scholarly journals Human Leucocyte Antigen G and Murine Qa-2 Are Critical for Myeloid Derived Suppressor Cell Expansion and Activation and for Successful Pregnancy Outcome

2022 ◽  
Vol 12 ◽  
Author(s):  
Stefanie Dietz ◽  
Julian Schwarz ◽  
Ana Velic ◽  
Irene González-Menéndez ◽  
Leticia Quintanilla-Martinez ◽  
...  
Keyword(s):  
Pregnancy Outcome ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Late Pregnancy ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
The Impact

During pregnancy, maternal immune system has to balance tightly between protection against pathogens and tolerance towards a semi-allogeneic organism. Dysfunction of this immune adaptation can lead to severe complications such as pregnancy loss, preeclampsia or fetal growth restriction. In the present study we analyzed the impact of the murine MHC class Ib molecule Qa-2 on pregnancy outcome in vivo. We demonstrate that lack of Qa-2 led to intrauterine growth restriction and increased abortion rates especially in late pregnancy accompanied by a disturbed trophoblast invasion and altered spiral artery remodeling as well as protein aggregation in trophoblast cells indicating a preeclampsia-like phenotype. Furthermore, lack of Qa-2 caused imbalanced immunological adaptation to pregnancy with altered immune cell and especially T-cell homeostasis, reduced Treg numbers and decreased accumulation and functional activation of myeloid-derived suppressor cells. Lastly, we show that application of sHLA-G reduced abortion rates in Qa-2 deficient mice by inducing MDSC. Our results highlight the importance of an interaction between HLA-G and MDSC for pregnancy success and the therapeutic potential of HLA-G for treatment of immunological pregnancy complications.

scholarly journals Human leucocyte antigen G (HLA-G) and its murine homologue Qa-2 protect from pregnancy loss

2021 ◽  
Author(s):  
Stefanie Dietz ◽  
Julian Schwarz ◽  
Ana Velic ◽  
Irene Gonzalez Menendez ◽  
Leticia Quintanilla-Martinez ◽  
...  
Keyword(s):  
Pregnancy Loss ◽  
Therapeutic Potential ◽  
Suppressor Cells ◽  
Late Pregnancy ◽  
Immunological Tolerance ◽  
Growth Restriction ◽  
Maternal Immune System ◽  
Murine Homologue ◽  
The Impact

Abstract During pregnancy, the maternal immune system has to balance tightly between protection against pathogens and tolerance towards a semi-allogeneic organism. Dysfunction of this immune adaptation can lead to severe complications such as pregnancy loss, preeclampsia or fetal growth restriction. The MHC-Ib molecule HLA-G is well known to mediate immunological tolerance. However, no in-vivo studies have yet demonstrated a beneficial role of HLA-G for pregnancy success. Myeloid derived suppressor cells (MDSC) are suppressively acting immune cells accumulating during pregnancy and mediating maternal-fetal tolerance. Here, we analyzed the impact of Qa-2, the murine homologue to HLA-G, on pregnancy outcome in vivo. We demonstrate that lack of Qa-2 led to intrauterine growth restriction and increased abortion rates especially in late pregnancy accompanied by changes in uterine gene expression, altered spiral artery remodeling and protein aggregation in trophoblast cells indicating a preeclampsia-like phenotype. Furthermore, lack of Qa-2 caused decreased accumulation of MDSC and impaired MDSC function. Lastly, we show that application of sHLA-G reduced abortion rates in Qa-2 deficient mice by inducing MDSC. Our results highlight the importance of an interaction between HLA-G and MDSC for pregnancy success and the therapeutic potential of HLA-G for the treatment of immunological pregnancy complications.

scholarly journals Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis

2021 ◽  
Vol 22 (21) ◽  
pp. 11478
Author(s):  
Qi He ◽  
Maria Jamalpour ◽  
Eric Bergquist ◽  
Robin L. Anderson ◽  
Karin Gustafsson ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Lung Metastasis ◽  
Immune Cells ◽  
Tyrosine Kinases ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Barrier Properties

Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The Shb gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the Shb gene using the Cdh5-CreERt2 transgene, resulting in inactivation of the Shb-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of Shb expression. Instead, Shb deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific Shb deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.

scholarly journals Early Myeloid Derived Suppressor Cells (eMDSCs) Are Associated With High Donor Myeloid Chimerism Following Haploidentical HSCT for Sickle Cell Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Deepali K. Bhat ◽  
Purevdorj B. Olkhanud ◽  
Arunakumar Gangaplara ◽  
Fayaz Seifuddin ◽  
Mehdi Pirooznia ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Graft Rejection ◽  
Immune Cell ◽  
Plasma Concentrations ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Post Transplant

