In addition to identifying the major B- and T-cell subpopulations involved in autoimmune rheumatic diseases (ARDs), in recent years special attention has been paid to studying the expression of their activation markers and immune checkpoints (ICPs). The activation markers on B and T cells are a consequence of the immune response, and these molecules are considered as sensitive specific markers of ARD activity and as promising targets for immunotherapy. ICPs regulate the activation of the immune response by preventing the initiation of autoimmune processes, and they modulate it by reducing immune cell-induced organ and tissue damage. The article considers the possible correlation of ICPs with the activity of ARDs, the efficacy of specific ARD treatments, and the prospects for the use of activation molecules and activation/blocking ICPs for the treatment of ARDs.
Introduction. Natural killer T lymphocytes (NKT) take place between the innate and acquired immune response. The ability of these cells to activate the antitumor immune response and inhibit immunological activity makes them the target of research in cancer patients. The radicality of surgical treatment of patients with metastatic melanoma (stage III–IV) is relatively conventional. In this regard, the possibility of adjuvant effective therapy of melanoma is actively investigated worldwide.The aim of the study is investigation of the importance of increasing the number of NKT cells in the peripheral blood of patients with metastatic melanoma after radical surgical removal of the tumor. Patients were treated with adjuvant regimen antitumor autologous dendritic cell therapy in form of vaccination.Materials and methods. The study included 39 patients with stage III and IV metastatic melanoma with regional and / or distant metastases after radical surgery. From the peripheral blood monocytes of each patient, an autologous vaccine was created from mature dendritic cells loaded with tumor lysate. The therapy continued until objective progression. The study included patients who received from 5 to 120 injections. The follow-up period ranged from 5 to 168 months.Results. It was shown that 14 (36 %) of patients had the number of NKT cells exceeding the norm (0–10 %) and in the course of vaccine therapy they had the progression of the disease in the period up to 2 years. In patients with relapse-free course of the disease in vaccine therapy (n = 13), the number of NKT lymphocytes did not exceed the norm both before and during therapy. Significantly shorter time to progression was revealed in patients with high initial content of NKT lymphocytes compared with patients with normal indices of NKT cells (6.5 months) – 95 % confidence limit 2,4–10,7 % vs 96,2 months (95 % confidence limit 63.8–128.6 %). Conclusion. An increased number of NKT cells in patients with stage III–IV metastatic melanoma after radical surgical treatment is a marker of early progression.
Introduction. Age is considered as an important clinical and pathological factor in cancer patients. Malignant tumors are more likely to develop in older people, but the disease is less aggressive than in young patients. According to various authors, the influence of age on the development of tumors largely depends on the age-related features of the immune system.The aim of the present study was to determine the relationship of indicators of systemic antitumor immune response with the age of patients with primary operable breast cancer and cancer of the oral mucosa.Materials and methods. The study included patients with all subtypes of primary-operable breast cancer (n = 145) and patients with cancer of the oral mucosa (n = 29). Immunophenotyping of peripheral blood lymphocytes was performed using a wide panel of monoclonal antibodies to markers of adaptive and innate immunity cells.Results. In elder patients (40 years and older) with primary-operable breast cancer, the percentage of activated CD25+ lymphocytes and CD4+CD25+ and CD3+CD4+ T cells, NKT cells, activated HLA-DR+ lymphocytes, including activated CD3+HLA-DR+ T cells before treatment, was statistically significantly higher than in patients younger than 40 years. Patients of this group showed increase of CD8+CD - 11b+CD28– CTLs and a decrease in the number of naive lymphocytes (CD4 – CD62L+ and CD8+CD11b – CD28+) in comparison with control percentage, and the downward trend in CD4+CD25+CD127– Treg, with increased numbers of CD4+CD25+ T cells. In patients with cancer of the oral mucosa, an increase in the number of cells of some populations of the immune effector link and a decrease in the number of suppressor lymphocytes were revealed with age.Conclusion. The results suggest that age-related differences in the state of systemic antitumor immune response contribute to a more favorable course of breast cancer and some other malignancies in older persons. It is obvious that the features of age differences in the immune response to the tumor should be taken into account when prescribing systemic therapy, including immunotherapy.All patients gave written informed consent to participate in the study
