Lethal pulmonary embolism in a pregnant woman with severe acute respiratory syndrome coronavirus-2 receiving prophylactic anticoagulation: a case report.

BACKGROUND: A limited number of studies have described thrombotic complications in pregnant women with COVID-19. Here we report on fatal pulmonary embolism in a pregnant woman with laboratory confirmed SARS-CoV-2 infection. CASE PRESENTATION: A 28-year-old Kazakh woman was hospitalized with muscle pain, dry cough and a temperature of 37.5 °C at the 29th week of gestation. Upon admission, a blood test demonstrated elevated neutrophil-to-lymphocyte ratio, decreased levels of erythrocytes and hemoglobin, as well as prolonged prothrombin and activated partial thromboplastin time. Within 14 days of admission, she experienced respiratory distress and underwent transfer to the intensive care unit, intubation and a cesarean section. The patient received intravenous antibiotics, antiviral medications, systemic corticosteroids and dual anticoagulation with aspirin and enoxaparin. Death outcome was reported on day 18 of illness despite aggressive supportive care. Histological analysis demonstrated that obstruction of the main pulmonary arthery and disseminated intravascular coagulation were the causes of death. CONCLUSIONS: This case demonstrates that in the management of pregnancy and childbirth in patients with suspected or confirmed COVID-19 infection, special attention should be paid to coagulation system parameters and timely appropriate prophylaxis of thromboembolic complications, which has yet to be determined.

Molecular detection and characterization of bovine viral diarrhea virus type 2 and bluetongue virus 9 in forest flies (Hippobosca equina) collected from livestock in southern Kazakhstan.

Keds are hematophagous ectoparasites of animals belonging to the family Hippoboscidae (Diptera: Hippoboscoidea). Because of their importance as vectors of some pathogens of medical and veterinary importance, they have received special attention. There are numerous studies demonstrating the presence of various parasites and pathogenic bacteria in keds. At the same time, there are very few reports on ked-related viruses. The aim of this study was to perform a molecular survey of viral pathogens in the forest fly (Hippobosca equina) from southern Kazakhstan. In this study, 104H. equina were collected from livestock in Turkistan oblast (southern region of Kazakhstan), which has the largest concentration of livestock in the country. Insect homogenates were screened by PCR for pestiviruses, orbiviruses, flaviviruses, orthobunyaviruses, phleboviruses, orthopoxviruses, capripoxviruses, parapoxviruses, and asfiviruses. The causative agents of two livestock diseases, bovine viral diarrhea virus (BVDV) (3/104; 2.88%; 95% confidence interval (CI): 0.6-8.2%) and bluetongue virus (BTV) (1/104; 0.96%; 95% CI: 0.02-5.24%), were identified and subjected to further analysis. The BTV strain was isolated and all ten genomic RNA segments were sequenced using the Sanger technique. The isolated BTV strain showed >99.6% identity in all genomic segments with the BTV-9 strains belonging to the 'western' topotype. Partial analysis of the 5'-untranslated region demonstrated that both BVDV strains are closely related to Pestivirus B. Flaviviruses, phleboviruses, orthobunyaviruses, poxviruses, and asfiviruses were not detected. This is the first report describing BVDV type 2 in Kazakhstan. The study also confirms the presence of BTV serotype 9 in southern Kazakhstan. The data presented here can help improve preventive measures to control the spread of viral diseases in livestock by using forest flies as an object of epidemiological studies. However, further studies are needed to investigate the vector capacity of H. equina and its suitability for xenodiagnosis of veterinary relevant pathogens.

Molecular and seroepidemiological investigation of Сoxiella burnetii and spotted fever group rickettsiae in the southern region of Kazakhstan.