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a widely available curative option for patients with sickle cell disease (SCD). Our original non-myeloablative haplo-HSCT trial employing post-transplant (PT) cyclophosphamide had a low incidence of GVHD but had high rejection rates. Here, we aimed to evaluate immune reconstitution following haplo-HSCT and identify cytokines and cells associated with graft rejection/engraftment. 50 cytokines and 10 immune cell subsets were screened using multiplex-ELISA and flow cytometry, respectively, at baseline and PT-Days 30, 60, 100, and 180. We observed the most significant differences in cytokine levels between the engrafted and rejected groups at PT-Day 60, corresponding with clinical findings of secondary graft rejection. Of the 44 cytokines evaluated, plasma concentrations of 19 cytokines were different between the two groups at PT-Day 60. Factor analysis suggested two independent factors. The first factor (IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, and TGFb1 contributed significantly) was strongly associated with engraftment with OR = 2.7 (95%CI of 1.4 to 5.4), whereas the second factor (GROa and IL-18 contributed significantly) was not significantly associated with engraftment. Sufficient donor myeloid chimerism (DMC) is critical for the success of HSCT; here, we evaluated immune cells among high (H) DMC (DMC≥20%) and low (L) DMC (DMC<20%) groups along with engrafted and rejected groups. We found that early myeloid-derived suppressor cell (eMDSC) frequencies were elevated in engrafted patients and patients with HDMC at PT-Day 30 (P< 0.04 & P< 0.003, respectively). 9 of 20 patients were evaluated for the source of eMDSCs. The HDMC group had high mixed chimeric eMDSCs as compared to the LDMC group (P< 0.00001). We found a positive correlation between the frequencies of eMDSCs and Tregs at PT-Day 100 (r=0.72, P <0.0007); eMDSCs at BSL and Tregs at PT-Day 100 (r=0.63, P <0.004). Of 10 immune regulatory cells and 50 cytokines, we observed mixed chimeric eMDSCs and IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, TGFb1 as potential hits which could serve as prognostic markers in predicting allograft outcome towards engraftment following haploidentical HSCT employing post-transplant cyclophosphamide. The current findings need to be replicated and further explored in a larger cohort.

scholarly journals Noncapped Genomic RNA Are Critical for Alphaviral Infection and Pathogenicity

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 44
Author(s):  
Autumn T. LaPointe ◽  
Kevin J Sokoloski
Keyword(s):  
Growth Kinetics ◽  
Particle Production ◽  
Immune Cell ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Genomic Rnas ◽  
Viral Rnas ◽  
The Impact

Alphaviruses are positive-sense RNA arthropod-borne viruses that represent a significant threat to public health. During alphaviral replication, significant quantities of viral genomic RNAs that lack a canonical 5’ cap structure are produced and packaged into viral particles, despite the fact that the noncapped genomes cannot be translated and are essentially noninfectious. Previously, we have reported that the capping efficiency of nsP1, the alphaviral capping enzyme, of Sindbis virus (SINV) could be modulated via point mutation. It was found that increasing RNA capping efficiency led to decreased viral growth kinetics via decreased particle production, despite increased innate immune evasion, whereas decreasing capping efficiency led to wild-type growth kinetics and particle production. This led to the conclusion that the noncapped viral RNAs meaningfully contribute to the biology of alphaviral infections at the molecular level. To determine the importance of the noncapped viral RNAs in vivo, we characterized the impact of altered capping efficiency in a murine model of infection utilizing a neurovirulent strain of SINV. Mice infected with the nsP1 mutant with decreased capping exhibited wild-type rates of mortality, weight loss, and neurological symptoms. Conversely, the mice infected with the increased capping nsP1 mutant showed significantly reduced mortality and morbidity compared to mice infected with the wild-type virus. Interestingly, viral titers in the ankle, serum, and brain were equivalent between the wild-type virus and the two mutant viruses. Importantly, examination of the brain tissue revealed that mice infected with the increased capping mutant had significantly reduced immune cell infiltration and expression of proinflammatory cytokines compared to the decreased capping mutant and wild-type virus. Collectively, these data indicate that the noncapped viral RNAs have important roles during the early and late stages of alphaviral infection and suggest a novel mechanism by which noncapped viral RNA aids in viral pathogenesis.

scholarly journals Modeling the impact of growth and leptin deficits on the neuronal regulation of blood pressure

