Programmed Death-1 Signaling Pathway Research Articles

Differential expression of programmed death 1 (PD-1) on various immune cells and its role in human leprosy.

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Leprosy patients have been found to have defects in T cells activation, which is critical to the clearance of the bacilli. Treg cell suppression is mediated by inhibitory cytokines such as IL10, IL-35 and TGF-β and its frequency is higher in leprosy patients. Activation and overexpression of programmed death 1 (PD-1) receptor is considered to one of the pathways to inhibit T-cell response in human leprosy. In the current study we address the effect of PD-1 on Tregs function and its immuno-suppressive function in leprosy patients. Flow cytometry was used to evaluate the expression of PD-1 and its ligands on various immune cells T cells, B cells, Tregs and monocytes. We observed higher expression of PD-1 on Tregs is associated with lower production of IL-10 in leprosy patients. PD-1 ligands on T cells, B cells, Tregs and monocytes found to be higher in the leprosy patients as compared to healthy controls. Furthermore, in vitro blocking of PD-1 restores the Tregs mediated suppression of Teff and increase secretion of immunosuppressive cytokine IL-10. Moreover, overexpression of PD-1 positively correlates with disease severity as well as Bacteriological Index (BI) among leprosy patients. Collectively, our data suggested that PD-1 overexpression on various immune cells is associated with disease severity in human leprosy. Manipulation and inhibition of PD-1 signaling pathway on Tregs alter and restore the Treg cell suppression activity in leprosy patients.

Low-Dose Decitabine Restores Immune Tolerance in ITP By Modulating Regulatory T Cells

Immune thrombocytopenia (ITP) is an aquired autoimmune disease triggered by increased platelet destruction and impaired platelet production. Loss of immune tolerance is considered to be the pivotal mechanism of ITP. Decitabine, a hypomethylating agent promoting cell differentiation at low dose, has been applied in the treatment of myelodysplastic syndrome (MDS) with a considerable platelet response. Our previous and current studies demonstrated that low-dose decitabine could significantly increase the number of mature polyploidy megakaryocytes and had a long-term efficacy that could not be explained by its role on promoting platelet production in ITP patients. Recent reports have demonstrated that decitabine could decrease the production of interferon-γ (IFN-γ) and tumor necrosis factor-a (TNF-a), and increase immune suppressive regulatory T cells. Thus, low-dose decitabine might correct the loss of immune tolerance to induce a more durable response in patients with ITP.CD4+CD25+Foxp3+ regulatory T cells (Tregs), which play an important role in maintenance of peripheral tolerance, were reported to be decreased in number and function in ITP (Stasi R et. al. Blood 2008). In the in vitro study, peripheral blood mononuclear cells (PBMCs) were isolated and cultured with 100nM decitabine or PBS for 72h. We performed flow cytometry to determine the percentage of Tregs. It was shown that the percentage of Tregs in PBMCs and CD4+ T cells were significantly elevated after decitabine treatment. We also sorted the CD4+CD25+CD127- Tregs from ITP patients and co-cultured them with CFSE-labeled CD4+CD25-T cells to evaluate the suppressive activity of Tregs. The results indicated that the inhibitory function of Tregs after decitbine treatments was significantly elevated compared with controls.As compared to healthy individuals, patients with ITP also had increased number of TH1, TH17, TH22, Bregs and CD16+ monocytes. We subsequently investigated the effects of low-dose decitabine on those cells in patients with active ITP. Three cycles of decitabine were administered intravenously at a dose of at 3.5 mg/m2 for 3 days per cycle with a 4-week interval between cycles. After decitabine treatment, there was a significant increase in the relative number of CD25+Foxp3+ Tregs in the CD4+ T cell population. We also observed an increase in Tregs function after the decitabine treatment. In contrast, decitabine could significantly decrease the percentage of CD4+IFN-γ+TH1 in the CD4+T cell population and the percentage of CD16+monoyctes. However, we have not observed the effect of decitabine on the CD4+IFN-γ-CD17+TH17, CD4+IFN-γ-CD22+TH22, and CD19+CD24+CD38+Bregs by now.We further established the murine ITP model by transferring the splenocytes of C57BL/6 CD61 knockout mice, which were immunized against platelets from wild-type syngeneic C57BL/6 mice into severe combined immunodeficient (SCID) mice. We treated the ITP mice model with a low-dose range of decitabine (0.01, 0.03 or 0.10 mg/kg) intravenously three times a week. Our data showed a significant effect on PLT increase and the expansion of the Tregs population and the suppression of TH1 cells and CD16+ monocytes .In addition, programmed death-1 (PD-1) is a co-receptor that is expressed predominantly by T cells as well as B cells, monocytes and was found to be lower on the PBMCs and in serum of ITP patients (Zhong J et. al. Hematology. 2016). And research has reported that PD-1 signaling pathway is important in the pathogenesis of autoimmune diseases by inhibition of self-reactive T cells and increasing the development and functions of Tregs. Furthermore, it was reported that the expression of PD-1 is enhanced by decitabine in MDS (Yang H et. al. Leukemia 2014). In our current studies, decreased PD-1 expression on CD4+T cells of ITP patients was observed and decitabine could elevate the PD-1 expression on CD4+T cells after the decitabine treatment in ITP patients. Therefore, decitabine may correct the loss of immune tolerance by upregulating the Expression of PD-1 and be a promising therapeutic strategy for the management in ITP patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Progress in programmed death-1 signaling pathway in sepsis