Ticks are involved in the circulation of a number of human pathogens, including spotted fever group (SFG) Rickettsia spp. and Coxiella burnetii. Little is known about the occurrence of these microorganisms in the southern region of Kazakhstan. In 2018-2022, a total of 726 ticks were collected from bitten humans, livestock, and vegetation in four oblasts of the southern region of Kazakhstan and subjected to DNA extraction. The overall infection rate of Coxiella spp. and Rickettsia spp. in the ticks was 3.3% (24/726) and 69.9% (300/429), respectively. Phylogenetic analysis of ompA and gltA genes revealed the presence of three pathogenic SFG rickettsiae: Candidatus R. tarasevichiae, R. aeschlimannii and R. raoultii in ticks collected from bitten humans. In addition, Candidatus R. barbariae was detected in six Rhipicephalus turanicus ticks for the first time in Kazakhstan. To determine the seroprevalence of C. burnetii infection, we performed a serological analysis of samples collected from 656 domestic ruminants (cattle, sheep, and goats) in the region. Overall, 23.5% (154/656) of the animals tested were positive for IgG against C. burnetii. Seroprevalence at the herd level was 54% (28/52). Goats (43%; 12/28; odds ratio (OD) = 28.9, p < 0.05) and sheep (31.9%; 137/430; OD = 18.1, p < 0.05) had higher seroprevalence than cattle (2.5%; 5/198). Among the risk factors considered in this study, age (p = 0.003) and the oblast in which the animals were sampled (p = 0.049) were statistically associated with seropostivity for Q fever in sheep, according to the results of multivariate logistic regression analysis. Seroprevalence ranged from 0% to 55.5% in animals in different districts of the southern region of Kazakhstan. Active C. burnetii bacteremia was detected in four of 154 (2.6%) seropositive animals. The data obtained provide strong evidence of the presence of pathogenic rickettsiae and C. burnetii in the southern region of Kazakhstan and emphasize the need to improve epidemiological surveillance in the region.

Molecular and serological survey of bovine viral diarrhea virus infection in cattle in Kazakhstan.

The aim of this study was to estimate the occurrence of bovine viral diarrhea virus (BVDV) infection and to assess the population immunity in cattle vaccinated against BVDV in different regions of Kazakhstan. Cattle samples were collected in 12 oblasts (43 districts) of Kazakhstan. A total of 2477 cattle from 114 herds and 21 Bukhara deer (Cervus elaphus bactrianus) were examined by ELISA and conventional RT-PCR. Univariate and multivariate logistic regression analysis was performed to identify risk factors associated with BVDV infection in the country. In total, antibodies against BVDV were found in 79.3% (1965/2477) of all the animals and 92.1% (105/114) of all the herds examined. Seroprevalence in unvaccinated and vaccinated animals was 48.6% (447/920) and 98.7% (1391/1410), respectively. Seroprevalence in deer was 19.1% (4/21). The BVDV RNA was detected in six unvaccinated cattle (0.2%). Sequence analysis of the 5'-untranslated region demonstrated that four of the detected strains belonged to BVDV-1 and two strains to BVDV-2. Regression analysis revealed that age, production type, housing method, farm size, and geographic location were risk factors for BVDV infection in cattle in Kazakhstan. The present data confirm circulation of BVDV-1 and BVDV-2 in Kazakhstan and highlight the need to improve strategies for prevention and control of BVDV infection in the country.

A Case of Combined Infection with Tick-Borne Encephalitis and Lyme Borreliosis with Severe Meningoencephalitis and Complete Recovery.

Here, we present a case of severe meningoencephalitis caused by combined infection with tick-borne encephalitis (TBE) and Lyme borreliosis (LB) in a 25-year-old woman in a rural area of Zhambyl region, Kazakhstan. She presented with fever, nausea, vomiting, weakness, sweating, severe headache, arthralgia, and malaise. The course of illness was further complicated by encephalitis with symmetric lesions of the midbrain cerebral peduncles and serous meningitis. TBE and LB co-infection were established by a two-fold increase in serum IgG titers between day 21 and day 25 of illness. Both infections responded well to combined therapy with human TBE immunoglobulins, antibiotics, antiviral drugs, glucocorticoids, and diuretics. The outcome of the disease was favorable and the patient recovered completely.

Prevalence and genetic diversity of coronaviruses, astroviruses and paramyxoviruses in wild birds in southeastern Kazakhstan.