2016 ◽  
Vol 231 (2) ◽  
pp. R47-R60 ◽  
Author(s):  
Baiba Steinbrekera ◽  
Robert Roghair
Keyword(s):  
Intrauterine Growth Restriction ◽  
Therapeutic Potential ◽  
Growth Restriction ◽  
Neuronal Regulation ◽  
Antenatal Steroid ◽  
Life Threatening ◽  
Neurodevelopmental Impairment ◽  
The Impact ◽  
Circulating Levels ◽  
Regulation Of Blood Pressure

The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency and aberration in sex hormone levels. As a neurotrophic hormone that is intimately involved in the cardiovascular regulation and whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus a therapeutic agent. As a product of maternal and late fetal adipocytes and the placenta, circulating leptin typically surges late in gestation and declines after delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish the circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction–adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates the leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation.

scholarly journals IMMU-01. MYELOID-DERIVED SUPPRESSOR CELL HETEROGENEITY DRIVES GLIOBLASTOMA PROGRESSION IN A SEX-DEPENDENT MANNER

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi118-vi118
Author(s):  
Defne Bayik ◽  
Daniel Silver ◽  
Chihyun Park ◽  
Dionysios Watson ◽  
Mia Sorensen ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Ex Vivo ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Fold Increase ◽  
Dependent Manner ◽  
Ki 67 ◽  
Accumulation Pattern ◽  
Therapeutic Opportunity

Abstract An immunosuppressive tumor microenvironment is a major factor facilitating glioblastoma (GBM) progression and therapeutic resistance. Immunotherapies have had variable success in improving the outcome of GBM patients, suggesting that there is a need to gain insight into the mechanisms of immunosuppression. Our group previously demonstrated that myeloid-derived suppressor cells (MDSCs) expand in GBM patients and infiltrate tumors, where they suppress the activity of cytotoxic cells. However, the mechanisms by which individual MDSC subsets promote tumorigenesis remain understudied. Using the syngeneic mouse glioma models GL261, CT-2A and SB28, we show that monocytic MDSCs (mMDSCs) are prevalent in tumors and that their frequency is significantly higher in males, who constitute 60% of GBM patients and have a worse prognosis than females. mMDSC abundance was further associated with poor survival, and male mice reached morbidity endpoint earlier. Consistent with preclinical observations, male GBM patient specimens had significantly more IBA+CD204+ immunosuppressive myeloid cells compared to female GBM tissue. In contrast, female tumor-bearing mice had a two-fold increase in circulating granulocytic MDSC (gMDSC) frequency, while this population remained unchanged in males. Female-to-male bone marrow chimeras demonstrated that intrinsic discrepancies in immune cell characteristics drive the sex differences in survival. Consistent with the differential MDSC accumulation pattern, targeting gMDSCs with anti-Ly6G neutralizing antibodies extended the lifespan of female mice without providing a survival advantage to males. However, mMDSCs were protected from the anti-Ly6C depletion strategy due to their systemic and local proliferation, as indicated by ex vivo Ki-67 staining and subsequently confirmed by gene expression analysis. Drug-prediction algorithms using the differential RNA sequencing profiles demonstrated that mMDSCs can be targeted by chemotherapeutics, while immunomodulatory drugs are effective against gMDSCs. Collectively, these findings indicate that MDSC subset variation might represent a therapeutic opportunity for improved therapeutic efficacy of immunotherapies while accounting for sex as a biological variable.

scholarly journals Structural, Pro-Inflammatory and Calcium Handling Remodeling Underlies Spontaneous Onset of Paroxysmal Atrial Fibrillation in JDP2-Overexpressing Mice

2020 ◽  
Vol 21 (23) ◽  
pp. 9095
Author(s):  
Mariana S. Parahuleva ◽  
Jens Kockskämper ◽  
Jacqueline Heger ◽  
Wolfram Grimm ◽  
Anna Scherer ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Immune Cell ◽  
Marker Gene ◽  
Fold Increase ◽  
Calcium Handling ◽  
In Vivo Studies ◽  
Western Blots ◽  
The Impact ◽  
Spontaneous Onset

