A mAb to SIRPα downregulates the priming of naive CD4 + T cell in Primary immune thrombocytopenia

IF 3.7 4区 医学 Q2 CELL BIOLOGY Cellular immunology Pub Date : 2023-09-01 DOI:10.1016/j.cellimm.2023.104757
Dongmei Xie, Zhihui Feng, Wen Yang, Yacan Wang, Renxia Li, Shiqi Zhang, Zeping Zhou
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Abstract

SIRPα is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on monocytes, dendritic cells, and macrophages. Studies recently showed that SIRPα is essential for priming of CD4 + T cells by DCs and for development of Th17 cell-mediated autoimmune diseases. We have now further evaluated the importance of SIRPα and that of its ligand CD47 in primary immune thrombocytopenia (ITP). In this study, we show that there was a low expression state of SIRPα on the surface of monocytes. Treatment of cells culture from ITP patients with a mAb to SIRPα that blocks the binding of SIRPα to CD47 downregulated the ITP response. The abilities of monocytes from ITP patients to stimulate an allogenic MLR were reduced. The proliferation of, and production of IL-2, by CD4 + T cells from ITP patients were inhibited, the Treg cell numbers and the production of IL-10 pairs were upregulated, and the production of TGF-β not was inhibited, by a mAb to SIRPα. Moreover, a mAb to SIRPα, the expression of HLA-DR and CD86 were markedly inhibited and the expression of CD80 was slightly upregulated, on the surface of CD14 + monocytes from ITP patients as compared with healthy subjects. However, blockade of SIRPα increased the secretion of TLR-dependent cytokines TNF-α, IL-6 and IL-1β by PBMCs, which may be considered as a reserve in response to danger signals. These results suggest that SIRPα on monocytes is essential for the priming of naive T cells and the development of ITP. Therefore, SIRPα is a potential therapeutic target for ITP and other autoimmune diseases.

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对SIRPα的单抗下调原发性免疫性血小板减少症患者初始CD4 + T细胞的启动
SIRPα是一种跨膜蛋白,通过其细胞质区域结合蛋白酪氨酸磷酸酶SHP-1和SHP-2,并在单核细胞、树突状细胞和巨噬细胞上大量表达。最近的研究表明,SIRPα对于DC启动CD4+T细胞和Th17细胞介导的自身免疫性疾病的发展至关重要。我们现在已经进一步评估了SIRPα及其配体CD47在原发性免疫性血小板减少症(ITP)中的重要性。在本研究中,我们发现单核细胞表面存在SIRPα的低表达状态。用阻断SIRPα与CD47结合的SIRPα单克隆抗体治疗ITP患者的细胞培养物可下调ITP反应。ITP患者的单核细胞刺激同种异体MLR的能力降低。SIRPα单克隆抗体抑制ITP患者CD4+T细胞的增殖和IL-2的产生,上调Treg细胞数量和IL-10对的产生,抑制TGF-β的产生。此外,与健康受试者相比,ITP患者的CD14+单核细胞表面的SIRPαmAb、HLA-DR和CD86的表达受到显著抑制,CD80的表达略有上调。然而,SIRPα的阻断增加了PBMC分泌TLR依赖性细胞因子TNF-α、IL-6和IL-1β,这可能被认为是对危险信号的反应储备。这些结果表明,单核细胞上的SIRPα对幼稚T细胞的启动和ITP的发展至关重要。因此,SIRPα是ITP和其他自身免疫性疾病的潜在治疗靶点。
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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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