A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab.

AIMS/HYPOTHESIS: We hypothesised that islet beta cell antigen presentation in the gut along with a tolerising cytokine would lead to antigen-specific tolerance in type 1 diabetes. We evaluated this in a parallel open-label Phase 1b study using oral AG019, food-grade Lactococcus lactis bacteria genetically modified to express human proinsulin and human IL-10, as a monotherapy and in a parallel, randomised, double-blind Phase 2a study using AG019 in combination with teplizumab. METHODS: Adults (18-42 years) and adolescents (12-17 years) with type 1 diabetes diagnosed within 150 days were enrolled, with documented evidence of at least one autoantibody and a stimulated peak C-peptide level >0.2 nmol/l. Participants were allocated to interventions using interactive response technology. We treated 42 people aged 12-42 years with recent-onset type 1 diabetes, 24 with Phase 1b monotherapy (open-label) and 18 with Phase 2a combination therapy. In the Phase 2a study, after treatment of the first two open-label participants, all people involved were blinded to group assignment, except for the Data Safety Monitoring Board members and the unblinded statistician. The primary endpoint was safety and tolerability based on the incidence of treatment-emergent adverse events, collected up to 6 months post treatment initiation. The secondary endpoints were pharmacokinetics, based on AG019 detection in blood and faeces, and pharmacodynamic activity. Metabolic and immune endpoints included stimulated C-peptide levels during a mixed meal tolerance test, HbA1c levels, insulin use, and antigen-specific CD4+ and CD8+ T cell responses using an activation-induced marker assay and pooled tetramers, respectively. RESULTS: Data from 24 Phase 1b participants and 18 Phase 2a participants were analysed. No serious adverse events were reported and none of the participants discontinued AG019 due to treatment-emergent adverse events. No systemic exposure to AG019 bacteria, proinsulin or human IL-10 was demonstrated. In AG019 monotherapy-treated adults, metabolic variables were stabilised up to 6 months (C-peptide, insulin use) or 12 months (HbA1c) post treatment initiation. In participants treated with AG019/teplizumab combination therapy, all measured metabolic variables stabilised or improved up to 12 months and CD8+ T cells with a partially exhausted phenotype were significantly increased at 6 months. Circulating preproinsulin-specific CD4+ and CD8+ T cells were detected before and after treatment, with a reduction in the frequency of preproinsulin-specific CD8+ T cells after treatment with monotherapy or combination therapy. CONCLUSIONS/INTERPRETATION: Oral delivery of AG019 was well tolerated and safe as monotherapy and in combination with teplizumab. AG019 was not shown to interfere with the safety profile of teplizumab and may have additional biological effects, including changes in preproinsulin-specific T cells. These preliminary data support continuing studies with this agent alone and in combination with teplizumab or other systemic immunotherapies in type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03751007, EudraCT 2017-002871-24 FUNDING: This study was funded by Precigen ActoBio.

New molecular targets in the treatment of rheumatoid arthritis.

PURPOSE OF REVIEW: This review will discuss selected emerging molecular targets and associated potential therapeutic agents for rheumatoid arthritis (RA)-directed treatment. RECENT FINDINGS: Agents in active development for RA treatment include those targeted to CD40 and CD40 ligand, programmed death protein 1 (PD-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Several other molecules with a strong theoretical role in RA pathogenesis and/or demonstrated efficacy in other autoimmune diseases are also being evaluated as potential drug targets in preclinical or translational studies in RA. These targets include interleukin 1 receptor associated kinases 1 and 4 (IRAK1, IRAK4), tyrosine kinase 2 (Tyk2), bradykinin receptor 1 (B1R), OX40 and OX40 ligand. SUMMARY: Identification of molecular targets for RA treatment remains an active area of investigation, with multiple therapeutic agents in clinical and preclinical development.

Activation of cytotoxic lymphocytes through CD6 enhances killing of cancer cells.

