Division of Clinical Immunology and Internal Medicine, University of Genoa Medical School, Genoa, Italy.
Transfusion. 2010 Mar;50(3):547-55. doi: 10.1111/j.1537-2995.2009.02479.x. Epub 2009 Nov 9.
Numerous mechanisms have been proposed to explain the beneficial action of intravenous immune globulin (IVIG) in autoimmune and systemic inflammatory disorders. Among others' data, an in vitro increase of intracellular TGF-beta expression when culturing CD4+ T lymphocytes in the presence of IVIG has been reported. As IVIG infusion involves administration of soluble contaminants likewise all hemoderivative preparations, we hypothesized that, besides several other immunomodulatory proposed mechanisms, the clinical effects of IVIG therapy might be, at least partly, due to contaminating soluble HLA Class I (sHLA-I) molecules capable to exert pleiotropic immunomodulatory effects among which TGF-beta(1) modulation.
Ex vivo and in vitro transcriptional and posttranscriptional modulation of TGF-beta(1) in CD8+ T lymphocytes and neutrophils after IVIG infusion was analyzed.
Ex vivo analysis of cells drawn from 10 enrolled IVIG recipients pointed out a significant increase of TGF-beta(1) mRNA and intracellular TGF-beta(1) molecules in both leukotypes. In vitro comparable results were obtained incubating CD8+ T lymphocytes and neutrophils from healthy donors with IVIG. The immunodepletion of sHLA-I and/or soluble Fas ligand (sFasL) abolished TGF-beta(1) modulation in both leukotypes. Coculture with human immunoglobulin (Ig)M monoclonal antibody or chimeric IgG (MabThera, Roche), whose manufacturing excludes "contamination," did not exert any mRNA modulation. Finally, IgM or MabThera plus purified sHLA-I molecules enhanced TGF-beta(1) mRNA in both white blood cells to levels comparable to those obtained with IVIG incubation.
On the whole, these data lead us to speculate that the ability of IVIG administration to modulate TGF-beta(1) might be related to the immunomodulatory activities of sHLA-I and sFasL molecules on activated CD8+ T lymphocytes and neutrophils.
许多机制被提出以解释静脉注射免疫球蛋白（IVIG）在自身免疫和系统性炎症性疾病中的有益作用。在其他数据中，当在 IVIG 存在下培养 CD4+T 淋巴细胞时，已报道细胞内 TGF-β表达的体外增加。由于 IVIG 输注涉及到同样所有血液衍生制剂的可溶性污染物的给药，我们假设，除了其他几种免疫调节提出的机制外，IVIG 治疗的临床效果可能至少部分是由于能够发挥 TGF-β（1）调节等多种免疫调节作用的污染可溶性 HLA 类 I（sHLA-I）分子。
分析 IVIG 输注后 CD8+T 淋巴细胞和中性粒细胞中 TGF-β（1）的体外和转录后转录调节。
对来自 10 名接受 IVIG 治疗的患者的细胞进行的体外分析表明，两种白细胞类型中 TGF-β（1）mRNA 和细胞内 TGF-β（1）分子均显著增加。在孵育来自健康供体的 CD8+T 淋巴细胞和中性粒细胞的体外实验中获得了类似的结果。用 IVIG 免疫耗竭 sHLA-I 和/或可溶性 Fas 配体（sFasL）可消除两种白细胞类型中 TGF-β（1）的调节。与人类免疫球蛋白（Ig）M 单克隆抗体或嵌合 IgG（MabThera，罗氏）共培养，其制造不“污染”，不会引起任何 mRNA 调节。最后，IgM 或 MabThera 加纯化的 sHLA-I 分子增强了两种白细胞中的 TGF-β（1）mRNA，使其达到与 IVIG 孵育相同的水平。
总的来说，这些数据使我们推测 IVIG 给药调节 TGF-β（1）的能力可能与 sHLA-I 和 sFasL 分子对激活的 CD8+T 淋巴细胞和中性粒细胞的免疫调节活性有关。
