Recent Advances in Immunotherapeutic Approaches for Recurrent Reproductive Failure

Human reproduction is an insufficient process, disturbed by various factors, such as immunologic aberrations of mother. Immunologic abnormalities, including cellular and humoral immunity imbalance, cause dysregulated immune responses against embryo, fetus, and associated components and lack of maternal immunotolerance, which compromise the maintenance of pregnancy. Therefore, evaluation of immunologic parameters, including cellular and humoral immunity assessment (T and B lymphocyte, T helper subtypes, NK cells, cytokines, and autoantibodies), especially in women with a history of pregnancy loss or implantation failure, would help clinicians to manage the disorder and prevent next unfavorable pregnancy outcomes. Moreover, several immunomodulatory approaches have been introduced to modulate the abnormal immunologic responses in patients who experience reproduction failure, especially those diagnosed with immunologic basis. Anticoagulants, corticosteroids, intravenous immunoglobulin, immunosuppressive medications used in inhibition of graft rejection, such as calcineurin inhibitors, recombinant cytokines, and cell therapy approaches, are among these modalities. Here, we discuss the proposed mechanisms of immunologic abnormalities involved in the etiopathogenesis of reproduction disorders, besides the suggested immunologic tests and immunotherapeutic approaches which may be helpful in management of these disorders

Effects of toll-like receptor agonists and SARS-CoV-2 antigens on interferon (IFN) expression by peripheral blood CD3+ T cells from COVID-19 patients

Background: Signaling by toll-like receptors (TLRs) initiates important immune responses against viral infection. The role of TLRs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well elucidated. Thus, we investigated the interaction of TLRs agonists and SARS-COV-2 antigens with immune cells in vitro. Material & methods: 30 coronavirus disease 2019 (COVID-19) patients (15 severe and 15 moderate) and 10 age and sex-matched healthy control (HC) were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and activated with TLR3, 7, 8, and 9 agonists, the spike protein (SP) of SARS-CoV-2, and the receptor binding domain (RBD) of SP. Frequencies of CD3+IFN-β+ T cells, and CD3+IFN-γ+ T cells were evaluated by flow cytometry. Interferon (IFN)-β gene expression was assessed by qRT-PCR. Results: The frequency of CD3+IFN-β+ T cells was higher in PBMCs from moderate (p < 0.0001) and severe (p = 0.009) patients at baseline in comparison with HCs. The highest increase in the frequency of CD3+IFN-β+ T cells in cell from moderate patients was induced by TLR8 agonist and SP (p < 0.0001 for both) when compared to HC, while, the highest increase of the frequency of CD3+IFN-β+ T cells in sample of severe patients was seen with TLR8 and TLR7 agonists (both p = 0.002). The frequency of CD3+IFN-γ+ T cells was significantly increased upon stimulation with TLR agonists in cell from patients with moderate and severe COVID-19, compared with HC (all p < 0.01), except with TLR7 and TLR8 agonists. The TLR8 agonist did not significantly increase the frequency of CD3+IFN-γ+ T cells in PBMCs of severe patients, but did so in cells from patients with moderate disease (p = 0.01). Moreover, IFN-β gene expression was significantly upregulated in CD3+T cells from moderate (p < 0.0001) and severe (p = 0.002) COVID-19 patients, compared to HC after stimulation with the TLR8 agonist, while, stimulation of T cells with SP, significantly up-regulated IFN-β mRNA expression in cells from patients with moderate (p = 0.0003), but not severe disease. Conclusion: Stimulation of PBMCs from COVID-19 patients, especially patients with moderate disease, with TLR8 agonist and SP increased the frequency of IFN-β-producing T cells and IFN-β gene expression

Immune checkpoint inhibitors and SARS-CoV2 infection

Infection with severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) triggers coronavirus disease 2019 (COVID-19), which predominantly targets the respiratory tract. SARS-CoV-2 infection, especially severe COVID-19, is associated with dysregulated immune responses against the virus, including exaggerated inflammatory responses known as the cytokine storm, together with lymphocyte and NK cell dysfunction known as immune cell exhaustion. Overexpression of negative immune checkpoints such as PD-1 and CTLA-4 plays a considerable role in the dysfunction of immune cells upon SARS-CoV-2 infection. Blockade of these checkpoints has been suggested to improve the clinical outcome of COVID-19 patients by promoting potent immune responses against the virus. In the current review, we provide an overview of the potential of checkpoint inhibitors to induce potent immune responses against SARS-CoV-2 and improving the clinical outcome of severe COVID-19 patients

Effects of Toll Like Receptor Agonists and SARS-Cov-2 Antigens on Interferon (IFN) Expression by Peripheral Blood CD3+ T Cells in COVID-19 Patients

Background: Signaling by toll like receptors (TLRs) initiates important immune responses against viral infection. The role of TLRs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is not well elucidated. Thus, we investigated the interaction of TLRs agonists and SARS-COV-2 antigens with immune cells in vitro. Material &amp;amp; methods: 30 coronavirus disease 2019 (COVID-19) patients (15 severe and 15 moderate) and 10 age and sex matched control (HC) were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and activated with TLR3, 7, 8 and 9 agonists, the spike protein (SP) of SARS-CoV-2 and the Receptor Binding Domain (RBD) unit of SP. Frequencies of CD3+IFN-&amp;beta;+ T cells, and CD3+IFN-g+ T cells was evaluated by flow cytometry. Interferon (IFN)-b gene expression was assessed by qRT-PCR. Results: The frequency of CD3+IFN-&amp;beta;+ T cells was higher in moderate and severe patients at baseline in comparison with HCs. Stimulation of PBMCs from moderate patients with SP and TLR8 agonist significantly upregulated the frequency of CD3+IFN-&amp;beta;+ T cells (P=0.0005 and 0.0024, respectively) when compared to non-stimulated (NS) samples. The greatest increase in CD3+IFN-b+ T cell frequency in PBMCs from severe patients was seen with TLR8 and TLR7 agonists when compared to NS (P= 0.003 and 0.0167, respectively). TLR stimulation did not significantly enhance the frequency of CD3+IFN-g+ T cells generated from PBMCs from moderate and severe patients compared with unstimulated controls. However, the frequency of CD3+IFN-ɣ+ T cells in PBMCs from moderate patients was upregulated by agonists of TLR3, 8 and 9, SP and RBD when compared with NS samples from HCs. The expression of the IFN-&amp;beta; gene after stimulation of CD3+T cells with the TLR8 agonist was also up-regulated in moderate than severe patients (moderate vs. severe: p=0.0006). In addition, stimulation of CD3+ T cells with SP, up-regulated the expression of IFN-&amp;beta; gene expression in cells from patients with moderate disease (moderate vs. severe: p=0.01). Conclusion: Stimulation of PBMCs from COVID-19 patients with a TLR8 agonist and with SP enhanced IFN-b protein and gene levels. This may potentiate immune responses against SARS-CoV-2 infection and prevent viral replication and spread.</jats:p