Immune checkpoint inhibitors (ICIs) have demonstrated efficacy and improved survival in a growing number of cancers. Despite their success, ICIs are associated with immune-related adverse events that can interfere with their use. Therefore, safer approaches are needed. CD6, expressed by T-lymphocytes and human NK cells, engages in cell-cell interactions by binding to its ligands CD166 (ALCAM) and CD318 (CDCP1). CD6 is a target protein for regulating immune responses and is required for the development of several mouse models of autoimmunity. Interestingly, CD6 is exclusively expressed on immune cells while CD318 is strongly expressed on most cancers. Here we demonstrate that disrupting the CD6-CD318 axis with UMCD6, an anti-CD6 monoclonal antibody, prolongs survival of mice in xenograft mouse models of human breast and prostate cancer, treated with infusions of human lymphocytes. Analysis of tumor-infiltrating immune cells showed that augmentation of lymphocyte cytotoxicity by UMCD6 is due to effects of this antibody on NK, NKT and CD8 + T cells. In particular, tumor-infiltrating cytotoxic lymphocytes from UMCD6-treated mice expressed higher levels of perforin and were found in higher proportions than those from IgG-treated mice. Moreover, RNA-seq analysis of human NK-92 cells treated with UMCD6 revealed that UMCD6 up-regulates the NKG2D-DAP10 receptor complex, important in NK cell activation, as well as its downstream target PI3K. Our results now describe the phenotypic changes that occur on immune cells upon treatment with UMCD6 and further confirm that the CD6-CD318 axis can regulate the activation state of cytotoxic lymphocytes and their positioning within the tumor microenvironment.

Th2 cell clonal expansion at diagnosis in human type 1 diabetes.

Soon after diagnosis with type 1 diabetes (T1D), many patients experience a period of partial remission. A longer partial remission is associated with a better response to treatment, but the mechanism is not known. The frequency of CD4+CD25+CD127hi (127-hi) cells, a cell subset with an anti-inflammatory Th2 bias, correlates positively with length of partial remission. The purpose of this study was to further characterize the nature of the Th2 bias in 127-hi cells. Single cell RNA sequencing paired with TCR sequencing of sorted 127-hi memory cells identifies clonally expanded Th2 clusters in 127-hi cells from T1D, but not from healthy donors. The Th2 clusters express GATA3, GATA3-AS1, PTGDR2, IL17RB, IL4R and IL9R. The existence of 127-hi Th2 cell clonal expansion in T1D suggests that disease factors may induce clonal expansion of 127-hi Th2 cells that prolong partial remission and delay disease progression.

Association of baseline soluble immune checkpoints with the risk of relapse in PR3-ANCA vasculitis following induction of remission.

OBJECTIVES: We investigated whether soluble immune checkpoints (sICPs) predict treatment resistance, relapse and infections in patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). METHODS: Plasma sICP concentrations from available samples obtained during conduct of the RAVE trial were measured by immunoabsorbent assays from patients with either proteinase 3 (PR3) or myeloperoxidase (MPO)-ANCA vasculitis and were correlated with clinical outcomes, a set of biomarkers and available flow cytometry analyses focusing on T cell subsets. Log-rank test was used to evaluate survival benefits, and optimal cut-off values of the marker molecules were calculated using Yeldons J. RESULTS: Analysis of 189 plasma samples at baseline revealed higher concentrations of sTim-3, sCD27, sLag-3, sPD-1 and sPD-L2 in patients with MPO-ANCA vasculitis (n=62) as compared with PR3-ANCA vasculitis (n=127). Among patients receiving rituximab induction therapy (n=95), the combination of lower soluble (s)Lag-3 (<90 pg/mL) and higher sCD27 (>3000 pg/mL) predicted therapy failure. Twenty-four out of 73 patients (32.9%) in the rituximab arm reaching remission at 6 months relapsed during follow-up. In this subgroup, high baseline values of sTim-3 (>1200 pg/mL), sCD27 (>1250 pg/mL) and sBTLA (>1000 pg/mL) were associated with both sustained remission and infectious complications. These findings could not be replicated in 94 patients randomised to receive cyclophosphamide/azathioprine. CONCLUSIONS: Patients with AAV treated with rituximab achieved remission less frequently when concentrations of sLag-3 were low and concentrations of sCD27 were high. Higher concentrations of sTim-3, sCD27 and sBTLA at baseline predicted relapse in patients treated with rituximab. These results require confirmation but may contribute to a personalised treatment approach of AAV.