Sepsis includes a highly diverse and dynamic mixture of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS). In the past, drugs produced to block the early inflammatory response had little effect on reversing the development of sepsis. Recent studies have shown that the mortality and prognosis of patients are significantly correlated with the immunosuppression of sepsis and the overexpression of co-inhibitory molecules. Programmed death-1 (PD-1) is a recently focused co-inhibitory molecule, which can regulate the functions of a variety of immune cells and participate in innate immunity and acquired immunity. It has important value in risk stratification and prognosis prediction of patients with sepsis, and can be used as one of the intervention targets for immune regulation in sepsis in the future. The role of PD-1 signaling pathway in immunosuppression and its effect on patients' prognosis is reviewed in this article, providing new directions for the treatment of sepsis.

Expression and clinical significance of programmed death-1 on lymphocytes and programmed death ligand-1 on monocytes in the peripheral blood of patients with cervical cancer.

The programmed death-1 (PD-1) signaling pathway serves a critical role in immune regulation and tolerance by suppressing the activation and proliferation of T cells. The aim of the present study was to investigate the effect of PD-1 and programmed death-ligand 1 (PD-L1) on the development of cervical carcinoma and cervical intraepithelial neoplasia (CIN). A total of 40 healthy controls (HC), 40 patients with CIN and 66 newly diagnosed cervical cancer patients were recruited. The expression level of PD-1 expression on peripheral cluster of differentiation (CD)4+ and CD8+ T cells and PD-L1 on monocytes was analyzed by flow cytometry. The expression level of soluble PD-L1 in serum was determined by an ELISA. The results of the present study demonstrated that the PD-1 expression level on CD4+ and CD8+ T cells was significantly increased in CIN and cervical cancer, compared with that in HC. In addition, the PD-1 expression level on CD4+ and CD8+ T cells was increased in cervical cancer, compared with that in CIN. However, the expression level of PDL-1 on CD14+ monocytes was increased in cancer and CIN, but limited in cancer and CIN. In addition, PD-1 expression on CD4+ T cells was positively associated with PD-1 expression on CD8+ T cells in cervical cancer (P<0.05). Further analyses revealed that the proportion of PD-1 on CD4+ and CD8+ T cells were positively associated with tumor stages. However, no difference in the degree of soluble PD-1 among cancer, CIN and HC cells was revealed. The results suggested that the PD-1 signaling pathway is involved in the development of CIN and cervical cancer.

Soluble Programmed Death 1 (PD-1) Is Decreased in Patients With Immune Thrombocytopenia (ITP): Potential Involvement of PD-1 Pathway in ITP Immunopathogenesis.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by dysregulation of T cells. Programmed death (PD) 1 and programmed death 1 ligand 1 (PD-L1) are cosignaling molecules, and the major role of the PD-1 pathway is the inhibition of self-reactive T cells and to protect against autoimmune diseases. We measured levels of serum soluble PD 1 (sPD-1) and serum soluble PD-L1 (sPD-L1) in 67 patients with ITP (24 newly diagnosed ITP [ndITP], 43 chronic ITP [cITP]) and 21 healthy controls (HCs). We determined decreased serum sPD-1 levels both in patients with ndITP and in patients with cITP when compared to HC. Moreover, there was a positive correlation between sPD-1 levels and platelet counts. The sPD-L1 levels were decreased in patients with ndITP when compared to patients with cITP. This is the first study investigating PD-1 signaling pathway in ITP. Decreased sPD-1 levels may have a role in ITP pathogenesis as without the inhibitory regulation of PD-1, sustained activation of T cells may cause inflammatory responses which is the case in ITP.

Programmed death-1 pathway in cancer and autoimmunity.

Programmed death-1 (PD-1) is a co-receptor that is expressed predominantly by T cells. The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. A major functional role of the PD-1 signaling pathway is the inhibition of self-reactive T cells, which serve to protect against autoimmune diseases. Elimination of the PD-1 pathway can therefore result in the breakdown of immune tolerance that can ultimately lead to the development of pathogenic autoimmunity. Conversely, tumor cells can at times co-opt the PD-1 pathway to escape from immunosurveillance mechanisms. Therefore, blockade of the PD-1 pathway has become an attractive target in cancer therapy. Recent clinical trials have shown that anti-PD-1 agents have profound effects on solid tumor regression. Current approaches include six agents that are either PD-1 and PD-L1 targeted neutralizing antibodies or fusion proteins. More than forty clinical trials are underway to better define the role of PD-1 blockade in variety of tumor types. In this review we will highlight the basic biology of the PD-1 system and discuss its potential roles in both autoimmunity and cancer. We propose that future research on PD-1 may lead to the translation of fundamental regulatory pathways into the development of practical new approaches for the treatment of autoimmune diseases and cancer.