Changes In Adaptive Immunity Research Articles

Adaptive immune changes associate with clinical progression of Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear.MethodsWe comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF).ResultsWe found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity.ConclusionsOur findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology.

ОСОБЕННОСТИ ГУМОРАЛЬНОГО ИММУННОГО ОТВЕТА У БОЛЬНЫХ С НАРУШЕНИЯМИ УГЛЕВОДНОГО ОБМЕНА В ПОСТКОВИДНОМ ПЕРИОДЕ

Intensive research is currently underway on the impact of the SARS-CoV-2 virus on the human body. One of the often-found consequences of such exposure is endocrine dysfunction. It has been previously shown that the detected hyperglycemia in patients infected with SARS-COV-2 is due to the consequences of direct damage by the SARS-CoV-2 virus, activation of the immune system and inflammation, as well as the consequences of the use of glucocorticosteroids. Changes in adaptive immunity are characteristic of both hyperglycemia and post-COVID syndrome. Of interest is the combination of these conditions, namely, the development of hyperglycemia in the post-COVID period and the resulting humoral immune response. This study is devoted to identifying the features of B-cell immunity in individuals with post-COVID syndrome and disorders of carbohydrate metabolism. The study included 72 people with carbohydrate metabolism disorders in the post-COVID period. In patients, the lymphocytic link of immunity was assessed: the relative and absolute number of B-lymphocytes (CD45+CD19+), B1-lymphocytes (CD45+CD5+CD19-CD27-), B2-lymphocytes (CD45+CD19+CD5-CD27-), general population Memory B cells (CD45+CD19+CD5-CD27+). In post-covid patients with type 2 diabetes mellitus, more significant changes in the B-cell link were revealed in comparison with patients with impaired glucose tolerance, including a statistically significant increase in the number of B-lymphocytes. Also, in the group of patients with type 2 diabetes mellitus, the number of B2-lymphocytes is significantly higher in the absence of differences in the levels of B1-lymphocytes, which is possibly characteristic of the autoimmune nature of the diseases, and is associated with the secretion of high-affinity antibodies, which presumably explains the more severe clinical course of COVID-19 in the study group. At the same time, in patients with type 2 diabetes mellitus, the number of B1- and B2-lymphocytes of memory cells is significantly lower compared to patients with impaired glucose tolerance in the post-COVID period, which suggests the ineffectiveness of the formed immune response, which confirms more frequent repeated cases. COVID-19 in this group of patients.

Features of the functioning of the natural defense mechanisms of piglets under the influence of immunotropic substances

The number of studies related to detailed characteristics of immune system development in early stages of ontogenesis are directed to expansion of concepts of mechanisms of inherent and adaptive immunity in premature newborns. However, discrepancy in publication data and absence of clear conceptions about unique features of immune system in newborn piglets for different gestation periods have significant actuality for further investigation. The study was carried out to establish characteristics of phenotypic and functional characteristics of the immune cells and establishment of adaptive immunity in piglets. The antibody repertoire of sow has interested immunologists for decades, in part because of the ease with which large quantities of high affinity antibodies can be observed in serum, and into other fluids because of the presence of genetic variants for both light and heavy chain of all known immunoglobulin types. The integrative analysis of the cellular and humoral immunity in piglets during early ontogenesis carried out to clarify the exact mechanisms of the immune response modulation. Effectiveness and selectivity of the immunotropic chemicals application to regulate immune cell populations in piglets is presented. The progress in immune cell populations is regulated by the various cytokines production in the universal concentration-dependent manner. Furthermore, the development of the immune functions cross reacts with innate immunity mechanisms including anti-bacterial enzymes, epithelial barrier integrity in the both skin and intestine. The interaction between multiple components of innate immunity is a critic initiator of the dynamic changes in adaptive immunity. The natural resistance targets to the establishment of infection root and delays disease progression. The duration of the exposure to colostrum in important role in the dynamics of immune response as well as its efficacy. The chapter discusses the plural mechanisms so far proposed to be responsible for the modulation natural resistance.