Knowledge of PCOS in physicians-in-training: identifying gaps and educational opportunities.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. A recent study found that many obstetrics and gynecology (ObGyn) practicing physicians are unaware of the Rotterdam criteria recommended for diagnosis. Our objective was to identify gaps in trainee knowledge of PCOS diagnostic criteria and management. An online survey was sent out to US ObGyn physicians-in-training in 2018. The primary outcomes were identification of at least one component of each Rotterdam criteria (Rot-3): (1) oligomenorrhea/amenorrhea, (2) clinical or biochemical hyperandrogenism, and (3) ovarian volume or antral follicle count, and identification of all five components (Rot-5). Secondary outcomes were identification of comorbidities and management of PCOS. Multivariable logistic regression was used controlling for gender, seniority (PGY) status, program type, completion of an REI rotation, and number of PCOS patients seen. 85.4% of 347 trainees completing the survey reported using Rotterdam criteria to diagnose PCOS. However, only 55% identified Rot-3 and less than 10% identified Rot-5. Seniority (PGY4 OR 2.2; 95% CI: 1.2-4.1; p = .01) and completion of REI rotation (OR 1.8 95% CI: 1.2, 1.8; p = .006) were associated with identifying Rot-3. Similar findings were noted with identifying Rot-5. Our study identified significant gaps in knowledge regarding PCOS, suggesting an urgent need for improving strategies for trainee education to increase patient satisfaction and provide comprehensive care.

Two-dose versus single-dose methotrexate for treatment of ectopic pregnancy: a meta-analysis.

OBJECTIVE: To compare the treatment success and failure rates, as well as side effects and surgery rates, between methotrexate protocols. DATA SOURCES: PubMed, Embase, and the Cochrane library searched up to July 2018. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials that compared women with ectopic pregnancies receiving the single-dose, two-dose, or multi-dose methotrexate protocols. STUDY APPRAISAL AND SYNTHESIS METHODS: Odds of treatment success, treatment failure, side effects, and surgery for tubal rupture, as well as length of follow-up until treatment success, were compared using random and fixed effects meta-analysis. Sensitivity analyses compared treatment success in the groups with high human chorionic gonadatropin (hCG) values and a large adnexal mass, as defined by individual studies. The Cochrane Collaboration tool was used to assess risk of bias. RESULTS: The 2-dose protocol was associated with higher treatment success compared to the single-dose protocol (odds ratio [OR], 1.84; 95% CI, 1.13, 3.00). The 2-dose protocol was more successful in women with high hCG (OR, 3.23; 95% CI, 1.53, 6.84) and in women with a large adnexal mass (OR, 2.93; 95% CI, 1.23, 6.9). The odds of surgery for tubal rupture were lower in the 2-dose protocol (OR, 0.65; 95% CI, 0.26, 1.63), but this was not statistically significant. The length of follow-up was 7.9 days shorter for the 2-dose protocol (95% CI, -12.2, -3.5). The odds of side effects were higher in the 2-dose protocol (OR, 1.53; 95% CI, 1.01, 2.30). Compared to the single-dose protocol, the multi-dose protocol was associated with a nonsignificant reduction in treatment failure (OR, 0.56; 95% CI, 0.28, 1.13) and a higher chance of side effects (OR, 2.10; 95% CI, 1.24, 3.54). The odds of surgery for tubal rupture (OR, 1.62; 95% CI, 0.41, 6.49) and time to follow-up (OR, -1.3; 95% CI, -5.4, 2.7) were similar. CONCLUSION: The 2-dose methotrexate protocol is superior to the single-dose protocol for the treatment of ectopic pregnancy in terms of treatment success and time to success. Importantly, these findings hold true in patients thought to be at a lower likelihood of responding to medical management, such as those with higher hCGs and a large adnexal mass.