Introduction. Long-term monitoring of immune system parameters in cancer patient in FSBI “N.N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of Russia, as well as the absence of an immunological research algorithm and a spectrum of significant markers, served as the basis for this study.Purpose. To present reference values and determine the normal range for subpopulations of systemic immunity lymphocytes.Materials and methods. The phenotype of peripheral blood lymphocytes was studied in 186 healthy donors (86 men and 100 women), mean age 41,9 ± 12,5 years. To assess the multivariate phenotype by flow cytometry, monoclonal antibodies to CD45, CD3, CD4, CD8, CD16, CD56, CD19, CD25, CD28, CD11b, CD127, HLA-Dr, TCR-γ / δ, Perforin and Granzime B labeled various fluorochromes.Results. A panel of markers of immunocompetent cells of systemic immunity was developed as a basis for assessing the state of the immune system of cancer patients. Reference values and normal boundaries are given for characterizing the linearity of cells with detailing of the phenotypic and functional heterogeneity of the population of CD8+-lymphocytes, activation markers and the pool of naive cells; characteristics of various types of regulatory cells, functional activity of cells of the effector link of immunity. A comparative analysis of immunoregulatory indices was carried out and the vulnerability of the formula CD3+CD4+/CD3+CD8+ to the CD4+/CD8+ index was proved.Conclusion. The spectrum of the proposed indicators is the product of many years of research carried out in the laboratory of clinical immunology of the Federal State Budgetary Institution “N.N. Blokhin National Medical Research Center of Oncology” оf the Ministry of Health of the Russian Federation, in order to search for significant criteria for assessing the state of the immune system in cancer.
Background. To enhance the antitumor immune response, new promising methods of immunotherapy are being developed. They consist in the blockade and activation of immune check-point molecules, in particular, the blockade of the Lag‐3 molecule (lymphocyte-activation gene 3) and the activation of the GITR receptor (Glucocorticoid induced TNF receptor). In the studies of combined use with PD-1 blockers, encouraging results were obtained, which makes the assessment of the expression of Lag-3 and GITR on immunocompetent cells of peripheral blood (PB) and tumor tissue necessary for the personalization of such treatment and understanding of the mechanisms of the antitumor immune response. Materials and methods. The study included peripheral blood samples and surgical material from 39 breast cancer patients being treated at the Blokhin National Medical Research Center of Oncology. The subpopulation composition and expression of PD-1, Lag-3, and GITR molecules were evaluated by flow cytometry. Results. The analysis of the main populations of PB lymphocytes showed that in patients with breast cancer, the content of NKT-lymphocytes was increased, and the proportions of lymphocytes expressing CD11b and CD25 markers were increased compared to the donor group. It was revealed that the tumor tissue is dominated by T-cells, an increase in the proportion of which occurs due to a reduced content of NK-lymphocytes and B-lymphocytes. The structure of Tumor-infiltrating lymphocytes (TILs) is dominated by subpopulations with immunosuppressive activity, which is indicated by a decrease in the content of CD11b+, CD25+ and perforin-positive cells, increased expression of Lag-3 and PD-1. For PB and tumor tissue, the average degree of dependence of Lag-3 expression on the content of PD-1+ lymphocytes was shown. There is an increase in the content of immunosuppressive subpopulations with high PD-1 values in PB and TILs. The direct dependence of the number of perforin-containing lymphocytes and CD11b expression on the GITR content in the PB was established, but it is not typical for breast cancer tissue. Conclusion. Since the blockade of the Lag-3 molecule by monoclonal antibodies can enhance the effect of anti-PD-1 therapy in cancer patients, it is necessary to evaluate the expression and co-expression of these two markers. A high content of GITR-positive lymphocytes in the tumor tissue, on the one hand, and a decrease in the proportion of effector subpopulations of lymphocytes, on the other, indicates the influence of the tumor microenvironment on the functioning of GITR-mediated activation of the immune response. Further investigation of GITR expression and functional activity is required to understand the nature of this contradiction.
