ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases.

Lymphopenia, Lymphopenia-Induced Proliferation, and Autoimmunity

Immune homeostasis is a tightly regulated system that is critical for defense against invasion by foreign pathogens and protection from self-reactivity for the survival of an individual. How the defects in this system might result in autoimmunity is discussed in this review. Reduced lymphocyte number, termed lymphopenia, can mediate lymphopenia-induced proliferation (LIP) to maintain peripheral lymphocyte numbers. LIP not only occurs in normal physiological conditions but also correlates with autoimmunity. Of note, lymphopenia is also a typical marker of immune aging, consistent with the fact that not only the autoimmunity increases in the elderly, but also autoimmune diseases (ADs) show characteristics of immune aging. Here, we discuss the types and rates of LIP in normal and autoimmune conditions, as well as the coronavirus disease 2019 in the context of LIP. Importantly, although the causative role of LIP has been demonstrated in the development of type 1 diabetes and rheumatoid arthritis, a two-hit model has suggested that the factors other than lymphopenia are required to mediate the loss of control over homeostasis to result in ADs. Interestingly, these factors may be, if not totally, related to the function/number of regulatory T cells which are key modulators to protect from self-reactivity. In this review, we summarize the important roles of lymphopenia/LIP and the Treg cells in various autoimmune conditions, thereby highlighting them as key therapeutic targets for autoimmunity treatments.

SARS-CoV-2 infection induces mixed M1/M2 phenotype in circulating monocytes and alterations in both dendritic cell and monocyte subsets

Clinical manifestations of SARS-CoV-2 infection range from mild to critically severe. The aim of the study was to highlight the immunological events associated with the severity of SARS-CoV-2 infection, with an emphasis on cells of innate immunity. Thirty COVID-19 patients with mild/moderate symptoms and 27 patients with severe/critically severe symptoms were recruited from the Clinical Center of Kragujevac during April 2020. Flow cytometric analysis was performed to reveal phenotypic and functional alterations of peripheral blood cells and to correlate them with the severity of the disease. In severe cases, the number of T and B lymphocytes, dendritic cells, NK cells, and HLA-DR-expressing cells was drastically decreased. In the monocyte population proportion between certain subsets was disturbed and cells coexpressing markers of M1 and M2 monocytes were found in intermediate and non-classical subsets. In mild cases decline in lymphocyte number was less pronounced and innate immunity was preserved as indicated by an increased number of myeloid and activated dendritic cells, NK cells that expressed activation marker at the same level as in control and by low expression of M2 marker in monocyte population. In patients with severe disease, both innate and adoptive immunity are devastated, while in patients with mild symptoms decline in lymphocyte number is lesser, and the innate immunity is preserved.

The relationship between the low Apgar scores of the newborns and hematologic parameters which are inflammatory markers

Objective: To investigate the relationship between the 5-minute Apgar scores of the newborns checked in the cases induced due to prolonged pregnancy and neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), and to investigate the contributions of these parameters as prognostic markers in the low Apgar scores. Methods: A total of 169 primigravida cases for which delivery by induction was decided due to prolonged pregnancy after they completed 41 weeks of gestation between 2017 and 2018 were included in the study. The detailed previous histories of all cases were obtained at admission and they underwent cervicovaginal examination, obstetric ultrasonography for the assessment of fetal biometry and amniotic fluid, and complete blood count including hemoglobin level, total white blood cell count, differential leukocyte number and platelet count. NLR and PLR were calculated as the ratio of neutrophil number to lymphocyte number and the ratio of platelet number to lymphocyte number, respectively. The Apgar scores in the newborn assessment were determined according to the usual criteria 1 and 5 minutes after the birth. The independent samples t-test, Mann-Whitney U test and chi-square test were used for the analysis of the data. Results: The mean NLR and PLR values of the cases were calculated 4.8±2.8 and 148.8±74.9, respectively. While 108 (64%) patients delivered vaginally, 61 (36%) patients delivered by cesarean section. The Apgar score was >7 in 142 (84%) patients and <7 in 27 (16%) patients. NLR and PLR values were significantly higher in the group with Apgar score <7 than the group with Apgar score ≥7 (p<0.05). Conclusion: The elevations in NLR and PLR is the usual part of a health pregnancy; however, excessively elevated inflammation has been associated with poor prenatal and developmental outcomes in various populations. In conclusion, these markers can be used as the parameters helping clinicians to predict poor obstetric outcomes.