Immunomodulatory Effects of Transfusions on Maternal Immunity in Pregnancy

Pregnancy represents a unique immunological state where maternal immune adaptations play a pivotal role in supporting fetal development while maintaining tolerance to the semi-allogeneic fetus. Blood transfusions, often necessary during pregnancy for various medical conditions, present an intriguing avenue for understanding alterations in maternal immunity. This comprehensive review aims to elucidate the intricate immunomodulatory effects of blood transfusions on maternal immunity during pregnancy. Beginning with an exploration of normal immunological changes in pregnancy, this review navigates through the immunomodulatory challenges posed by blood transfusions. The impact of donor factors, transfusion-related immunological components, and their influence NEWPORT INTERNATIONAL JOURNAL OF BIOLOGICAL AND APPLIED SCIENCES (NIJBAS) Volume 3 Issue 3 2023 ©NIJBAS Publications 2023 OPEN ACCESS ONLINE ISSN: 2992-5797 PRINT ISSN: 2992-6122 ©Obeagu et al., 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Page | 2 on the maternal immune system are scrutinized. Mechanistic insights into altered cytokine responses, adaptive immune changes, and the role of regulatory T cells post-transfusion form critical focal points. Clinically, discerning the implications of altered maternal immunity on fetal, neonatal health, and obstetric outcomes is essential. Assessing risks and benefits associated with transfusions in pregnancy further underscores the clinical relevance of understanding these immunomodulatory effects. Despite advancements, this review acknowledges research gaps and limitations, highlighting the need for future investigations. Recommendations for prospective studies and potential clinical implications conclude this review, emphasizing the significance of comprehending immunomodulation in maternal immunity post-transfusion for optimizing maternal-fetal health. In conclusion, this review encapsulates current knowledge, challenges, and future directions in comprehending the complex interplay between blood transfusions and maternal immune responses during pregnancy, offering valuable insights into a crucial aspect of perinatal medicine. Keywords: blood transfusions; maternal immunity; pregnancy; immunomodulation; cytokines; alloimmunization; inflammation; transplacental immunomodulation

A survey of the adaptive immune genes of the polka-dot batfish Ogcocephalus cubifrons

BackgroundThe anglerfish, belonging to the teleost order Lophiiformes, are a diverse and species-rich group of fish that are known to exhibit a number of unique morphological, reproductive and immunological adaptations. Work to date has identified the loss of specific adaptive immune components in two of the five Lophiiformes sub-orders (Lophioidei and Ceratioidei), while no anomalies have been identified to date in two other sub-orders, Antennaroidei and Chaunacoidei. The immunogenome of the fifth sub-order, Ogcocephaloidei has not yet been investigated, and we have therefore used whole genome shotgun sequencing, combined with RNA-seq, to survey the adaptive immune capabilities of the polka-dot batfish, O. cubifrons, as a representative of this as yet unexplored sub-order.ResultsWe find that the O. cubifrons genome encodes the core genes needed to mount adaptive T and B cell responses. These genes include those necessary for rearranging and editing antigen receptors, the antigen receptors themselves; as well as the co-receptors, signalling molecules, and antigen presenting molecules (both class I and class II) needed for B cell and T cell development and activation.ConclusionsFrom an immune perspective, the polka-dot batfish has a canonical complement of adaptive immune genes, and does not exhibit any of the adaptive immune changes previously identified in monkfish and oceanic anglerfish.

Age-related Differences in T-cell Subsets and Markers of Subclinical Inflammation in Aging Are Independently Associated With Type 2 Diabetes in the Health and Retirement Study

ObjectivesAge-related changes in adaptive immunity and subclinical inflammation are both important risk factors for diabetes in older adults. We evaluated the independent association between T-cell subsets, subclinical inflammation, and diabetes risk in the Health and Retirement Study (HRS). MethodsWe measured 11 T-cell subsets, 5 pro-inflammatory markers, and 2 anti-inflammatory markers from the 2016 wave of the HRS (baseline). Diabetes/prediabetes status was estimated at the 2016, 2018, and 2020 waves of HRS, based on levels of blood glucose/glycated hemoglobin in plasma or self-reported status. We used survey generalized logit models to evaluate the cross-sectional associations and Cox proportional hazard models to evaluate longitudinal associations. ResultsAmong 8,540 participants (56 to 107 years of age), 27.6% had prevalent type 2 diabetes and 31.1% had prediabetes in the 2016 survey. After adjusting for age, sex, race/ethnicity, education, obesity, smoking, comorbidity index, and cytomegalovirus seropositivity, individuals with type 2 diabetes had lower naive T cells and higher memory and terminal effector T cells as compared with normoglycemic individuals. Among 3,230 normoglycemic participants in the 2016 survey, the incidence of diabetes was 1.8% over 4 years of follow-up. The baseline percentage of CD4+ effector memory T cells was associated with a lower risk of incident diabetes (hazard ratio [HR]=0.63, 95% confidence interval [CI] 0.49 to 0.80, p=0.0003) after adjustment for covariates. Baseline level of interleukin-6 (IL-6) was associated with risk of incident diabetes (HR=1.52, 95% CI 1.18 to 1.97, p=0.002). The associations between age-related changes in CD4+ effector memory T cells and risk of incident diabetes remained unchanged after adjustment for subclinical inflammation, although adjusting for CD4+ effector memory T cells nullified the association between IL-6 and incident diabetes. ConclusionsThis study showed that the baseline percentage of CD4+ effector memory T cells was inversely associated with incident diabetes independent of subclinical inflammation, but CD4+ effector memory T-cell subsets affected the relationship between IL-6 and incident diabetes. Further studies are needed to confirm and investigate mechanisms by which T-cell immunity affects diabetes risk.