Background:B-cells play a pivotal role in primary Sjogren’s syndrome (SS) pathogenesis. Recent studies have shown disturbances in the peripheral B cell populations in primary SS.Objectives:To examine В-cell subsets in peripheral blood of SS patients (pts) and to analyze the association between B-cell subsets and SS activity.Methods:Twenty active SS pts (19F/1M): median age 42 years (range) (32-54); disease duration 3 (2-10) years; ESSDAI score ≥5 in 6 pts, <5 in 14 pts), were included. SS was diagnosed based on the ACR-EULAR 2016 criteria. Twenty healthy donors composed the control group. CD19+B cells, memory B-cells (CD19+CD27+), non-switched memory B-cells (CD19+IgD+CD27+), switched memory B-cells (CD19+IgD-CD27+), naïve (CD19+IgD+CD27-), double negative (CD19+IgD-CD27-), transitional (CD19+IgD+CD10+CD38+) B-cells, plasmablasts (CD19+СD38+++IgD-CD27+), and plasma cells (CD19+СD38+) were analyzed by multicolor flow cytometry using cytometer Navios (Beckman Coulter, USA).The nonparametric Mann-Whitney test, the unpaired Student’s t test for group comparison, and the Pearson`s x2 criterion were used for statistical analysis. Data were shown as median (Me) with an interquartile range of 25 - 75 percentile. The differences were considered statistically significant when p <0.05. Statistica 10 for Windows (StatSoft Inc., USA) package was used for statistical data processing.Results:The percentages/absolute numbers of plasmablasts, plasma cells and transitional B-cells in SS were significantly higher than in healthy donors, р<0.01 for all cases (Table 1).Table 1.B-cell subsets in patients with SS, SS and MALT lymphoma and healthy donors.B-cell subsetsSSHDPt 1FN%Abs. cells/μl%Abs. cells/μl%Abs. cells/μlB lymphocyte12,8 (7,9 – 19,7)151 (95-112)8,5 (7,2-11,0)200 (100-200)4,531**plasma cells6,9 (4,2-10)12 (6-22)0,1 (0,05-0,1)0,1 (0-0,2)5,713*plasmablasts0,88 (0.37-1.8)2 (1-3)0,1 (0,1-0,2)0,2 (0,1-0,4)26,612*/**transitional B-cells5.7 (0.9-17)8 (4-32)0,1 (0-0,1)0,1 (0-0,3)00*switched cells9.1 (5.9-20.7)18 (11-29)12,8 (9,3-17,0)20 (10-40)5216**non-switched memory B-cells4.13 (2.7-5.4)7 (3-15)7,4 (3,7-11,1)10 (5-20)165**SS Sjogren’s patients; HD healthy donors, Pt 1 patient with SS and MALT lymphoma* SS and HD groups compared, р<0.01** Pt 1 and SS group comparedOne of the patients (Pt 1) was diagnosed with MALT lymphoma of the parotid salivary gland; she had a distinct B-lymphocyte subpopulations distribution, which was different from the rest of the SS group. She had the lowest percentage / absolute B lymphocyte count of all patients with SS, the highest percentage of switched cells and non-switched memory B-cells, and the highest percentages/absolute numbers of plasmablasts. For this reason, the patient was excluded from the subsequent analysis (Table 1).Patients with activity of SS by ESSDAI ≥ 5 had a significantly higher percentage of B cells (p=0.007), and significantly higher absolute B lymphocyte count of naïve cells (p=0.04) and plasmablasts (p=0.048).Conclusion:Immunophenotyping showed disturbed homeostasis of the B-cells subpopulations in our SS cohort. A significant increase in plasmablasts in SS, as well as a positive correlation of the level of plasmablasts with the SS activity and presence of lymphoma could suggest the important role of these cells in the pathogenesis of SS.Disclosure of Interests:None declared.
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