Increased odds of disordered eating in polycystic ovary syndrome: a systematic review and meta-analysis.

PURPOSE: We aimed to identify the risk of eating disorders (ED) in women with polycystic ovary syndrome (PCOS) compared to controls. METHODS: We performed a systematic review and meta-analysis of studies that included women with well-defined PCOS and controls and used validated ED screening/diagnostic tools to measure mean ED score, prevalence of abnormal ED scores, and/or prevalence of specific ED diagnoses such as bulimia nervosa and binge eating disorder. RESULTS: Eight studies, including 470 women with PCOS and 390 controls, met inclusion criteria for the systematic review. Meta-analysis of seven of those studies found that the odds of an abnormal ED score (OR 3.05; 95% CI 1.33, 6.99; four studies) and the odds of any ED diagnosis (OR 3.87; 95% CI 1.43, 10.49; four studies) were higher in women with PCOS compared to controls. CONCLUSIONS: Our study suggests that women with PCOS are at increased odds of having abnormal ED scores and specific ED diagnoses. Given the potential implications of an ED on weight management strategies, our findings support routine screening for ED in this population. LEVEL OF EVIDENCE: Level I, systematic review and meta-analysis.

High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis.

STUDY QUESTION: Do women with polycystic ovary syndrome (PCOS) have an increased prevalence of moderate and severe depressive and anxiety symptoms compared with control women, and do these symptoms correlate with age, BMI, testosterone, hirsutism or insulin resistance (IR)? SUMMARY ANSWER: Women with PCOS have significantly increased odds of moderate and severe depressive and anxiety symptoms, independent of obesity, and the symptoms are weakly associated with age, BMI, elevated testosterone, hirsutism and IR. WHAT IS KNOWN ALREADY: Previous studies have reported that women with PCOS have an increased prevalence of mild depressive and anxiety symptoms or an increase in mean depression and anxiety scores, although these scores are usually within the normal range. Thus, it is therefore not clear whether these findings are clinically significant. The prevalence of moderate and severe depressive and anxiety symptoms, which require follow-up and would benefit from treatment, is not known in this population. STUDY DESIGN, SIZE, DURATION: A comprehensive systematic review (SR) was performed up to January 2016 and included 30 cross-sectional studies, representing 3050 subjects with PCOS and 3858 controls, from 10 different countries. The meta-analysis (MA) on depressive symptoms included 18 studies and the MA on anxiety symptoms included 9 studies. A separate SR identified 15 studies for the meta-regression examining the associations with PCOS-related symptoms or comorbidities. PARTICIPANTS/MATERIALS, SETTING, METHODS: All studies included adult women with PCOS, defined by the National Institutes of Health or Rotterdam criteria, and a control group without PCOS. Ovid, Embase, PsychInfo and Cochrane were searched up to January 2016. Included studies used a validated screening tool to compare the prevalence or mean scores of depressive and/or anxiety symptoms. Random effects MA was used to estimate the pooled odds ratio (OR) of depressive and anxiety symptoms. Sensitivity analyses of methodological characteristics and a meta-regression of the pooled standardized mean difference (SMD) to evaluate PCOS-related clinical and laboratory associations were performed. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS had increased odds of any depressive symptoms (OR: 3.78; 95% CI: 3.03-4.72; 18 studies) and of moderate/severe depressive symptoms (OR: 4.18; 95% CI: 2.68-6.52; 11 studies). Women with PCOS had increased odds of any anxiety symptoms (OR: 5.62; 95% CI: 3.22-9.80, nine studies) and of moderate/severe anxiety symptoms (OR: 6.55; 95% CI: 2.87, 14.93; five studies). When subjects were matched on BMI, women with PCOS still had higher odds of both depressive (OR: 3.25; 95% CI 1.73-6.09; four studies) and anxiety symptoms (OR: 6.30, 95% CI: 1.88-21.09; three studies). There was no substantial heterogeneity among studies in the overall MA on depressive symptoms (I2 = 22.4%, P = 0.19), but there was significant heterogeneity among studies in the analysis on anxiety symptoms (I2 = 59.6%, P= 0.01). In the meta-regression evaluating pooled SMDs between groups, women with PCOS and concurrent depression had higher mean values of age, BMI, hirsutism score and IR, while women with PCOS and concurrent anxiety had higher mean values of BMI, hirsutism score and free testosterone (P < 0.05 for all comparisons). LIMITATIONS, REASON FOR CAUTION: All studies were cross-sectional, thus we can only hypothesize that the diagnosis of PCOS precedes the diagnosis of depression and anxiety. There were large variations in methodological characteristics especially in the studies screening for anxiety; however, they only partly explained effect size variation. WIDER IMPLICATIONS OF THE FINDINGS: This evidence-synthesis analysis shows that PCOS diagnosis is associated with an increased risk of moderate and severe depressive and anxiety symptoms and suggests that providers should consider screening women with PCOS for both depression and anxiety. Although age, obesity, hyperandrogenism and IR do not explain the entire association, well-designed studies are needed to assess the impact of treatment of these factors on depressive and anxiety symptoms in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): No funding was used for this study. There are no conflicts of interest. REGISTRATION NUMBER: N/A.