Background: Cardiac-specific JDP2 overexpression provokes ventricular dysfunction and atrial dilatation in mice. We performed in vivo studies on JDP2-overexpressing mice to investigate the impact of JDP2 on the predisposition to spontaneous atrial fibrillation (AF). Methods: JDP2-overexpression was started by withdrawal of a doxycycline diet in 4-week-old mice. The spontaneous onset of AF was documented by ECG within 4 to 5 weeks of JDP2 overexpression. Gene expression was analyzed by real-time RT-PCR and Western blots. Results: In atrial tissue of JDP2 mice, besides the 3.6-fold increase of JDP2 mRNA, no changes could be detected within one week of JDP2 overexpression. Atrial dilatation and hypertrophy, combined with elongated cardiomyocytes and fibrosis, became evident after 5 weeks of JDP2 overexpression. Electrocardiogram (ECG) recordings revealed prolonged PQ-intervals and broadened P-waves and QRS-complexes, as well as AV-blocks and paroxysmal AF. Furthermore, reductions were found in the atrial mRNA and protein level of the calcium-handling proteins NCX, Cav1.2 and RyR2, as well as of connexin40 mRNA. mRNA of the hypertrophic marker gene ANP, pro-inflammatory MCP1, as well as markers of immune cell infiltration (CD68, CD20) were increased in JDP2 mice. Conclusion: JDP2 is an important regulator of atrial calcium and immune homeostasis and is involved in the development of atrial conduction defects and arrhythmogenic substrates preceding paroxysmal AF.

scholarly journals IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi129-vi129
Author(s):  
Marilin Koch ◽  
Mykola Zdioruk ◽  
M Oskar Nowicki ◽  
Estuardo Aguilar ◽  
Laura Aguilar ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Symptomatic Treatment ◽  
Tumor Cell Death ◽  
The Impact

Abstract RATIONALE Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored. METHODS We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model. RESULTS Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184). CONCLUSION Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.

scholarly journals Perinatal Plasma Monocyte Chemotactic Protein-1 Concentrations in Intrauterine Growth Restriction

2007 ◽  
Vol 2007 ◽  
pp. 1-5 ◽  
Author(s):  
Despina D. Briana ◽  
Maria Boutsikou ◽  
Stavroula Baka ◽  
George Papadopoulos ◽  
Dimitrios Gourgiotis ◽  
...  
Keyword(s):  
Immune Response ◽  
Pregnancy Outcome ◽  
Gestational Age ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
Intrauterine Growth ◽  
Monocyte Chemotactic Protein ◽  
Chemotactic Protein ◽  
Appropriate For Gestational Age

Monocyte chemotactic protein-1 (MCP-1) plays vital roles in immune response, angiogenesis, and pregnancy outcome. We investigated plasma MCP-1 concentrations in 40 mothers and their 20 intrauterine-growth-restricted (IUGR) and 20 appropriate-for-gestational-age (AGA) fetuses and neonates on postnatal days 1 (N1) and 4 (N4). Maternal and fetal MCP-1 concentrations were decreased (P<001andP= .018, resp.), whereas N1 MCP-1 concentrations were elevated in IUGR group (P= .012). In both groups, fetal MCP-1 concentrations were lower compared to N1 and N4 ones (P= .045,P= .012, resp., for AGA,P<.001 in each case for IUGR). Reduced maternal and fetal MCP-1 concentrations in IUGR may reflect failure of trophoblast invasion, suggesting that down-regulation of MCP-1 may be involved in the pathogenesis of IUGR. Increased MCP-1 concentrations in IUGR neonates and higher postnatal ones in all infants may be attributed to gradual initiation of ex utero angiogenesis, which is possibly enhanced in IUGR.

Evaluation of Chemical, Antipsoriatic and Antiangiogenic Properties of Salt from Lonar Crater Lake Water

2019 ◽  
Vol 4 (3) ◽  
pp. 159-165
Author(s):  
Prakash Bansode ◽  
Indumathi Somasundaram ◽  
Apurva Birajdar ◽  
Sanjay Mishra ◽  
Dhanashree Patil ◽  
...  
Keyword(s):  
Lake Water ◽  
Crater Lake ◽  
Skin Diseases ◽  
Therapeutic Potential ◽  
Chorioallantoic Membrane ◽  
Soda Lake ◽  
Antiangiogenic Activity ◽  
The Impact ◽  
Lonar Crater

Lonar Crater lake was created by the impact of a massive meteor during the Pleistocene Epoch. Being a hypersaline and hyperalkaline soda lake, rich microbial diversity is reported earlier. Lonar lake water is used by local people and tribals against skin diseases. These observations prompted us to investigate the therapeutic potential of lake water against skin diseases. In this context, we have conducted pilot study to assess the antipsoriatic and antiangiogenic activity of the salt obtained from lake water using THP1 cell line by MTT assay and antiangiogenic activity by in vivo chicken chorioallantoic membrane (CAM) assay, as there is a close relation between psoriasis and angiogenesis. The results revealed that salt possess remarkable antipsoriatic and antiangiogenic activity.

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