Wild birds are natural reservoirs of many emerging viruses, including some zoonoses. Considering that the territory of Kazakhstan is crossed by several bird migration routes, it is important to know pathogenic viruses circulating in migratory birds in this region. Therefore, the aim of this study was to identify the host range, diversity and spatial distribution of avian paramyxoviruses, coronaviruses, and astroviruses in free-ranging wild birds in the southeastern region of Kazakhstan. For this purpose, we collected tracheal and cloacal swabs from 242 wild birds belonging to 51 species and screened them using conventional PCR assays. Overall, 4.1% (10/242) and 2.9% (7/242) of all examined birds tested positive for coronaviruses and astroviruses, respectively. Coronaviruses were found in the orders Pelecaniformes (30%; 3/10), Charadriiformes (30%; 3/10), Columbiformes (20%; 2/10), Anseriformes (10%; 1/10), and Passeriformes (10%; 1/10). All detected strains belonged to the genus Gammacoronavirus. Astroviruses were detected in birds representing the orders Passeriformes (57%; 4/7), Coraciiformes (14%; 1/7), Charadriiformes (14%; 1/7), and Columbiformes (14%; 1/7). Paramyxoviruses were observed in only two birds (0.8%; 2/242). Both strains were closely related to the species APMV-22, which had not been previously detected in Kazakhstan. Phylogenetic analysis of the partial RdRp gene sequences of the virus strains revealed three different clades of astroviruses, two clades of coronaviruses, and one clade of paramyxoviruses. The results of this study provide valuable information on the diversity and spatial distribution of paramyxoviruses, coronaviruses, and astroviruses in wild birds in southeastern Kazakhstan and highlight the importance of further thorough monitoring of wild birds in this region.

Identification and characterization of bluetongue virus in Culicoides spp. and clinically healthy livestock in southeastern Kazakhstan.

OBJECTIVE: Bluetongue is an arthropod-borne disease of ruminants. Here, we investigated the seroprevalence of bluetongue virus (BTV) in livestock and performed the first genetic characterization of BTV isolated from sheep and Culicoides midges in the southeastern region of Kazakhstan. METHODS: Blood samples were collected from 1241 asymptomatic livestock. In addition, 497 Culicoides midges were collected. Samples were analyzed for specific anti-BTV antibodies and BTV RNA by ELISA and conventional RT-PCR, respectively. RESULTS: The overall seroprevalence of BTV antibodies was shown to be 4.3 % (46/1079) in small ruminant and 1 % (1/82) in cattle. Anti-BTV antibodies were not detected in camels (0/80). The minimum infection rate of BTV in Culicoides was shown to be 0.24 %. Seg-2 and Seg-10 sequence analysis demonstrated that all isolates belonged to the 'western' topotype of the BTV-9 strain. CONCLUSION: The present data confirm circulation of BTV in southeastern Kazakhstan.

Myeloid-derived suppressor cells in COVID-19: A review.

Coronavirus disease 2019 (COVID-19) is a potentially life-threatening infection characterized by excessive inflammation, coagulation disorders and organ damage. A dysregulated myeloid cell compartment is one of the most striking immunopathologic signatures of this newly emerged infection. A growing number of studies are reporting on the expansion of myeloid cells with immunoregulatory activities in the periphery and airways of COVID-19 patients. These cells share phenotypic and functional similarities with myeloid-derived suppressor cells (MDSCs), which were first described in cancer patients. MDSCs are a heterogeneous population of pathologically activated myeloid cells that exert immunosuppressive activities against mainly effector T cells. The increased frequency of these cells in COVID-19 patients suggests that they are involved in immune regulation during this infection. In this article, we review the current findings on MDSCs in COVID-19 and discuss the complex role of these cells in the immunopathology of COVID-19.

Fc Receptor is Involved in Nk Cell Functional Anergy Induced by Miapaca2 Tumor Cell Line.

