Changes of immune status in patients with different PD-L1 expression after stereotactic body radiation therapy of oligometastasis

Purpose. To study the influence of PD-L1 expression on the dynamics of immunological changes before and at different intervals after stereotactic body radiation therapy (SBRT) of metastatic lesions in patients with metastatic forms of solid tumors. Materials and methods. A quantitative assessment and analysis of blood immunological parameters was conducted before irradiation, via 3-4 weeks and via 6-8 weeks after SBRT in patients with malignant tumors with oligometastases in the liver or lungs, in groups with negative and positive expression of PD-L1. All peripheral blood samples were analyzed by flow cytometry. Statistical analysis was performed using Friedman and Nemenyi criteria. Results. 3-4 weeks after the end of SBRT in group CPS <1 we observed statistically significant increase of activated T-helpers (CD3+CD4+HLA-DR+), activated cytotoxic T-lymphocytes (CD3+СD8+HLA-DR+), T-lymphocytes (CD3+CD19-) and T-helpers (CD3+CD4+). Wherein, activated T-helpers and activated cytotoxic T-lymphocytes statistically significantly increased 6-8 weeks after SBRT compared with the study before irradiation. In group CPS> 1, we revealed statistically significant increase of activated T-helpers 6-8 weeks after and decrease of T-regulatory lymphocytes (CD4+CD25brightCD127low) 3-4 weeks after completion of SBRT compared with the study before radiotherapy. When we analyzed the indicators by the TPS index, most of the statistically significant changes were recorded in the group with negative expression (TPS <1): increasing of activated T-helpers and activated cytotoxic T-lymphocytes 3-4 weeks and 6-8 weeks after SBRT and decreasing of T-regulatory lymphocytes 3-4 weeks after irradiation compared with the study before irradiation. Conclusion. Groups with negative PD-L1 expression (CPS <1 and TPS <1) are associated with a more activated antitumor T-cell immune response compared to patients with positive PD-L1 status (CPS≥1 and TPS≥1), however, further researches are needed.

Type and Intensity as Key Variable of Exercise in Metainflammation diseases: A Review

Monocyte and lymphocyte subpopulations exhibit functions that vary between the anti- and pro-inflammatory spectrum, such as classic CD16- and non-classical CD16+ monocytes, as well as T helper 2 lymphocytes (Th2), the Th1/Th17 lymphocytes ratio, and T regulatory lymphocytes (Treg). Metabolic disease-associated inflammation is accompanied by an imbalance in monocyte and lymphocyte phenotypes and functionality, as well as a stronger proportion of inflammatory subpopulations. These changes appear to be important for the development and progression of diseases like diabetes and cardiovascular disease. On the other hand, the regular practice of physical exercise is an important tool to restore the functionality of monocytes and lymphocytes, and to balance the subtypes ratio. However, key variables regarding exercise prescription, such as the type of exercise, intensity, and volume differentially impact on the acute and chronic immune response in individuals diagnosed with meta inflammation diseases. Here, we discuss the impact of different physical exercise protocols, acutely and chronically, on monocytes and lymphocytes of individuals with metabolic disease-associated inflammation. In this review, we focus on the best effects of different exercise protocols to dose the “exercise pill” in different inflammatory status.

Immune Response to SARS-CoV-2 Vaccine in 2 Men

<b><i>Introduction:</i></b> In the trials of corona virus vaccines, detailed analyses of subsets of lymphocytes were not carried out. We present perhaps the most comprehensive immunological analysis of 29 subsets of B and T cells in 2 healthy subjects receiving 2 doses of the Pfizer SARS-CoV-2 (COVID-19) vaccine. <b><i>Methods:</i></b> Analyses were performed prior to vaccination, 3 weeks following the 1st dose, and 4 weeks following the 2nd dose. Total, naïve (T_N), and different memory and effector subsets (T_CM, T_EM, and T_EMRA) of CD4+ and CD8+ T cells; SARS-CoV-2 spike protein-specific tetramer+, and cytotoxic CD8+ T; subsets of T follicular cells (T_FH, T_FH1, T_FH2, T_FH1/T_FH17, and T_FH17); B-cell subsets (mature B cells, naive B cells, transitional B cells, marginal zone B cells, class-switched memory B cells, germinal center B cells, and CD21^low B cells), and plasmablasts; and regulatory lymphocytes (CD4+ Treg, CD8+ Treg, Breg, and T_FR cells) were evaluated with specific monoclonal antibodies by flow cytometry. <b><i>Results:</i></b> A lack of COVID-19 IgG antibodies after the 1st dose in one of 2 subjects was associated with increased regulatory lymphocytes and decreased plasmablasts. Seroconversion after the 2nd dose in this subject was associated with decreased T_FR cells and increased plasmablasts. In both subjects, CD4 T_EM and CD8 T_CM were markedly increased following the 2nd dose. T_FH1 and regulatory lymphocytes were increased (except Breg) following the 1st dose. A striking increase in SARS-CoV-2-specific CD8+ T cells was observed following the 2nd dose. <b><i>Conclusion:</i></b> Our data support the need for 2nd dose of vaccine to induce strong SARS-CoV-2 CD8 T-cell specific response and generation of memory subsets of CD4+ and CD8+ T cells. Regulatory lymphocytes appear to play a role in the magnitude of response.

