Attempt to assess direct interactions between tumor burden, myeloid-derived suppressor cells and PD-1- and TIM-3-expressing T cells in multiple myeloma patients

The avoidance of immune surveillance by malignant plasma cells (PCs) in multiple myeloma (MM) is mediated by different mechanisms, among which an induction of T cell exhaustion and expansion of myeloid-derived suppressor cells (MDSCs) appear to play substantial roles, but it is still a lack of data on possible MDSC-mediated induction of T cell exhaustion. The aim of the present work was to evaluate possible relationship between frequencies of MM PCs, MDSCs and phenotypically exhausted PD-1+ and TIM-3+ T cells in bone marrow (BM) samples and peripheral blood (PB) of MM patients at various disease stages. Peripheral blood (n = 88) and BM samples (n = 56) were obtained from MM patients (newly diagnosed (n = 6), patients in remission (n = 71) and with progressive disease (n = 11)). Frequencies of T cells expressing checkpoint receptors PD-1 and TIM-3, polymorphonuclear MDSCs (PMN-MDSCs, Lin-CD14-HLA-DR- CD33+CD15+/CD66b+), monocyte MDSCs (M-MDSCs, CD14+HLA-DRlow/-), early MDSCs (E-MDSCs, Lin-HLA-DR-CD33+CD15-/CD66b-), and MM PCs (CD45dimCD38+CD138+CD56+CD19-CD117+CD27- CD81-) were assessed with flow cytometry. Circulating and BM-resident PD-1+/TIM-3+T cell subsets, BM E-MDSCs, as soon as MM PCs and serum beta2-microglobulin (B2-M) levels were gradually increased in patients at different stages. Despite that, there were no associations between the markers of tumor load and the studied cell subsets. In patients in remission, BM PMN-MDSCs negatively correlated with CD4+T cells, CD4+PD-1+ and CD8+TIM-3+T cell subsets; there were positive correlations between BM E-MDSCs and CD4+PD-1+TIM-3+ cells and PB M-MDSCs and CD8+PD-1+ and (as a trend) CD8+TIM-3+T cells. We found no associations for the samples of patients at diagnosis and with progression. We can conclude that a possible mutual influence of malignant PCs, MDSCs and PD-1+/TIM-3+T cells is nonlinear, especially during a manifest tumor growth at diagnosis and progression. The detected negative correlations between resident PMN- MDSCs and T cell subsets might be associated with MDSC suppressive function, affecting both predominantly activated PD-1+ cells and exhausted TIM-3+ subsets. The positive correlations between BM E-MDSCs and CD4+PD-1+TIM-3+ cell subset and circulating M-MDSCs and PD-1+ and TIM-3+ CD8+T cells might confirm an ability of MDSCs to induce T cell exhaustion

IMMUNOMODULATORY EFFECT OF CIRCULATING BONE MARROW PROGENITORS AS A POSSIBLE MECHANISM OF NEUROPROTECTION IN TRAUMATIC BRAIN INJURY

We have previously shown that acute traumatic brain injury (TBI) is accompanied by increased level of circulating bone marrow progenitors, and favorable outcome is associated with early mobilization of CD34+CD45+ hematopoietic progenitor cells (HP). The present study was aimed at investigating whether patients with early HP mobilization differed from those with mobilization failure by systemic inflammatory reaction and immune parameters. The TBI patients were characterized by increased levels of serum C-reactive protein (CRP), IL-1в, IL-6, IL-8, MCP-1, G-CSF and IL-1ra indicative for presence of systemic inflammatory response. Importantly, patients with lacking mobilization of early HPs were shown to have significantly higher serum levels of CRP, MCP-1, MIP-1в, and G-CSF and a lower level of VEGF. In addition, patients with lack of early HP mobilization differed by significantly lower absolute number of lymphocytes, CD3+ T cells, CD4+ T cells, CD16+ NK cells and proliferative response of mononuclear cells to stimulation with ConA as well as by 4-fold higher rate of infectious complications compared with the opposite group. These data suggest that correlation of early mobilization of CD34+CD45+ cells with a favorable outcome in TBI patients may be partially mediated by anti-inflammatory and immunomodulatory effects of circulating bone marrow progenitors

