一种有限的资源，而且至少在可预见的未来无法通过生物技术进步生产，其广泛使用应限于已证明疗效的疾病治疗。否则可能会剥夺合适患者获得有价值治疗的机会。