The role of transcription factor FoxP3 as a predictor of acute and chronic urticaria in children

Objective: To study the transcription factor FoxP3 in children with acute and chronic spontaneous urticaria as a possible predictor of the severity and chronicity of urticaria.Materials and Methods: A total of 264 children of both sexes aged from 6 to 16 years old with diff erent variants of urticaria course were examined. Clinical methods of the study included the analysis of anamnestic data and an objective examination of the child with the determination of the severity of urticaria. Immunological methods of the study included the identifi cation of T-regulatory lymphocytes with the CD4+CD25+ Foxp3+CD45+immunophenotype.Results: A signifi cant decrease in the level of transcription factor FoxP3 was found in children with severe acute urticaria and chronic urticaria compared to the control group.Conclusion: Th e degree of reduction in the level of FoxP3 signifi cantly aff ected the likelihood of the development of a severe course of acute urticaria and possible chronization of the disease.

Interpreting Immunoregulation in Lung Fibrosis: A New Branch of the Immune Model

Immunostimulation is recognized as an important contribution in lung fibrosis in some animal models and patient subsets. With this review, we illustrate an additional scenario covering the possible implication of immunoregulation during fibrogenesis. Available animal and human data indicate that pulmonary fibrosis also includes diverse and discrete immunoregulating populations comprising regulatory lymphocytes (T and B regs) and myeloid cells (immunosuppressive macrophages and myeloid-derived suppressive cells; MDSC). They are initially recruited to limit the establishment of deleterious inflammation but participate in the development of lung fibrosis by producing immunoregulatory mediators (mainly TGF-β1 and IL-10) that directly or indirectly stimulate fibroblasts and matrix protein deposition. The existence of this silent immunoregulatory environment sustains an alternative mechanism of fibrosis that explains why in some conditions neither pro-inflammatory cytokine deficiency nor steroid and immunosuppressive therapies limit lung fibrosis. Therefore, the persistent presence of immunoregulation is an important parameter to consider for refining therapeutical strategies in lung fibrotic disorders under non-immunostimulatory conditions.

Collagenous Gastritis in Primary Selective IgM Deficiency: Transition to EBV+ Gastric Adenocarcinoma

Selective IgM deficiency (SIgMD) and isolated collagenous gastritis are two independent rare disorders. Our purpose is to report the 1st case of SIgMD and isolated collagenous gastritis and collagenous gastritis that has transitioned to EBV + gastric adenocarcinoma. Gastric biopsy tissue was analyzed by EBV-related encoded RNA in situ hybridization assay. Subsets of CD4, CD8, T follicular helper cells (TFH), and members of the “regulatory lymphocytes club” were measured with multiple panels of monoclonal antibodies and isotype controls by multicolor flow cytometry. The patient was diagnosed with SIgMD (extremely low serum IgM 9 mg/dl and normal IgG and IgA and exclusion of secondary causes of low IgM). Soon after SIgMD diagnosis, the patient developed collagenous gastritis and, 8 years later, developed gastric adenocarcinoma that was positive for EBV. An extensive immunological analysis revealed reduced naïve CD4 and CD8 effector memory T cells and increased naïve and central memory CD8 T cells. Among the circulating follicular helper T cells (cTFH), TFH1 and TFH2 were increased whereas TFH17 was decreased. CD4 Treg cells and TFR cells were increased, whereas Breg and CD8 Treg were comparable to control. In conclusion, SIgMD may be associated with isolated collagenous gastritis, and collagenous gastritis may transition to EBV + gastric adenocarcinoma. A role of regulatory lymphocytes in gastric cancer is discussed.