Внескелетная саркома Юинга малого таза (обзор литературы и клиническое наблюдение)

Timely diagnosis of Ewing's sarcoma is an actual problem of our time, since this tumor is characterized by fairly rapid growth and aggressive course. According to literature data, it ranks 2-nd among all bone tumors, second only to osteosarcoma, and is 8.64%. This review article discusses the possibilities of radiation research methods in the early diagnosis of this tumor on the example a clinical observation of the extra-skeletal form of Ewing's sarcoma.Своевременная диагностика саркомы Юинга представляет собой актуальную проблему современности, так как данная опухоль характеризуется достаточно быстрым ростом и агрессивным течением. Согласно литературным данным, она занимает 2-е место среди всех костных новообразований и составляет 8,64%, уступая только остеосаркоме. В данной обзорной статье рассматриваются возможности лучевых методов исследования в ранней диагностике этой опухоли на примере клинического наблюдения внескелетной формы саркомы Юинга

Common variable immunodeficiency disorder: a clinical case

Primary immunodeficiency is a rare congenital pathology associated with failure of immune system, manifested by disturbances of its functions. These defects lead to increased susceptibility of patients to various infectious agents, as well as the development of autoimmune, malignant and other diseases. Primary immunodeficiency is classified as a rare disease, which was previously associated with a poor prognosis with a high risk of mortality in childhood. To date, the emergence of highly effective treatment methods has changed the course and prognosis of these diseases. Clinicians of various specialties increasingly meet with this pathology in everyday practice, including adult age cohorts. In this regard, early diagnosis of primary immunodeficiency in adults becomes relevant, being associated with choosing optimal therapy, prevention of severe internal organ damage, determination of management strategy for the patient, as well as the need to identify inherited disorders and provide information to the patient’s family. Delayed verification of the diagnosis may cause disability of the patient and development of irreversible, often fatal complications. This article presents our own clinical case with a newly diagnosed clinical condition: Common variable immunodeficiency disorder (CVID), the most common form of primary immunodeficiency in adults. The symptoms of common variable immunodeficiency disorder appear in these patients in adulthood, but a high-quality collected history of the disease will allow you to trace symptoms in the patients even since early childhood. There is a common gap for several years between the onset of the disease and clinical diagnosis, since erroneous diagnosis is often made due to non-specific clinical symptoms that resemble other, more frequent diseases. The prognosis of patients with CVID depends on several factors: frequency of infections, structural disorders in the lungs, the occurrence of autoimmune diseases and the success of infection prevention. Thus, a variety of clinical forms of primary immunodeficiency, lack of awareness of doctors about this pathology, complexity of immunological examination in the general medical network lead to the fact that CVID is not diagnosed for long terms, and patients do not receive the necessary pathogenetic therapy. There is a need for drawing attention of doctors of various disciplines to the fact that the recurrent inflammatory processes of various localization, which are difficult to respond to adequate traditional therapy, may be caused by changes in the immune system, including congenital, genetically determined immunodeficiency

THE COMPARATIVE ANALYSIS OF GRAFT CELL SUBTYPES AND ITS CYTOKINE PRODUCTION OF LYMPHOMA AND LEUCOSIS PATIENTS

Cell subtypes and cytokine profile of apheresis products collected from lymphoma and acute leucosis patients were analyzed. It was shown, that acute leucosis patients' grafts contained higher relative numbers of naïve T-cells, CD4+CD25high T-cells, T-lymphocytes (non-significant trend) and lower counts of granulocytes. Significant increase of relative numbers of dividing CD34+ cells (in S, G2/M phases of the cell cycle) was demonstrated, in acute leucosis patients' grafts. In lymphoma grafts the levels of CD34+ cells in G0/G1 phases were found, to be increased. Cells isolated from grafts of acute leucosis patients characterized by higher levels of proinflammatory cytokines production, such as IL-1, IL-6, MIP-1β, TNF-α, IL-8, IFN-γ (the last two ones— non-significant trend) and cytokines, essential for humoral immune response (IL-4 and — in trend — IL-10). The existing differences didn't influence on effectiveness of early lymphocyte recovery

