Shoker A, Miller R, Uldall R, Friedman E, Angra S, Cardella C J
Department of Medicine, University of Toronto, Ontario, Canada.
J Am Soc Nephrol. 1995 Jan;5(7):1441-50. doi: 10.1681/ASN.V571441.
Some uremic patients with a history of blood transfusion, pregnancy, and previous transplantation maintain high levels of alloreactive cytotoxic antibodies in the absence of continuous exogenous allogenic stimuli and are thus considered sensitized to the major histocompatibility proteins. To differentiate into antibody-producing cells, B lymphocytes must interact with T-helper (CD4+) cells. Whether ongoing help from these cells is necessary for the B cells to continue producing cytotoxic alloreactive antibodies in these sensitized uremic patients is unknown. To gain insight into the cellular mechanisms that are associated with sustained alloantibody production, T cell activation markers were measured and specific and nonspecific T-helper cell function was studied in three uremic groups with different levels of panel reactive antibodies: 10 patients whose sera reacted to more than 80% of a panel of normal lymphocytes for at least 6 months before the study were highly sensitized, 20 patients whose sera reacted to less than 80% of the panel were moderately sensitized, and 10 nonsensitized patients whose sera did not react to any cell on the panel. The number of total and activated T-helper cells was similar in the highly sensitized and nonsensitized patients. Peripheral blood lymphocyte proliferation in response to plant lectins, soluble OKT3, or alloantigens was similar in the three uremic groups. The spontaneous proliferation of pure T-helper cells and proliferative responses to immobilized OKT3 or alloantigens were also similar in highly sensitized and nonsensitized patients. Alloreactive interleukin-2-producing cell frequencies with pure CD4+ cells as responding cells were 771 +/- 77.9/10(6) cells in highly sensitized, 945 +/- 252/10(6) cells in nonsensitized, and 973 +/- 114/10(6) cells in controls (P = not significant). Panel reactive antibody levels did not correlate with any of the measures of T helper responses. There was a significant decrease of peripheral blood lymphocyte responses to alloantigens and anti-CD3 antibody in all uremic patients as compared with normals, suggesting a dysfunction in accessory cells that was quantitatively similar in sensitized and nonsensitized patients. In spite of the continuous production of alloantibodies by B cells, there is no evidence of either specific or nonspecific enhancement of T-helper cell function in sensitized patients. The absence of T cell immunity to alloantigens suggests that sustained activation of T-helper cells with subsequent interleukin-2 production is not necessary to maintain alloreactive B cell function.
一些有输血、妊娠和既往移植史的尿毒症患者，在没有持续外源性同种异体刺激的情况下，仍维持高水平的同种异体反应性细胞毒性抗体，因此被认为对主要组织相容性蛋白致敏。B淋巴细胞要分化为抗体产生细胞，必须与辅助性T（CD4+）细胞相互作用。在这些致敏的尿毒症患者中，这些细胞持续提供的辅助对于B细胞继续产生细胞毒性同种异体反应性抗体是否必要尚不清楚。为深入了解与持续产生同种异体抗体相关的细胞机制，我们检测了三个具有不同水平群体反应性抗体的尿毒症组中的T细胞活化标志物，并研究了特异性和非特异性辅助性T细胞功能：10例患者在研究前至少6个月血清与一组正常淋巴细胞中超过80%发生反应，为高度致敏；20例患者血清与该组中不到80%的细胞发生反应，为中度致敏；10例非致敏患者血清与该组中的任何细胞均无反应。高度致敏患者和非致敏患者中总的和活化的辅助性T细胞数量相似。三个尿毒症组中，外周血淋巴细胞对植物凝集素、可溶性OKT3或同种异体抗原的增殖反应相似。高度致敏患者和非致敏患者中，纯辅助性T细胞的自发增殖以及对固定化OKT3或同种异体抗原的增殖反应也相似。以纯CD4+细胞作为反应细胞时，高度致敏患者中产生白细胞介素-2的同种异体反应性细胞频率为771±77.9/10⁶细胞，非致敏患者为945±252/10⁶细胞，对照组为973±114/10⁶细胞（P=无显著性差异）。群体反应性抗体水平与辅助性T细胞反应的任何指标均无相关性。与正常对照相比，所有尿毒症患者外周血淋巴细胞对同种异体抗原和抗CD3抗体的反应均显著降低，提示辅助细胞功能障碍，在致敏和非致敏患者中在数量上相似。尽管B细胞持续产生同种异体抗体，但没有证据表明致敏患者中辅助性T细胞功能有特异性或非特异性增强。对同种异体抗原缺乏T细胞免疫表明，辅助性T细胞的持续活化及随后白细胞介素-2的产生对于维持同种异体反应性B细胞功能并非必要。
