We studied suppressor potential of myeloid-derived suppressor cells (MDSC) in multiple myeloma patients, including before and after mobilization of hematopoietic stem cells (HSC), by evaluating the ...expression of arginase-1 (Arg1), indolamine-2,3-dioxygenase (IDO), and PD-L1 in MDSC subsets. The study included 20 multiple myeloma patients in remission, 5 patients with progression, as well as 10 sex-and age-matched healthy donors. The expression of Arg1, IDO, and PD-L1 in circulating granulocytic MDSC (G-MDSC, Lin
–
HLA-DR
–
CD33
+
CD66b
+
), monocytic MDSC (M-MDSC, CD14
+
HLA-DR
low/–
), and early-stage MDSC (E-MDSC, Lin
–
HLA-DR
–
CD33
+
CD66b
–
) was evaluated by flow cytometry. Multiple myeloma patients in remission were characterized by reduced expression of Arg1 in M-MDSC in comparison with donors. The expression of Arg1 in M-MDSC depended on the number of induction therapy lines performed and was significantly lower in patients who received ⩾2 lines and responded with remission. Patients with multiple myeloma progression (resistant to therapy) showed significantly increased expression of Arg1 and PD-L1 in M-MDSC, as well as increased expression of Arg1 in E-MDSC. After G-CSF-induced mobilization of HSC, the content of circulating Arg1-expressing M-MDSC increased significantly. Considering the presence of MDSC in apheresis products, MDSC suppressive activity is discussed as a factor affecting the outcomes of autologous HSC transplantation 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-DR
low/-
), early MDSCs (E-MDSCs, Lin
-
HLA-DR
-
CD33
+
CD15
-
/CD66b
-
), and MM PCs (CD45
dim
CD38
+
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.
T cells expressing checkpoint receptors PD-1, TIM-3 etc., are potential targets for monoclonal antibody immunotherapy in multiple myeloma (MM). However, checkpoint expressing T cell compartment ...includes different subsets, and their dysregulation following anti-checkpoint therapy can lead to the development of adverse events.
The aim of this study
was to evaluate activation markers – homeostatic cytokine receptors and transcription factors expressed by PD-1and TIM-3-positive T cells.
Material and Methods.
Relative counts of circulating PD-1and/or TIM-3-positive and negative T cells expressing common ɣ-chain cytokine receptors CD25, CD122, CD127, phosphorylated STAT5, and transcription factor EOMES associated with T cell exhaustion were studied using flow cytometry in 17 healthy donors, 22 MM patients with remission and 7 MM patients with progressive disease.
Results.
T cells expressing PD-1 and/or TIM-3 inhibitory checkpoint receptors in MM patients consisted of CD25+EOMESactivated cells, CD4+CD25+CD127-FOXP3+ regulatory T cells (Treg), CD4+CD25-EOMES+ dysfunctional cells. CD25+ T cells from healthy donors and MM patients, regardless of the expression of the studied checkpoint receptors, were EOMES-negative. No such association was found for CD122 and CD127 cytokine receptors. EOMES is a marker of T cell exhaustion for CD4+ T cells, but not for CD8+ T cells, in which it is more associated with activation. The proportion of CD4+ Tregs among circulating PD-1+ and TIM-3+ T cells was relatively low. A higher content of cytokine receptors in the population of TIM-3+ T cells may indicate the predominant involvement of TIM-3 in the control of homeostatic proliferation of mature T cells under lymphopenic conditions, while the expression of PD-1 may be more associated with the regulation of activation through T cell receptor. PD-1+ and/or TIM-3+ levels of activated, dysfunctional, and regulatory T cells can potentially be used to predict the safety and efficacy of targeted immunotherapy.
Introduction
. Myeloid-derived suppressor cells (MDSCs) play an important role in restriction of the immune response and are associated with a poor prognosis in cancer. Mobilization of hematopoietic ...stem cells (HSCs) before high-dose chemotherapy (HCT) with autologous HSC transplantation (auto-HSCT) is accompanied by a signifcant increase in MDSC counts in peripheral blood and apheresis product of multiple myeloma (MM) patients. However, quantitative changes of these cells at the post-transplant and their role at the immune recovery remain unexplored.
The study was aimed
to analyze the dynamics of circulating MDSC counts and the expression of suppressor molecule arginase-1 in patients with MM in the frst 12 months after HCT and auto-HSCT and evaluate association between MDSCs and transplantation outcomes.
Material and Methods
. The study included 44 MM patients who underwent HCT and auto-HSCT. The relative number of granulocytic MDSCs (G-MDSCs), monocytic MDSCs (M-MDSCs), and early-stage MDSCs (E-MDSCs), as well as the expression of arginase-1 in each of MDSC subsets was evaluated by fow cytometry in patient peripheral blood samples.