Trained innate immunity, epigenetics, and food allergy.

In recent years the increased incidence of food allergy in Western culture has been associated with environmental factors and an inappropriate immune phenotype. While the adaptive immune changes in food allergy development and progression have been well-characterized, an increase in innate cell frequency and activation status has also recently received greater attention. Early in prenatal and neonatal development of human immunity there is a reliance on epigenetic and metabolic changes that stem from environmental factors, which are critical in training the immune outcomes. In the present review, we discuss how trained immunity is regulated by epigenetic, microbial and metabolic factors, and how these factors and their impact on innate immunity have been linked to the development of food allergy. We further summarize current efforts to use probiotics as a potential therapeutic approach to reverse the epigenetic and metabolic signatures and prevent the development of severe anaphylactic food allergy, as well as the potential use of trained immunity as a diagnostic and management strategy. Finally, trained immunity is presented as one of the mechanisms of action of allergen-specific immunotherapy to promote tolerogenic responses in allergic individuals.

Airway goblet cells resulting from conditional YAP/TAZ deletion promote distinct pulmonary inflammation

Abstract The aberrant presence of goblet cells, which are epithelial cells of the conducting airways that have specialized roles in secreting mucus, is frequently associated with distinct innate and adaptive immune changes that together are hallmarks of various pulmonary diseases. The transcriptional regulators YAP and TAZ, key effectors of Hippo pathway signaling, play a central role in suppressing the differentiation of airway goblet cells. Here we investigated the consequences of goblet cell production, resulting from the YAP/TAZ conditional depletion in Scgb1a1+ secretory cells, on lung immunity. We observed that loss of YAP/TAZ resulted in the production of goblet cells promoting local CD45+ immune cell expansion. To gain insight into immune changes associated with the production of YAP/TAZ-deleted goblet cells, we performed a single-cell RNA sequencing experiment on CD45+ cells isolated from control and Yap/Taz-cNull mouse lungs. Data analyses, along with follow-up validation experiments, demonstrated significant immune changes in Yap/Taz-cNull mice including an expansion of type 2 innate lymphoid cells (ILC2s), CD4+ T cells Th2 polarization, and alternative activation of alveolar macrophages, accompanied with elevated type 2 cytokine production. Gene expression analysis of YAP/TAZ-deleted airway cells revealed altered expression of notable immune-modulating factors, many of which are implicated in lung diseases. Collectively our study demonstrates that key immune-modulating signals arise from the secretory lung epithelium through reduced YAP/TAZ activity, raising interesting questions about the functions of YAP/TAZ in lung homeostasis and about the contributions of goblet cells to shaping lung immune responses.

Большие моторные функции и иммунные показатели у детей со спастическим церебральным параличом: есть ли связь

Cerebral palsy (CP) is a group of persistent motor and postural disorders that cause activity limitations, which are explained by non-progressive disorders in the developing brain [1]. Inflammation is detailed in the pathogenesis of most perinatal brain injuries, which contributes to the risk of cerebral palsy, including neonatal stroke, preterm birth, birth asphyxia, and infection [2, 3]. Systematic reviews of the clinical literature now support an association between higher levels of circulating pro-inflammatory mediators and the diagnosis of cerebral palsy, especially in prematurity [4]. However, the duration and extent of this inflammation, as well as the consequences for children with cerebral palsy, remain unclear. Inflammation in cerebral palsy may consist in a change in the cytokine status [4]; altered immune response [5]; adaptive immune changes, including the distribution and function of T- and B-cells [6], as well as other genetic and non-genetic changes in signaling pathways [7]. Inflammation following perinatal brain injury is commonly reported to change over time, between the acute and chronic phases of injury [8]. However, persistent inflammation (i.e., inflammation lasting months to years after the primary injury phase) has been postulated to have detrimental effects on the brain and may contribute to severe forms of the disease. This is supported by the persistent inflammation hypothesis, also known as programming effects, whereby prenatal, antenatal, or neonatal pro-inflammatory cytokines induce inflammation that contributes to long-term cytokine dysregulation [9]. The study in children with an early residual stage of cerebral palsy demonstrated the relationship between the functional level on the GMFCS scale (Gross Motor Function Classification System) and some indicators of immune status.