Impaired NK cytotoxicity has been linked to poor cancer prognosis, but its mechanisms are not clearly established. Increasing data demonstrate that NK cells lose cytotoxicity after interaction with NK cell-sensitive tumor cells. In this paper, we provide evidence that the human adenocarcinoma cell line MiaPaCa2 and TNFα and TGFß-treated MiaPaCa2 cultures (MiaPaCa2-TT) induced functional anergy of NK cells via FGL2 protein. MiaPaCa2-TT cultures decreased expression of IFNγ, CD107a, DNAM-1, and stimulated expression of PD1 by NK cells, as well as inhibited their cytotoxic activity in a greater manner compared to the parental culture. More importantly, we found that co-cultivation with anergized NK cells decreased expression of IFNγ and CD107a by naïve NK cells, which supports the hypothesis of NK cell functional anergy transmission. The obtained results suggest a mechanism by which tumor cells may inhibit cytotoxic functions of tumor-infiltrating and circulating NK cells in cancer.Abbreviations: CFSE: Carboxyfluorescein diacetate succinimidyl ester; CSCs: Cancer stem cells; FGL2: Fibrinogen-like protein 2; mAbs: Monoclonal antibodies; MiaPaCa2: Human adenocarcinoma cell line; MiaPaCa2-ТТ: Adenocarcinoma cell line MiaPaCa2 cells stimulated with TNFα and TGFß-1; PI: Propidium iodide; TGFß: Transforming growth factor beta; TME: Tumor microenvironment; TNFα: Tumor necrosis factor alfa.

Monitoring of pathogenic Borrelia burgdorferi sensu lato in the Almaty oblast, Kazakhstan.

Lyme borreliosis (LB) is one of the most common vector-borne diseases transmitted by ticks. It is caused by the Borrelia burgdorferi sensu lato (s.l.) genospecies. The Almaty oblast of Kazakhstan is considered endemic for LB. Nevertheless, there are significant gaps in the tick surveillance for LB agents in the region. We evaluated B. burgdorferi s.l. prevalence in 413 ixodid ticks collected from bitten people and the seroprevalence of antibodies to B. burgdorferi s.l. in 589 residents of the Almaty oblast, Kazakhstan. All samples were collected between 2018 and 2020. Borrelia burgdorferi s.l. DNA was detected in 24 % (9/38) of I. persulcatus ticks that attacked humans in the city of Almaty and the Talgar and Karasay districts. Multilocus sequence typing identified two novel B. afzelii sequence types in I. persulcatus. The seroprevalence of IgG antibodies against B. burgdorferi s.l. in the analyzed population was detected to be 5.8 %. The obtained results confirm active circulation of B. burgdorferi s.l. in the Almaty oblast of Kazakhstan and raise concern regarding LB preventive measures in the region.

The prevalence of Borrelia in Ixodes persulcatus in southeastern Kazakhstan.

Borreliosis is one of the most common vector-borne zoonotic diseases in the world. Limited data are available regarding Borrelia spp. and their genotypes in Kazakhstan. The goal of this study was to investigate the prevalence of Borrelia spp. in ixodid ticks collected in the southeastern region of Kazakhstan. A total of 1907 ixodid ticks were collected by flagging vegetation at three collection areas in the Almaty oblast between 2015 and 2018. They were grouped into 407 pools and examined by qPCR for Borrelia burgdorferi sensu lato (s.l.). A conventional PCR with specific primers targeting 16S rRNA gene was used to differentiate B. burgdorferi s.l. genospecies. Sequence analysis of the PCR products was performed for sixteen samples. Lyme borreliosis agents were only detected in adult questing Ixodes persulcatus. The overall B. burgdorferi s.l. prevalence in I. persulcatus estimated as the minimum infection rate reached 10.7 %. Borrelia burgdorferi sensu stricto was not detected in any of the tick pools. Partial 16S rRNA gene sequencing revealed the presence of B. miyamotoi, B. afzelii, and B. garinii. Borrelia afzelii was the dominant genospecies in Almaty oblast. A significantly lower proportion of B. garinii positive tick pools was detected in the Zailiyskiy Alatau as compared to the Dzungarian Alatau (χ2 = 16.243; p = 0.0001) and Yenbekshikazakh district (χ2 = 7.4156; p = 0.0065). The obtained results indicate the epidemiological significance of B. afzelii and B. garinii in southeastern Kazakhstan. These new data aim to improve the diagnostics of Lyme borreliosis and monitoring of tick-borne infections in Kazakhstan.

Oral administration of ammonium metavanadate and potassium dichromate distorts the inflammatory reaction induced by turpentine oil injection in male rats.