THE IMMUNOLOGICAL CHARACTERISTIC OF RA PATIENTS WITH ANAEMIA

Abstract. The aim of the investigation was to study the immunological characteristics of RA patients with anaemia. Clinical and laboratory data including the percentage of the main lymphocyte subclasses, phagocyte and DTH-effector activity, serum concentration of immunoglobulins, the percentage of cells producing IFNγ and/or IL-4 and percent of monocytes producing TNF. We revealed some significant clinical, laboratory and immunological differences between RA patients and healthy donors and between patients with and without anaemia. Our data demonstrate RA anemic patients to have more severe disorders than patients without anaemia. We also revealed some significant immunological differences between RA patients and healthy donors and between patients with and without anaemia, including percent of cells producing IFNγ and/or IL-4. Our data permit to conclude that RA patients have many different immunological disturbances, more severe in anaemic patients

IMMUNOLOGICAL FEATURES OF ALLERGIC AND NON-ALLERGIC FORMS OF ATOPIC DERMATITIS

Abstract. In spite of similar clinical patterns, there are numerous differences in immunopathogenesis of intrinsiс and extrinsiс forms of atopic dermatitis. Patients with both forms have decreased levels of CD8+CD25+ lymphocytes, decreased telomere DNA length of CD4+T-cells, decreased migration inhibition index in delayedtype hypersensitivity, decreased levels of CD16+NK-cells, decreased Fc-dependent monocyte and granulocyte phagocytosis, increased hydrogen peroxide production by neutrophils, increased levels of CD19+B-cells, as well as high IgA and IgG immunoglobulin levels. Extrinsiс form of atopic dermatitis are characterized by more severe clinical course, and by involvement of both immediate hypersensitivity (hyperproduction of IgE and decreased T-cells with intracellular IFNγ production), like as delayed-type hypersensitivity (decreased migration index along with decreased migration inhibition index). CD8+ play a large role in extrinsiс form of atopic dermatitis that may be traced as decreased telomere length of CD8+T- cells, decreased levels of CD8+CD45RO+ cells, increased levels of CD8+CD45RA+ naive cells and increased levels of CD28+ costimulatory molecules on CD8+cells. Increased levels of CD4+CD25+bright cells and strongly alterations of innate immunity determined of decreased H2O2 production by monocytes are shown in extrinsiс form. Hence, the severity index of atopic dermatitis is more expressed in extrinsic form of bronchial asthma and it is, probably, determined by more exaggerated immunological alterations

T–CELL VACCINE PREPARATION FOR MULTIPLE SCLEROSIS TREATMENT

Abstract. A two–stage technology of preparation of T–cell vaccine designated for multiple sclerosis treatment is described. At the first stage myelin–specific lymphocytes undergoe antigen–dependent cultural selection, whereas at the second stage they are grown by means of non–specific stimulation. The vaccine prepared in this way was found to induce specific anti–idiotypic immune response, directed against myelin–reactive T–lymphocytes. The results of 1–year follow–up of 18 vaccinated patients with a cerebral–spinal type of multiple sclerosis indicated the absence of side effects of T–cell vaccination, and suggest the possibility of effective application of this treatment within early stages of disease. (Med. Immunol., 2005, vol.7, № 1, pp 27532

THE PHENOTYPE AND FUNCTION OF MONOCYTES IN PATIENTS WITH PULMONARY TUBERCULOSIS

Abstract. Peripheral blood monocytes were investigated in the patients with pulmonary tuberculosis. It was established that population of CD14+16+ monocytes was twofold increased in the patients with tuberculosis. The higher level of CD14+CD16+ monocytes was associated with decreasing number of monocytes with intracellular TNF–α, and negative correlation between these parameters was revealed. On the contrary, the higher level of CD14+CD16+ monocytes was connected with increased number of IL–10–producing monocytes. IL–10–producing cells were established mainly in the population of CD16+ monocytes and so population of CD14+CD16+ monocytes may represent the cells with suppressive activity. Really, the CD14+CD16+ monocytes were increased in patients with defective antigen specific response. Enhancement of CD14+CD16+ monocytes was observed in patients with active tuberculosis independently of form and dissemination of disease and did not connected with concomitant viral or bacterial infection. (Med. Immunol., 2005, vol.7, № 1, pp 49556