Hebert L A, Cosio F G, Birmingham D J, Mahan J D, Sharma H M, Smead W L, Goel R
Department of Internal Medicine, Ohio State University, Columbus.
Kidney Int. 1991 Jan;39(1):44-56. doi: 10.1038/ki.1991.6.
This study was undertaken to develop a model of immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate that could be used in subsequent studies to examine critically the role of the erythrocyte complement receptor (E-CR) in the pathogenesis of IC-mediated disease. Cynomolgus monkeys were chosen for study because they constitutively express E-CR levels that are either less than, equal to, or greater than that seen in normal man. After immunization with bovine gamma globulin (BGG), the GN induction protocol was begun in 10 cynomolgus by initiating daily i.v. administration of BGG in amounts sufficient to achieve or exceed antigen/antibody equivalence (assessed by the quantitative precipitin assay) for precipitating antibody present in the plasma volume. We found that within eight weeks of daily BGG administration of all the cynomolgus developed IC-mediated GN, irrespective of the initial E-CR level of the animals. However, the high E-CR cynomolgus tended to receive the higher BGG doses because of higher initial antibody levels to BGG. When the total number of glomerular deposits (determined by morphometric studies) per total BGG dose for each animal was plotted against the initial CR/E of that animal, there was a tendency for the animals with higher CR/E levels to have a lower number of glomerular deposits/BGG dose (r = 0.62, P = 0.06). Also, the total number of glomerular deposits correlated with the severity of the GN. During the early weeks of the GN induction protocol, the IC that formed in vivo (assessed by infusion of 125I-BGG) bound in large amounts to the circulating erythrocytes of the cynomolgus with medium or high E-CR levels. However, when tested after the onset of heavy proteinuria, which occurred between weeks 5 and 8 of daily BGG administration, the IC that formed in the circulation bound only poorly to circulating erythrocytes. By this time the E-CR levels had declined to 43 +/- 9% of initial values (P less than 0.01). This study demonstrates that: 1) A workable model of IC-mediated GN has been developed in the nonhuman primate. 2) During the induction of GN, CR/E and the ability of the erythrocyte to bind IC in vivo are decreased significantly. This suggests that an intact E-CR system could play a role in the protection against IC-mediated disease. However, further study will be needed to test that hypothesis critically. The present model should be useful in such studies.
本研究旨在建立一种非人类灵长类动物免疫复合物（IC）介导的肾小球肾炎（GN）模型，该模型可用于后续研究，以严格检验红细胞补体受体（E-CR）在IC介导疾病发病机制中的作用。选择食蟹猴进行研究，因为它们组成性表达的E-CR水平低于、等于或高于正常人。用牛γ球蛋白（BGG）免疫后，对10只食蟹猴开始实施GN诱导方案，通过每日静脉注射足够量的BGG来启动该方案，注射量足以达到或超过抗原/抗体等价（通过定量沉淀试验评估），以沉淀血浆中存在的抗体。我们发现，在每日注射BGG的八周内，所有食蟹猴均发生了IC介导的GN，无论动物最初的E-CR水平如何。然而，由于对BGG的初始抗体水平较高，高E-CR食蟹猴往往接受更高剂量的BGG。当将每只动物每总BGG剂量的肾小球沉积物总数（通过形态计量学研究确定）与该动物的初始CR/E作图时，CR/E水平较高的动物每BGG剂量的肾小球沉积物数量有降低的趋势（r = 0.62，P = 0.06）。此外，肾小球沉积物总数与GN的严重程度相关。在GN诱导方案的早期几周内，体内形成的IC（通过注入125I-BGG评估）大量结合到E-CR水平中等或较高的食蟹猴的循环红细胞上。然而，在每日注射BGG第5至8周出现大量蛋白尿后进行检测时，循环中形成的IC与循环红细胞的结合较差。此时，E-CR水平已降至初始值的43±9%（P < 0.01）。本研究表明：1）已在非人类灵长类动物中建立了一种可行的IC介导的GN模型。2）在GN诱导过程中，CR/E和红细胞在体内结合IC的能力显著降低。这表明完整的E-CR系统可能在预防IC介导的疾病中发挥作用。然而，需要进一步研究来严格检验该假设。目前的模型应有助于此类研究。