Depression and Anxiety in Polycystic Ovary Syndrome: Etiology and Treatment.

PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive age women and is associated with an increased prevalence of depression and anxiety symptoms. This review presents potential mechanisms for this increased risk and outlines treatment options. RECENT FINDINGS: Women with PCOS have increased odds of depressive symptoms (OR 3.78; 95% CI 3.03-4.72) and anxiety symptoms (OR 5.62; 95% CI 3.22-9.80). Obesity, insulin resistance, and elevated androgens may partly contribute to this association. Therefore, in addition to established treatment options, treatment of PCOS-related symptoms with lifestyle modification and/or oral contraceptive pills may be of benefit. Screening for anxiety and depression is recommended in women with PCOS at the time of diagnosis. The exact etiology for the increased risk in PCOS is still unclear. Moreover, there is a paucity of published data on the most effective behavioral, pharmacological, or physiological treatment options specifically in women with PCOS.

Regulation of Th17 maturation by interleukin 4.

Regulation of immune responses and control of autoimmunity depend on layers of checkpoints, cell-cell interactions, and soluble mediators, both during lymphocyte development and in the course of immune responses. With the definition and study of multiple distinct T-cell subsets, it is now apparent that, while specialized regulatory T cells (Tregs) have essential roles in immune homeostasis, important regulatory interactions also occur between the known effector Th subsets such as Th1, Th2 and Th17. In this review, we discuss the regulatory effects of the Th2 cell cytokine interleukin 4 (IL-4) on Th17 cell function, and we highlight emerging data, which indicate the importance of this interaction in both animal model systems and human disease.

Management of polycystic ovary syndrome must include assessment and treatment of mental health symptoms.