Heavy metal pollution is rapidly increasing in the environment. It has been shown that exposure to vanadium and chromium is able to alter the immune response. Nevertheless, the mechanisms by which these metal pollutants mediate their immunomodulatory effects are not completely understood. Herein, we examined the effect of ammonium metavanadate and potassium dichromate on the development of an inflammatory response caused by subcutaneous injection of turpentine oil. We demonstrated that pretreatment of rats with ammonium metavanadate and potassium dichromate for two weeks prior to initiation of the inflammatory response resulted in a wider zone of necrosis surrounding the site of inflammation. The acute inflammatory process in the combined model was characterized by elevated serum levels of IL-10 and decreased serum levels of IL-6 as compared to rats not treated with ammonium metavanadate and potassium dichromate. Ammonium metavanadate and potassium dichromate administration induced a decrease in the proportion of splenic His48HighCD11b/c+ myeloid cells accompanied by a reduced infiltration of the wound with neutrophils. Further analysis showed decreased proportions of CD3+CD4+IFNγ+ and CD3+CD4+IL-4+ T cells in the rats with combined model as compared to inflamed rats not treated with ammonium metavanadate and potassium dichromate. The data suggest that consumption of vanadium and chromium compounds disrupts the inflammatory response through an altered balance of pro- and anti-inflammatory cytokines and inhibition of effector T cell activation and neutrophil expansion.

Tick-borne pathogens and their vectors in Kazakhstan - A review.

Tick-borne diseases (TBDs), in particular Crimean-Congo hemorrhagic fever (CCHF) and tick-borne encephalitis (TBE), have been found to be expanding beyond their traditional geographic locations in Kazakhstan, which led to increased awareness and concern against TBDs in recent years. The tick fauna of Kazakhstan includes more than 30 species of human-biting ixodid ticks, recognized as carriers of a number of dangerous infectious pathogens that cause CCHF, TBE, tularemia, tick-borne rickettsioses and Lyme borreliosis. This paper presents the current knowledge of the main vectors of tick-borne pathogens (TBP) occurring in Kazakhstan, as well as a review of recent studies of ticks performed with the use of molecular methods being currently developed and widely utilized by Kazakh epidemiologists.

Two case reports of neuroinvasive West Nile virus infection in the Almaty region, Kazakhstan.

BACKGROUND: West Nile virus (WNV) is a member of the genus Flavivirus, which transmitted to humans mainly by mosquitoes. Recent pilot serosurveillance data from the Almaty region, Kazakhstan, suggest widespread WNV circulation in this area. This report includes two cases of neuroinvasive WNV infection in the same family living in a rural area near Tekeli city, Eskeldinsky district, Almaty region, Kazakhstan. Occurring concurrently and manifesting as WNV infection with febrile illness and symptoms of meningoencephalitis. METHODS: The study performed retrospective analysis of clinical histories and achieved serum samples obtained from patients with febrile and meningoencephalitic syndromes of unknown origin in the Almaty region spanning from April 1 to October 31, 2019. All sera samples obtained from patients with clinically suspected cases of acute WNV infection were retrospectively tested for WNV and tick-borne encephalitis virus by commercial immunoassays. Two cases were selected. CASES PRESENTATION: We report two cases that occurred in August 2019 in a rural area near Tekeli city. Previously healthy 28- and 19-year-old husband and wife with febrile illness and neurological manifestations were hospitalized with the diagnosis of meningoencephalitis of unknown etiology and treated empirically. Retrospective serological analysis showed the presence of high titers of IgG against WNV on day 9 after onset of symptoms in cases. CONCLUSIONS: This is the first report of aseptic meningitis with WNV infection in the background in Kazakhstan. The obtained data suggest circulation of WNV in the Almaty region and emphasize importance of laboratory testing for WNV in suspicious cases occurring in the region.

No Association between the rs1799836 Polymorphism of the Monoamine Oxidase B Gene and the Risk of Autism Spectrum Disorders in the Kazakhstani Population.