Sepsis impedes EAE disease development and diminishes autoantigen-specific naive CD4 T cells

Evaluation of sepsis-induced immunoparalysis has highlighted how decreased lymphocyte number/function contribute to worsened infection/cancer. Yet, an interesting contrast exists with autoimmune disease development, wherein diminishing pathogenic effectors may benefit the post-septic host. Within this framework, the impact of cecal ligation and puncture (CLP)-induced sepsis on the development of experimental autoimmune encephalomyelitis (EAE) was explored. Notably, CLP mice have delayed onset and reduced disease severity, relative to sham mice. Reduction in disease severity was associated with reduced number, but not function, of autoantigen (MOG)-specific pathogenic CD4 T cells in the CNS during disease and draining lymph node during priming. Numerical deficits of CD4 T cell effectors are associated with the loss of MOG-specific naive precursors. Critically, transfer of MOG-TCR transgenic (2D2) CD4 T cells after, but not before, CLP led to EAE disease equivalent to sham mice. Thus, broad impairment of antigenic responses, including autoantigens, is a hallmark of sepsis-induced immunoparalysis.

SARS-CoV-2 infection induces mixed M1/M2 phenotype in circulating monocytes and alterations in both dendritic cell and monocyte subsets

Clinical manifestations of SARS-CoV-2 infection range from mild to critically severe. The aim of the study was to highlight the immunological events associated with the severity of SARS-CoV-2 infection, with an emphasis on cells of innate immunity. Thirty COVID-19 patients with mild/moderate symptoms and 27 patients with severe/critically severe symptoms were recruited from the Clinical Center of Kragujevac during April 2020. Flow cytometric analysis was performed to reveal phenotypic and functional alterations of peripheral blood cells and to correlate them with the severity of the disease. In severe cases, the number of T and B lymphocytes, dendritic cells, NK cells, and HLA-DR-expressing cells was drastically decreased. In the monocyte population proportion between certain subsets was disturbed and cells coexpressing markers of M1 and M2 monocytes were found in intermediate and non-classical subsets. In mild cases decline in lymphocyte number was less pronounced and innate immunity was preserved as indicated by an increased number of myeloid and activated dendritic cells, NK cells that expressed activation marker at the same level as in control and by low expression of M2 marker in monocyte population. In patients with severe disease, both innate and adoptive immunity are devastated, while in patients with mild symptoms decline in lymphocyte number is lesser, and the innate immunity is preserved.

Immunomodulatory Efficiency of Abelmoschus esculentus in Swiss Albino Mice

Background: Immunomodulation through natural or synthetic substances may be considered as an alternative for prevention and cure of infections. Methods: A total of nineteen groups of Swiss albino mice were experimented for immunological studies with an inclusion of control and immunised control. Lymphocyte count and DTH response in the experimental groups after the administration of plant drugs. The result showed remarkable changes in all kind of treated animals when compared to control. The increment in ‘B’ and “T lymphocyte number was much pronounced in mice by the administration of A. esculentus in combination with immuno-enhansive drug. Result: In DTH responses directly correlated with cell mediated immunity and were found to be highest at the maximum dose (100 mg/Kg) of plant extracts A. esculuntus. From the results it was clear that the plant extract induced immunomodulating potential of the test animal. On administration of plant extract an enhanced and visible DTH responses were observed.

IgG antibody seroconversion and the clinical progression of COVID-19 pneumonia: A retrospective, cohort study

Background: Coronavirus Disease 2019 (COVID-19) causes severe acute respiratory failure. Antibody-dependent enhancement (ADE) is known as the mechanism for severe forms of other coronavirus diseases. The clinical progression of COVID-19 before and after IgG antibody seroconversion was investigated. Methods: Fifty-three patients with reverse transcriptase PCR (RT-PCT)-confirmed COVID-19 viral pneumonia with or without respiratory failure were retrospectively investigated. The timing of the first IgG antibody against SARS-CoV-2-positive date, as well as changes of C-reactive protein (CRP) as an inflammatory marker and blood lymphocyte numbers, was assessed using serial preserved blood samples. Findings: Ten patients recovered without oxygen therapy (mild/moderate group), 32 patients had hypoxemia and recovered with antiviral drugs (severe/non-ICU group), and 11 patients had severe respiratory failure and were treated in the ICU (6 of them died; critical/ICU group). The first IgG-positive date (day 0) was observed from 5 to 18 days from the onset of disease. At day 0, a CRP peak was observed in the severe and critical groups, whereas there was no synchronized CRP peak on day 0 in the mild/moderate group. In the severe/non-ICU group, the blood lymphocyte number increased (P=0.0007) and CRP decreased (P=0.0007) after day 0, whereas CRP did not decrease and the blood lymphocyte number further decreased (P=0.0370) in the critical/ICU group. Interpretation: The respiratory failure due to COVID-19 viral pneumonia observed in week 2 may be related to an antibody-related mechanism rather than uncontrolled viral replication. In the critical form of COVID-19, inflammation was sustained after IgG seroconversion.