Results. At the engraftment (day +12 – +16, leukocytes >1×10
9
/l), M-MDSC relative count was increased (p
U
=0.038), as well as the relative (p
U
=0.003) and absolute (p
U
˂
0.0001) counts of G-MDSCs, decreasing after 6 months down to pre-transplant values (рU=0.007, рU=0.024 and рU=0.02, respectively) and remaining at the same level at the 12-month follow-up period. The absolute count of E-MDSCs by the time of the engraftment decreased transiently (p
U
=0.004 vs before HCT), gradually recovering by 12-month follow-up (p
U
=0.032 vs day +12 – +16). The remission within 12 months in the group with G-MDSCs˂0.17 % at the engraftment was observed in 67 ± 11 % of patients, with G-MDSCs >0.17 % – in 94 ± 6 % of patients (p=0.049). During the 12-month post-transplant, the number of M-MDSCs expressing arginase-1 has been increasing, with a tendency to lower values at the engraftment in patients with early MM relapse (p
U
=0.09).
Conclusion
. The association of early MM relapse after auto-HSCT with the lower count of G-MDSCs and the lower count of arginase-1
+
M-MDSCs at the engraftment suggests that MDSCs is involved in the restriction of homeostatic proliferation as a factor for more effective immune recovery.
Ebola hemorrhagic fever, also known as Ebola virus disease or EVD, is one of the most dangerous viral diseases in humans and animals. In this open-label, dose-escalation clinical trial, we assessed ...the safety, side effects, and immunogenicity of a novel, heterologous prime-boost vaccine against Ebola, which was administered in 2 doses to 84 healthy adults of both sexes between 18 and 55 years. The vaccine consists of live-attenuated recombinant vesicular stomatitis virus (VSV) and adenovirus serotype-5 (Ad5) expressing Ebola envelope glycoprotein. The most common adverse event was pain at the injection site, although no serious adverse events were reported. The vaccine did not significantly impact blood, urine, and immune indices. Seroconversion rate was 100 %. Antigen-specific IgG geometric mean titer at day 42 was 3,277 (95 % confidence interval 2,401-4,473) in volunteers immunized at full dose. Neutralizing antibodies were detected in 93.1 % of volunteers immunized at full dose, with geometric mean titer 20. Antigen-specific response in peripheral blood mononuclear cells was also detected in 100 % of participants, as well as in CD4+ and CD8+ T cells in 82.8 % and 58.6 % of participants vaccinated at full dose, respectively. The data indicate that the vaccine is safe and induces strong humoral and cellular immune response in up to 100 % of healthy adult volunteers, and provide a rationale for testing efficacy in Phase III trials. Indeed, the strong immune response to the vaccine may elicit long-term protection. This trial was registered with grls.rosminzdrav.ru (No. 495*), and with zakupki.gov.ru (No. 0373100043215000055).
La relevancia del problema a investigar está condicionada por el hecho de que el fenómeno de la maternindad temprana lleva un carácter social agudo. Debido a este hecho, el artículo está destinado a ...revelar las causas de la maternidad temprana y a buscar las vías de la solución del problema en el contexto de trabajo social y pedagógico. El método líder para la investigación de este problema es un estudio demoscópico que permite identificar las causas de la detección y elaborar recomendaciones relacionadas con la perfección de la ayuda social y pedagógica a las madres adolescentes. Fue revelado que es necesario prestar gran atención a la profiláctica del embarazo temprano y a la solución de las situaciones sociales de crisis.
Systemic lupus erythematosus(SLE) is an immune-mediateddisease that is responsiveto suppression or modulation of the immune system. Patients with SLE who experience persistent multiorgan dysfunction, ...despite standard doses of intravenous cyclophosphamide (Cy), represent a subset of patients at high risk of early death. We investigated the efficacy and toxicity of high-dose immunosuppression and autologous hematopoietic stem cell transplantation (SCT) to treat such patients. Six patients (all female, age 15-29 years) with severe refractory SLE were enrolled in the clinic of our institution from 1998 to 2003. All patients were seriously ill, with SLE disease activity indices (SLEDAI) of 6-30, includingtwo cases with central nervoussystem lupus, one case with lung vasculitis, and three cases with nephritis and nephrotic syndrome. All patients were registered in the European Group for Blood and Marrow Transplantation (EBMT)/European League Against Rheumatism (EULAR) database. Previous immunosuppression included pulse Cy intravenous, prednisolone (standard doses and pulse therapy), oral Cy and azathioprine, with little or no effect on disease progression.Autologous hemopoietic stem cells were collected from bone marrow (n 4) or mobilized from peripheral blood with Cy and granulocyte colony-stimulating factor (G-CSF) (n 2). Pre-transplant conditioning regimens included BEAM + ATG (n 2), melphalan 140 mg/m2 etoposid 1600 mg/m2 (n 2) and Cy 200 mg/kg + ATG (n 2). Median time to an absolute neutrophil count (ANC) greater than 0.5 ×10 50 ×10 9/L and platelet count greater than 9/L was 13 and 15 days, respectively. Three patients died on days 11, 22 and 63 due to transplant-relatedcomplications. The follow-up is now 60 and six months for two patients (complete remission), and 42 months for one other patient (partial response). All patients had experienced multiple and severe episodes of infections pre-SCT and long-term history of corticosteroid therapy (3-14 years). We conclude that achievement of prolonged, corticosteroid-freeremissions is a reality. Judicious selection of patients earlier in disease or in remission, but with a high risk of relapse or further progression, will diminish transplantation-relatedmortality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We showed that inhibition of cytokine production by bone marrow adherent cells and their soluble products is a mechanism of regulation of cytokine-producing activity of bone marrow erythrokaryocytes ...under normal conditions.
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