Autism spectrum disorders (ASDs) are heterogeneous diseases that are triggered by a number of environmental and genetic factors. The aim of the current study was to investigate an association of the rs1799836 genetic variant of the neurotransmitter-related gene MAOB with ASDs. In total, 262 patients diagnosed with ASDs and their 126 healthy siblings were included in the present study. All individuals represented a Kazakhstani population. The distributions of the rs1799836 genotype were in accordance with the Hardy-Weinberg equilibrium among both cases and controls. No statistically significant differences were found in the allelic distributions of this polymorphism between ASD and control subjects (A/G: for males OR = 1.11, 95% 0.59-2.06, p = 0.75; for females OR = 1.14, 95% 0.70-1.86, p = 0.76). However, the increased score in the overall CARS was significantly associated with the A allele of rs1799836 MAOB for females (OR = 2.31, 95% 1.06-5.04, p = 0.03). The obtained results suggest that the rs1799836 polymorphism of the MAOB gene may have little contribution to the development of ASDs but may be involved in pathways contributing to ASD symptom severity in females. Further large-scale investigations are required to uncover possible relationships between rs1799836 MAOB and ASD progression in a gender-specific manner and their possible application as a therapeutic target.

Exogenous Melatonin Up-Regulates Expression of CD62L by Lymphocytes in Aged Mice under Inflammatory and Non-Inflammatory Conditions.

It is well documented that age-related impaired functioning of immunocompetent cells is associated with an increase in the rates of chronic inflammatory diseases. Recently, an ability of melatonin to modulate inflammatory processes by regulating leucocyte recruitment has been demonstrated. However, to date, no studies have attempted to determine the impact of melatonin on the expression of CD62L by lymphocytes. CD62L, also known as L-selectin, is required for the entry of lymphocytes into secondary lymphoid organs, sites of tumor growth and chronic inflammation through high endothelial venules. Here, we investigated the effect of melatonin at physiological concentrations on the expression of CD62L by T and NK cells in vivo and in vitro. We demonstrated that NK and CD3+ T cells obtained from the spleen of aged mice were characterized by decreased expression of CD62L compared to young mice. Melatonin administration up-regulated the levels of surface CD62L on NK and T cell populations in aged mice under non-inflammatory conditions and on CD8+ T cells in aged mice with chronic inflammation. Pre-incubation with melatonin prevented the reduction in CD62L expression by CD8+ T cells induced by the co-cultivation of peripheral blood mononuclear cells with human pancreatic adenocarcinoma cell line (MiaPaCa-2). The obtained results suggest that melatonin can modulate lymphocyte homing into lymph nodes and sites of chronic inflammation and, therefore, can stimulate immune responses in chronic inflammatory conditions associated with aging.

Chronic Inflammation Contributes to Tumor Growth: Possible Role of L-Selectin-Expressing Myeloid-Derived Suppressor Cells (MDSCs).

Recent data have demonstrated that chronic inflammation is a crucial component of tumor initiation and progression. We previously reported that immature myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity toward effector T cells were expanded in experimental chronic inflammation. We hypothesized that elevated levels of MDSCs, induced by chronic inflammation, may contribute to the progression of tumor growth. Using the Ehrlich carcinoma animal model, we found increased tumor growth in mice with chronic adjuvant arthritis, which was accompanied by a persistent increase in the proportion of splenic monocytic and granulocytic MDSCs expressing CD62L (L-selectin), when compared to tumor mice without adjuvant arthritis. Depletion of inflammation-induced MDSCs resulted in decreased tumor growth. In vitro studies demonstrated that increased expression of CD62L by MDSCs was mediated by TNFα, elevated concentrations of which were found in tumor mice subjected to chronic inflammation. Moreover, the addition of exogenous TNFα markedly enhanced the suppressive activity of bone marrow-derived MDSCs, as revealed by the ability to impair the proliferation of CD8+ T cells in vitro. This study provides evidence that chronic inflammation may promote tumor growth via induction of CD62L expression by MDSCs that can facilitate their migration to tumor and lymph nodes and modulation of their suppressor activity.

Functional heterogeneity of circulating T regulatory cell subsets in breast cancer patients.