Single cell analysis of the peripheral immune landscape in Alzheimer reveals a distinct adaptive immune signature

AbstractBackgroundAlzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear.MethodWe comprehensively mapped systemic immune changes in AD patients from the Amsterdam Dementia Cohort with mild cognitive impairment (MCI; n = 21; 65y±6; 52% female) or dementia (n = 59; 63y±8; 53% female) compared to controls (n = 35; age 61y±6; 46% female), using high‐dimensional single‐cell characterization.ResultWe found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory re‐expressing CD45RA (TEMRA) cells in the MCI stage of AD. This subset formed unique, dynamic networks with subsets of CD4+ T cells. In addition, several innate and adaptive immune subsets correlated to cerebrospinal fluid (CSF) levels of amyloid‐β and phosphorylated tau, and measures for cognitive decline. Specifically, subsets of memory B cells were negatively associated with CSF biomarker levels of neurodegeneration and neuroinflammation in AD patients.ConclusionTogether, these findings highlight substantial adaptive immune changes in AD and signify the demand for a greater understanding of how these cells contribute to underlying brain pathology.

Single-cell phenotypes of peripheral blood immune cells in early and late stages of non-alcoholic fatty liver disease.

Immune and inflammatory cells respond to multiple pathological hits in the development of nonalcoholic steatohepatitis (NASH) and fibrosis. Relatively little is known about how their type and function change through the non-alcoholic fatty liver disease (NAFLD) spectrum. Here we used multi-dimensional mass cytometry and a tailored bioinformatic approach to study circulating immune cells sampled from healthy individuals and people with NAFLD. Cytometry by time of flight using 36 metal-conjugated antibodies was applied to peripheral blood mononuclear cells (PBMCs) from biopsy-proven NASH fibrosis (late disease), steatosis (early disease), and healthy patients. Supervised and unsupervised analyses were used, findings confirmed, and mechanisms assessed using independent healthy and disease PBMC samples. Of 36 PBMC clusters, 21 changed between controls and disease samples. Significant differences were observed between diseases stages with changes in T cells and myeloid cells throughout disease and B cell changes in late stages. Semi-supervised gating and re-clustering showed that disease stages were associated with fewer monocytes with active signalling and more inactive NK cells; B and T cells bearing activation markers were reduced in late stages, while B cells bearing co-stimulatory molecules were increased. Functionally, disease states were associated with fewer activated mucosal-associated invariant T cells and reduced toll-like receptor-mediated cytokine production in late disease. A range of innate and adaptive immune changes begin early in NAFLD, and disease stages are associated with a functionally less active phenotype compared to controls. Further study of the immune response in NAFLD spectrum may give insight into mechanisms of disease with potential clinical application.

Natural killer cells-related immune traits and amyotrophic lateral sclerosis: A Mendelian randomization study.

BackgroundObservational studies have suggested that peripheral immune disorders are associated with amyotrophic lateral sclerosis (ALS). Previous studies predominantly focused on changes in adaptive immunity. However, emerging evidence showed natural killer (NK) cells, an essential component of innate immunity, were involved in the degeneration of motor neurons. However, the causal relationship between dysregulated NK cells-related immune traits and ALS remains unclear.ObjectiveThis study aimed to explore the causal relationship between NK cells-related immune traits and the risk of ALS.Materials and methodsSingle nucleotide polymorphisms (SNPs) significantly associated with NK cells-related immune traits were selected as instrumental variables to estimate their causal effects on ALS. SNPs from a genome-wide association study (GWAS) on NK cells-related immune traits were used as exposure instruments, including an absolute NK-cells count, absolute HLA-DR+ NK-cells count, NK cells/lymphocytes, NK cells/CD3– lymphocytes, HLA DR+ NK cells/NK cells, HLA DR+ NK cells/CD3– lymphocytes, and the median fluorescence intensities of CD16–CD56+ on NK cells and HLA-DR+ NK cells. Summary-level GWAS statistics of ALS were used as the outcome data. Exposure and outcome data were analyzed using the two-sample Mendelian randomization (MR) method.ResultsEach one standard deviation increase in the expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells were associated with a lower risk of ALS in both the MR-Egger and inverse variance weighted methods (P < 0.05). The results proved robust under all sensitivity analyses. Neither instrumental outliers nor heterogeneity were detected.ConclusionOur results suggest that higher expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells are associated with a lower risk of ALS.

