Schena Francesca, Gambini Claudio, Gregorio Andrea, Mosconi Manuela, Reverberi Daniele, Gattorno Marco, Casazza Simona, Uccelli Antonio, Moretta Lorenzo, Martini Alberto, Traggiai Elisabetta
IRCCS Institute G. Gaslini Hospital, Genoa Italy.
Arthritis Rheum. 2010 Sep;62(9):2776-86. doi: 10.1002/art.27560.
Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent cells characterized by immunomodulatory properties and are therefore considered a promising tool for the treatment of immune-mediated diseases. This study was undertaken to assess the influence of murine BM-MSCs on the activation of B cells in (NZB × NZW)F(1) mice as an animal model of systemic lupus erythematosus (SLE).
We evaluated the in vitro effects of BM-MSCs on the proliferation and differentiation to plasma cells of splenic mature B cell subsets, namely follicular and marginal zone B cells isolated from (NZB × NZW)F(1) mice. Lupus mice were also treated with BM-MSCs, and serum autoantibodies, proteinuria, histologic changes in the kidney, and survival rates were monitored.
BM-MSCs inhibited antigen-dependent proliferation and differentiation to plasma cells of follicular and marginal zone B cells in vitro. This inhibitory effect was dependent on interferon-γ (IFNγ) and was mediated by cell-to-cell contact, involving the programmed death 1 (PD-1)/PD ligand pathway. In vivo treatment with BM-MSCs did not affect the levels of anti-double-stranded DNA antibodies or proteinuria. However, a reduction in glomerular immune complex deposition, lymphocytic infiltration, and glomerular proliferation was observed.
Our findings indicate that BM-MSCs affect B cell receptor-dependent activation of both follicular and marginal zone B cells from lupus mice. This inhibitory effect is IFNγ-dependent and cell contact-dependent. MSCs in vivo do not affect the production of autoantibodies, the level of proteinuria, or the mortality rates. Nonetheless, the significant improvement in histologic findings in the kidney supports the potential role of MSCs in the prevention of glomerular damage.
骨髓间充质干细胞（BM-MSCs）是具有免疫调节特性的多能细胞，因此被认为是治疗免疫介导疾病的一种有前景的工具。本研究旨在评估小鼠BM-MSCs对作为系统性红斑狼疮（SLE）动物模型的（NZB×NZW）F1小鼠B细胞活化的影响。
我们评估了BM-MSCs对从（NZB×NZW）F1小鼠分离的脾成熟B细胞亚群，即滤泡性和边缘区B细胞增殖和分化为浆细胞的体外作用。还用BM-MSCs治疗狼疮小鼠，并监测血清自身抗体、蛋白尿、肾脏组织学变化和存活率。
BM-MSCs在体外抑制滤泡性和边缘区B细胞的抗原依赖性增殖和分化为浆细胞。这种抑制作用依赖于干扰素-γ（IFNγ），并通过细胞间接触介导，涉及程序性死亡1（PD-1）/PD配体途径。BM-MSCs的体内治疗不影响抗双链DNA抗体水平或蛋白尿。然而，观察到肾小球免疫复合物沉积、淋巴细胞浸润和肾小球增殖减少。
我们的研究结果表明，BM-MSCs影响狼疮小鼠滤泡性和边缘区B细胞的B细胞受体依赖性活化。这种抑制作用是IFNγ依赖性和细胞接触依赖性的。体内的间充质干细胞不影响自身抗体的产生、蛋白尿水平或死亡率。尽管如此，肾脏组织学结果的显著改善支持了间充质干细胞在预防肾小球损伤中的潜在作用。