BACKGROUND: Regulatory T cells (Tregs) play a major role in tumor escape from immunosurveillance by suppressing effector cells. The number of Tregs is increased in tumor sites and peripheral blood of breast cancer patients. However, the data regarding phenotypic and functional heterogeneity of Treg subpopulations in breast cancer are limited. The present study aimed to investigate the number and suppressive potential of Tregs that possess natural naïve-(N nTregs), effector/memory-like (EM nTregs), and Tr1-like phenotypes in breast cancer patients and healthy women. METHODS: The study included 10 HW and 17 primary breast cancer patients. Numbers of CD4+CD25+FoxP3+CD45RA+ N nTregs, CD4+CD25+FoxP3+CD45RA- EM nTregs, and CD4+IL-4-IL-10+ Tr1 subsets and the expression of CTLA-4, CD39, GITR, LAP, and IL-35 by these Treg subsets were measured in freshly obtained peripheral blood by flow cytometry. RESULTS: Herein, we demonstrate that the percentages of N nTregs, EM nTregs, CD25+ and FoxP3+ Tr1 cells are elevated in the peripheral blood of breast cancer patients, but do not correlate with cancer stages. Nevertheless, the frequency of CD25+ Tr1 cells was associated with nodal involvement, while the number of EM nTregs correlated with clinical outcome. The expression of CTLA-4 and IL-35 by all assessed Treg subsets was increased throughout all tumor stages (I-III). CONCLUSIONS: Collectively, the current study shows phenotypic alterations in suppressive receptors of Treg subsets, suggesting that breast cancer patients have increased activity of N nTregs, EM nTregs and Tr1 cells; and EM nTregs and CD25+ Tr1 cells represent prospective markers for assessing disease prognosis.

Daunorubicin conjugated with alpha-fetoprotein selectively eliminates myeloid-derived suppressor cells (MDSCs) and inhibits experimental tumor growth.

Failure of antitumor immunity in cancer was shown to be mediated by myeloid-derived suppressor cells (MDSCs), which are considered to be one of the key factors contributing to the development of malignant diseases. Therefore, the development of pharmacological approaches to effectively eliminate MDSCs in organisms carrying growing tumors is a promising pathway for potential treatment. For this purpose we propose alpha-fetoprotein (AFP) conjugated with a cytotoxic agent as a vector molecule, specifically recognizing MDSCs. The present study was aimed at examination of this suggestion using both in vitro and in vivo approaches. MDSCs, obtained from the spleen of Ehrlich carcinoma bearing mice, selectively bound AFP labeled with fluorescein isothiocyanate. AFP conjugated to daunorubicin (AFP-DR) and DR alone showed similar in vitro cytotoxicity against the granulocytic MDSC subpopulation. The monocytic MDSC subpopulation was resistant to treatment with DR, whereas it was completely depleted in the presence of AFP-DR. Treatment of mice bearing Ehrlich carcinoma with AFP-DR resulted in reduced numbers of splenic MDSCs, normalization of NK cell levels, and inhibition of tumor growth. The obtained results demonstrate that cytotoxic conjugates based on AFP are promising anticancer drugs, which, in addition to the direct effect on tumor cells expressing receptors to AFP, may contribute to elimination of MDSCs.

Expansion of CD11b+Ly6Ghigh and CD11b+CD49d+ myeloid cells with suppressive potential in mice with chronic inflammation and light-at-night-induced circadian disruption.

OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are important negative regulators of immune processes in cancer and other pathological conditions. We suggested that MDSCs play a key role in pathogenesis of chronic inflammation, which precedes and, to a certain extent, induces carcinogenesis. The present study aimed at investigation of MDSCs arising during chronic inflammation and light-at-night (LN)-induced stress, which is shown to accelerate chronic diseases. SUBJECTS: 67 CD-1 mice and in vitro MDSC cultures. TREATMENT: Adjuvant arthritis was induced by a subdermal injection of complete Freund's adjuvant. LN was induced by illumination of 750 lx at night. METHODS: Flow cytometry for evaluation of cell phenotypes and MTT standard test for cell proliferation were used. RESULTS: Increased levels of splenic CD11b+Ly6Ghigh and CD11b+CD49d+ myeloid cells possessing suppressive potential in mice with adjuvant arthritis are shown. LN amplifies the process of CD11b+Ly6Ghigh expansion in mice with adjuvant arthritis. Expression of CD62L and CD195 is elevated on the myeloid cells during exposure to LN. CONCLUSIONS: Our study raises the possibility that CD11b+Ly6Ghigh and CD11b+CD49d+ MDSCs play an important role in the induction of immunosuppressive environment typical for chronic inflammation. Also, LN can affect immune responses during chronic inflammation through recruitment of MDSCs from the bone marrow.