SPECIFIC FEATURES OF THE DYNAMICS OF CD4+CD25+ SUBPOPULATIONS OF T-LYMPHOCYTES IN PATIENTS WITH SATISFACTORY EARLY RENAL ALLOGRAFT FUNCTION

Background. Experimental models indicate a certain role of T-regulatory lymphocytes in the induction of immunological tolerance. However, it is necessary to study their function and phenotype in more detail for the purposes of applying the mechanisms of tolerance induction. Objective. To assess the dynamics of CD3+CD4+CD25+ and CD3+CD4+CD25+highCD127+low indicators in renal transplant recipients with satisfactory early allograft function. Material and Methods. Kidney transplantation was performed in 197 recipients. We assessed CD3+CD4+CD25+ and CD3+CD4+CD25+highCD127+low level before the transplantation and on the 1st, 3rd, 7th, 30th and 90th days after the transplantation. The following groups of recipients were identified: PGF – those with satisfactory primary graft function, PGD – those with primary graft dysfunction, TR – those with transplant rejection in the early postoperative period. The comparison group (CG) consisted of healthy volunteers. Results. A significant increase in the relative and absolute level of CD3+CD4+CD25+highCD127+low from day 30 to 90 after surgery was revealed in recipients with a primary functioning graft. At the same time, CD3+CD4+CD25+ indicators in the recipients of the studied groups did not have significant differences throughout the study. Conclusions. CD3+CD4+CD25+highCD127+low monitoring can be used to identify patients with high tolerogenic potential.

Decreased nuclear translocation of FoxP3 transcription factor in patients with ST-segment elevation myocardial infarction

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Ministry of Science and Higher Education of Russian Federation T regulatory lymphocytes (Treg) participate in resolution of inflammation and are essential in post-infarct myocardial healing. The crucial mediator of Treg activity is transcription factor FoxP3. Nuclear localization of FoxP3 is an obligatory requirement for anti-inflammatory properties of the cells. FoxP3 is also expressed in conventional T-lymphocytes at the stage of their activation. Data on functional state of FoxP3 in chronic and acute coronary syndromes are absent. Purpose Our aim was to comparatively evaluate the level of FoxP3 nuclear translocation in subpopulations of FoxP3+ T-lymphocytes in patients with chronic and acute coronary syndromes. Methods We have recruited 14 patients with chronic coronary syndrome (CCS) (8 males; 6 females; 63.2 ± 9.0 y.o.) and 5 patients with acute anterior ST-segment elevation myocardial infarction (STEMI) (4 males; 1 female; 61.4 ± 11.2 y.o.). Reperfusion of the infarct-related artery (IRA) has been achieved in all STEMI patients (the mean time of recanalization constituted 5 hours), and coronary angioplasty and IRA stenting were performed. Health status was evaluated and functional class of chronic heart failure was assessed according to the 6-minute walk test. Peripheral blood mononuclear cells were isolated from heparinized blood of CCS patients and STEMI patients during the first day after the event. Frequency of T regulatory and T conventional lymphocytes and degree of FoxP3 nuclear translocation in them were evaluated by imaging flow cytometry. Results Numbers of T regulatory lymphocytes in STEMI patients were lower than in patients with CCS, while numbers of T conventional lymphocytes were higher. However these differences did not reach the level of statistical significance: 7.2 (6.2; 8.4)% vs. 6.7 (3.8; 7.0)% of T regulatory lymphocytes (p = 0.298) and 1.6 (1.3; 1.8)% vs. 2.1 (1.0; 2.8)% of T conventional cells (p = 0.754), in CCS and in STEMI patients, respectively. Meanwhile, STEMI patients displayed significantly lower nuclear translocation of FoxP3 in lymphocytes compared to CCS patients: 74.8 (64.9; 92.9)% vs. 98.2 (96.8; 98.7)% in T regulatory cells (p = 0.026) and 58.7 (33.9; 67.7)% vs. 88.3 (73.1; 96.9)% in T conventional lymphocytes (p = 0.034). Conclusions Our study is the first one to comparatively describe the FoxP3 nuclear translocation in patients with chronic coronary syndrome and STEMI. We showed that STEMI is primarily associated with the decrease of nuclear localization of FoxP3 rather than with changes in numbers of FoxP3+ T-lymphocytes in peripheral blood. The revealed phenomenon demonstrates that alterations of the balance between the suppressive and inflammatory activities of T-lymphocytes are observed already in the early inflammatory phase of STEMI, long before their expected clonal expansion.