Age-Related Adaptive Immune Changes in Parkinson's Disease.

Ageing is a major risk factor for most neurodegenerative diseases, including Parkinson’s disease (PD). Progressive age-related dysregulation of the immune system is termed immunosenescence and is responsible for the weakened response to novel antigens, increased susceptibility to infections and reduced effectiveness of vaccines seen in the elderly. Immune activation, both within the brain and periphery, is heavily implicated in PD but the role of immunosenescence has not been fully explored. Studies to date provide some evidence for an attenuation in immunosenescence in PD, particularly a reduction in senescent CD8 T lymphocytes in PD cases compared to similarly aged controls. Here, we discuss recent evidence of age-related immune abnormalities in PD with a focus on T cell senescence and explore their potential role in disease pathogenesis and development.

Chronic exposure to traffic-related air pollution reduces lipid mediators of linoleic acid and soluble epoxide hydrolase in serum of female rats

Chronic exposure to traffic-related air pollution (TRAP) is known to promote systemic inflammation, which is thought to underlie respiratory, cardiovascular, metabolic and neurological disorders. It is not known whether chronic TRAP exposure dampens inflammation resolution, the homeostatic process for stopping inflammation and repairing damaged cells. In vivo, inflammation resolution is facilitated by bioactive lipid mediators known as oxylipins, which are derived from the oxidation of polyunsaturated fatty acids. To understand the effects of chronic TRAP exposure on lipid-mediated inflammation resolution pathways, we measured total (i.e. free+bound) pro-inflammatory and pro-resolving lipid mediators in serum of female rats exposed to TRAP or filtered air (FA) for 14 months. Compared to rats exposed to FA, TRAP-exposed rats showed a significant 36–48% reduction in fatty acid alcohols, specifically, 9-hydroxyoctadecadienoic acid (9-HODE), 11,12-dihydroxyeicosatetraenoic acid (11,12-DiHETE) and 16,17-dihydroxydocosapentaenoic acid (16, 17-DiHDPA). The decrease in fatty acid diols (11,12-DiHETE and 16, 17-DiHDPA) corresponded to a significant 34–39% reduction in the diol to epoxide ratio, a marker of soluble epoxide hydrolase activity; this enzyme is typically upregulated during inflammation. The findings demonstrate that 14 months exposure to TRAP reduced pro-inflammatory 9-HODE concentration and dampened soluble epoxide hydrolase activation, suggesting adaptive immune changes in lipid mediator pathways involved in inflammation resolution.

Primary immune responses are negatively impacted by persistent herpesvirus infections in older people: results from an observational study on healthy subjects and a vaccination trial on subjects aged more than 70 years old.

SummaryBackgroundAdvanced age is accompanied by a decline of immune functions, which may play a role in increased vulnerability to emerging pathogens and low efficacy of primary vaccinations in elderly people. The capacity to mount immune responses against new antigens is particularly affected in this population. However, its precise determinants are not fully understood. We aimed here at establishing the influence of persistent viral infections on the naive T-cell compartment and primary immune responsiveness in older adults.MethodsWe assessed immunological parameters, related to CD8+ and CD4+ T-cell responsiveness, according to the serological status for common latent herpesviruses in two independent cohorts: 1) healthy individuals aged 19y to 95y (n = 150) and 2) individuals above 70y old enrolled in a primo-vaccination clinical trial (n = 137).FindingsWe demonstrate a prevalent effect of age and CMV infection on CD8+ and CD4+ naive T cells, respectively. CMV seropositivity was associated with blunted CD4+ T-cell and antibody responses to primary vaccination.InterpretationThese data provide insights on the changes in adaptive immunity over time and the associated decline in vaccine efficacy with ageing. This knowledge is important for the management of emerging infectious diseases in elderly populations.

Neuroinflammation in Alzheimer's disease

Alzheimer's disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation plays a critical function. Yet, little is known about the contribution of the adaptive immune response in AD. Here we used integrated analyses of multiple cohorts to identify peripheral and central adaptive immune changes in AD. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of AD consisting of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells.

