{"id":1323,"date":"2019-10-26T02:53:48","date_gmt":"2019-10-26T07:53:48","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=1323"},"modified":"2020-02-17T02:23:26","modified_gmt":"2020-02-17T07:23:26","slug":"pd-1","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/pd-1\/","title":{"rendered":"PD-1"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Programmed cell death 1<\/u><\/a>\u00a0(PD-1) is a costimulatory molecule that belongs to the CD28\/CTLA-4 family. PD-1 recruits and activates an activation signaling pathway such as protein tyrosine phosphatase by binding to programmed cell death ligand 1 or 2 (PD-L1<\/u><\/a>\u00a0or PD-L2). Abnormal PD-1\/PD-L signaling can cause the immune microenvironment in the body to lose its steady state, leading to autoimmune diseases or tumors. PD-1 is an important factor in maintaining immune tolerance. Under physiological conditions, PD-1 recognizes antigen through T cell receptor (TCR), regulates the function of T cells in peripheral tissues, and regulates the body\u2019s foreign antigen or autoantigen, an immune response that prevents the development of immune-related diseases. Different from traditional tumor treatments, PD-1\/PD-L1\u00a0immune checkpoint inhibitors<\/u><\/a>\u00a0use the body\u2019s own immune system to kill tumors, demonstrating excellent efficacy in a variety of solid tumors and hematological malignancies. The greatest advantage of these immune checkpoint inhibitors is their long-lasting response and long-term survival.<\/p>\n

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Figure 1 Mechanisms of programmed cell death protein 1 (PD1) signalling in T cells. ( Sharpe et al 2017)<\/p>\n

PD-1 \/ PD-L1 signaling pathway<\/b><\/strong><\/p>\n

PD-L1 (B7-H1\/CD273) and PD-L2 (B7-DC\/CD274), the two ligands for PD-1, have similar effects. The main functions of both, inhibition of T cell receptor-mediated B cell proliferation and production of interleukin 2, 10, interferon gamma and other cytokines, are combined with PD-1 and lead to cell cycle arrest, thereby inhibiting T cell activation. Because PD-L1 is the main component of these two PD-1 ligands, the current research is mainly focused on PD-L1. PD-1 on the surface of activated T lymphocytes can specifically recognize PD-L1 on antigen-presenting cells (APC), thereby activating PD-1\/PD-L1 pathway and attenuating the effects of Ras-MAPK and other pathways, which then leads to a decrease in the expression of three transcription factors, AP-1, NF-AT and\u00a0NF-\u03baB<\/u><\/a>, causing an inhibition of T cell proliferation and differentiation, as well as the secretion of cytokines.<\/p>\n

PD-1 and diseases<\/b><\/strong><\/p>\n

The expression of PD-1 is associated with the development and progression of various autoimmune diseases. Studies have shown that PD-1 knockout mice can elicit multiple autoimmune diseases. For example, PD-1 knockout mice with a C57BL\/6 gene background develop lupus-like glomerulonephritis and lethal dilated cardiomyopathy. PD-1 signaling pathway is also involved in the progression of viral and microbial infectious diseases. Virus-specific cytotoxic T cells (CTLs) were found to be PD-1 positive in LCMV-infected mice, but were not found in the acute infection model. These PD-1 positive failing CTLs were found in patients with chronic\u00a0HIV<\/u><\/a>,\u00a0HCV<\/u><\/a>, and\u00a0HBV<\/u><\/a>\u00a0infection. In addition, PD-1 expression was positively correlated with viral load.<\/p>\n

Anti-PD-1 drug and its clinical application<\/b><\/strong><\/p>\n

(1)\u00a0Nivolumab<\/u><\/a>\u00a0(Opdivo). A fully human IgG4 that can restore the immune effect of T lymphocytes during anti-tumor therapy is used to treat liver cancer, gastric cancer, metastatic non-small cell lung cancer, etc.<\/p>\n

(2)\u00a0Pembrolizumab<\/u><\/a>\u00a0(Keytruda). This humanized IgG4 was the first PD-1 monoclonal antibody marketed in the United States.<\/p>\n

(3)\u00a0Pidilizumab<\/u><\/a>. A PD-1 humanized IgG-1\u03ba monoclonal antibody is used to treat melanoma and recurrent follicular lymphoma.<\/p>\n

(4)\u00a0AMP-224<\/u><\/a>. Developed for the treatment of advanced solid tumors, this PD-L2 IgG2a fusion protein causes an infusion reaction but no drug-related inflammatory adverse reactions clinically.<\/p>\n

References<\/p>\n

1. Longo, D. L. , & Boussiotis, V. A. . (2016). Molecular and biochemical aspects of the pd-1 checkpoint pathway.New England Journal of Medicine<\/i><\/em>, 375(18), 1767-1778.<\/p>\n

2. Liu, J. , Zhang, S. , Hu, Y. , Yang, Z. , & Lu, X. . (2016). Targeting pd-1 and tim-3 pathways to reverse cd8 t-cell exhaustion and enhance ex vivo t-cell responses to autologous dendritic\/tumor vaccines.Journla of Immunotherapy<\/i><\/em>, 39(4), 171-180.<\/p>\n

3. Sharpe, A. H. , & Pauken, K. E. . (2017). The diverse functions of the pd1 inhibitory pathway.\u00a0Nature Reviews Immunology<\/i><\/em>.<\/p>\n

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