"An Intrinsic Program Determines Key Age-Associated Changes in Adaptive Immunity that Limit Response to Non-Pathogens."

As mice age their adaptive immune system changes dramatically, leading to weakened responses to newly encountered antigens and poor efficacy of vaccines. A shared pattern emerges in the aged, with both CD4 T and B cell responses requiring higher levels of pathogen recognition. Moreover, in aged germ-free mice we find accumulation of the same novel age-associated T and B cell subsets that we and others have previously identified using mice maintained in normal laboratory animal housing conditions, suggesting that their development follows an intrinsic program.

Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer.

Leflunomide (Lef) is an agent used in autoimmune disorders that interferes with DNA synthesis. De Novo pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combination with Gem, in a syngeneic mouse model of pancreatic cancer.Methods: MTS proliferation assays were conducted to assess growth inhibition by Gem (0-20 nM), Lef (0-40 uM) and Gem+Lef in KPC (KrasLSL.G12D/+;p53R172H/+; PdxCretg/+) cells in vitro. An in vivo heterotopic KPC model was used and cohorts were treated with: PBS (control), Gem (75 mg/kg/q3d), Lef (40 mg/kg/d), or Gem+Lef. At d28 post-treatment, tumor burden, proliferation index (Ki67), and vascularity (CD31) were measured. Changes in the frequency of peripheral and intratumoral immune cell subsets were evaluated via FACS. Liquid chromatography-mass spectrometry was used for metabolomics profiling.Results: Lef inhibits KPC cell growth and synergizes with Gem in vitro (P<0.05; Combination Index 0.44 (<1 indicates synergy). In vivo, Lef alone and in combination with Gem delays KPC tumor progression (P<0.001). CTLA-4+T cells are also significantly decreased in tumors treated with Lef, Gem or in combination (Gem+Lef) compared to controls (P<0.05). Combination therapy also decreased the Ki67 and vascularity (P<0.01). Leflunomide inhibits de novo pyrimidine synthesis both in vitro (p<0.0001) and in vivo (p<0.05).Conclusions: In this study, we demonstrated that Gem+Lef inhibits pancreatic cancer growth, decrease T cell exhaustion, vascularity and as proof of principle inhibits de novo pyrimidine synthesis. Further characterization of changes in adaptive immunity are necessary to characterize the mechanism of tumor growth inhibition and facilitate translation to a clinical trial.

Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease

AbstractBackgroundAlzheimer’s disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation plays a critical function. Yet, little is known about the contribution of the adaptive immune response in AD. Here we used integrated analyses of multiple cohorts to identify peripheral and central adaptive immune changes in AD.MethodFirst, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of AD consisting of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells.ResultIn a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single cell RNA sequencing revealed their enhanced T cell receptor (TCR) signaling. Notably, by utilizing multiple single cell TCR sequencing strategies on a third cohort, we discovered clonally expanded CD8+ TEMRA cells in patient cerebrospinal fluid (CSF). Finally, we used machine learning, cloning, and peptide screens to demonstrate specificity of clonally expanded AD CSF TCRs to two separate Epstein‐Barr virus antigens.ConclusionThese results reveal a novel blood‐CSF adaptive immune response in AD and provide evidence of clonal, antigen‐experienced T cells patrolling the intrathecal space of brains affected by age‐related neurodegeneration.

Immune Status Creative Analysis in Patients after Coronary Artery Bypass Surgery (CABS) With the use of Cardiopulmonary Bypass (CPB) Machine

An analysis of the immune status in 53 patients that underwent coronary artery bypass grafting under cardiopulmonary bypass was carried out in the preoperative period and on day 1 and 7 after the surgical intervention. Significant changes in innate and adaptive immunity were revealed. In the first case, they were expressed as an inflammatory process developed throughout the postoperative period; it was confirmed with an increase in leukocytes, total and stab granulocytes, monocytes, oxidative stress of phagocytes, CD64+ and CD40+ granulocytes, endogenous intoxication with the developed significant deficiency in CD4+ monocytes, and regulatory NK cells; while immediately after the surgery, it was confirmed by IgG and IgM levels.Some changes in adaptive immunity manifested through its activation, confirmed by an increased CD4+, CD11b+, HLA-DR+, and CD4+CD25+lymphocyte content, together with a deficiency noted in total lymphocytes and CD8+ lymphocytes.