Polycystic ovary syndrome (PCOS) is an endocrine disorder with reproductive and metabolic manifestations affecting millions of women worldwide. The health risks associated with PCOS, however, go beyond physical health. Over the past decade, data have emerged demonstrating a high risk of concurrent mental health conditions, specifically depression and anxiety, but extending into other aspects of psychological health, including body image distress, eating disorders, and sexual dysfunction. International surveys suggest physician knowledge about the mental health associations with PCOS is poor and that patients are often dissatisfied regarding counseling-related psychological issues. We performed a review of mental health comorbidities in individuals with PCOS, including depression, anxiety, body image distress, eating disorders, psychosexual dysfunction, and decreased quality of life, as well as evaluated the impact of common PCOS treatments on these conditions. Most meta-analyses in reproductive age women demonstrate increased risks of these conditions, although data are more limited in adolescents and older adults. In addition, the impact of PCOS treatments on these conditions as well as data on first-line treatments in the PCOS population is limited. All providers involved in the multidimensional care of individuals with PCOS should be aware of these mental health risks to provide appropriate screening, counseling and referral options. Future studies should be designed to evaluate targeted treatment for individuals with PCOS.

Xanthogranulomatous oophoritis mimicking a dermoid cyst with ovarian torsion: A case report and review of the literature.

Xanthogranulomatous oophoritis (XO) is a rare pseudotumor representing a destructive chronic inflammatory process often mistaken for malignancy or tubo-ovarian abscess. Xanthogranulomatous inflammation is most commonly seen in the kidneys and gallbladder and very rarely affects the genitourinary system. Definitive treatment is with surgical removal of affected tissue. This report presents the case of a 42-year-old woman with an 8 cm complex right adnexal cyst concerning for a dermoid cyst presenting with intermittent torsion. Final pathology after right salpingo-oophorectomy demonstrated xanthogranulomatous oophoritis. This case is of clinical significance for distinguishing the condition from common benign pathology or cancer since the recommended surgical procedure is different than for a dermoid cyst or malignancy. Correct identification of the condition is crucial for appropriate treatment and to avoid unnecessary morbid procedures if the mass is mistaken for malignancy or future repeat surgery if mistaken for a dermoid cyst or other common benign condition. This case documents the presentation of xanthogranulomatous oophoritis masquerading as a dermoid cyst for a condition with very few reported cases worldwide.

The details matter: personalized prediction of live birth after in vitro fertilization in women with polycystic ovary syndrome.

OBJECTIVE: To derive and internally validate a clinical prediction model for live birth (LB) in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF). DESIGN: Retrospective cohort study. SETTING: Four academic reproductive endocrinology clinics. PATIENTS: A total of 207 women with PCOS confirmed using Rotterdam criteria undergoing their first fresh IVF cycle. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The primary outcome was cumulative LB per IVF cycle start. This included any LB that resulted from either fresh embryo transfer or any subsequent frozen embryo transfer from embryos obtained at the index oocyte retrieval. A prediction model was derived using multivariable logistic regression. Covariates considered for inclusion in the prediction model included demographic characteristics, medical history, and prior fertility treatment. Predicted probabilities for LB were calculated using the prediction model which included the 90% shrinkage factor for each adjusted odds ratio. RESULTS: The final model, on the basis of maximization of the area under the receiver operating characteristic curve, included age < 35 years, White race, presence of polycystic ovaries on ultrasound (polycystic ovary morphology), normal body mass index (<25 kg/m2), being metabolically healthy (no metabolic risk factors), and being a nonresponder to ovulation induction agents including letrozole and clomiphene citrate. The area under the receiver operating characteristic curve score for the model was 0.68 (95% confidence interval [CI]: 0.60, 0.77). Predicted probabilities of LB ranged from 8.1% (95% CI: 2.8, 21.5) for a woman who had no favorable predictors to 74.2% (95% CI: 59.5, 84.9) for a woman who had all favorable predictors. CONCLUSION: Our study demonstrated that, in addition to anovulation, the underlying pathophysiology and associated comorbidities alter the likelihood of a successful pregnancy in women with PCOS undergoing IVF. Further validation of this model is needed before it can serve as a tool to personalize prediction estimates for the probability of LB in women with PCOS.

Short-lived effector CD8 T cells induced by genetically attenuated malaria parasite vaccination express CD11c.

Vaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodent Plasmodium yoelii model. Protection is dependent on CD8(+) T cells, involves perforin and gamma interferon (IFN-γ), and is correlated with the expansion of effector memory CD8(+) T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8(+) T cell phenotype and demonstrated significant upregulation of CD11c on CD3(+) CD8b(+) T cells in the liver, spleen, and peripheral blood. CD11c(+) CD8(+) T cells are predominantly CD11a(hi) CD44(hi) CD62L(-), indicative of antigen-experienced effector cells. Following in vitro restimulation with malaria-infected hepatocytes, CD11c(+) CD8(+) T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), perforin, and CD107a. CD11c(-) CD8(+) T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8(+) T cells. Coculture of CD11c(+), but not CD11c(-), CD8(+) T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8(+) T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c(+) CD8(+) T cell response, but CD11c expression was lost as the CD8(+) T cells entered the memory phase. Further analyses showed that CD11c(+) CD8(+) T cells are primarily KLRG1(+) CD127(-) terminal effectors, whereas all KLRG1(-) CD127(+) memory precursor effector cells are CD11c(-) CD8(+) T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes.

Sensitivity and resistance to regulation by IL-4 during Th17 maturation.

Th17 cells are highly pathogenic in a variety of immune-mediated diseases, and a thorough understanding of the mechanisms of cytokine-mediated suppression of Th17 cells has great therapeutic potential. In this article, we characterize the regulation of both in vitro- and in vivo-derived Th17 cells by IL-4. We demonstrate that IL-4 suppresses reactivation of committed Th17 cells, even in the presence of TGF-ß, IL-6, and IL-23. Downregulation of IL-17 by IL-4 is dependent on STAT6 and mediated by inhibition of STAT3 binding at the Il17a promoter. Although Th1 cytokines were shown to induce IFN-γ expression by Th17 cells, IL-4 does not induce a Th2 phenotype in Th17 cells. Suppression by IL-4 is stable and long-lived when applied to immature Th17 cells, but cells that have undergone multiple rounds of stimulation, either in vivo during a Th17-mediated inflammatory disease, or in vitro, become resistant to suppression by IL-4 and lose the ability to signal through IL-4R. Thus, although IL-4 is a potent suppressor of the Th17 genetic program at early stages after differentiation, prolonged stimulation renders Th17 cells impervious to regulatory cytokines.

Immune Dysfunction in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged individuals with ovaries. It is associated with anovulation and increased risk to fertility and metabolic, cardiovascular, and psychological health. The pathophysiology of PCOS is still inadequately understood, although there is evidence of persistent low-grade inflammation, which correlates with associated visceral obesity. Elevated proinflammatory cytokine markers and altered immune cells have been reported in PCOS and raise the possibility that immune factors contribute to ovulatory dysfunction. Because normal ovulation is modulated by immune cells and cytokines in the ovarian microenvironment, the endocrine and metabolic abnormalities associated with PCOS orchestrate the accompanying adverse effects on ovulation and implantation. This review evaluates the current literature on the relationship between PCOS and immune abnormalities, with a focus on emerging research in the field.

Immunosuppression causes dynamic changes in expression QTLs in psoriatic skin.

Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. While the role of the immune compartment (e.g., T cells) is well established, the changes in the skin compartment are more poorly understood. Using longitudinal skin biopsies (n = 375) from the "Psoriasis Treatment with Abatacept and Ustekinumab: A Study of Efficacy"(PAUSE) clinical trial (n = 101), we report 953 expression quantitative trait loci (eQTLs). Of those, 116 eQTLs have effect sizes that were modulated by local skin inflammation (eQTL interactions). By examining these eQTL genes (eGenes), we find that most are expressed in the skin tissue compartment, and a subset overlap with the NRF2 pathway. Indeed, the strongest eQTL interaction signal - rs1491377616-LCE3C - links a psoriasis risk locus with a gene specifically expressed in the epidermis. This eQTL study highlights the potential to use biospecimens from clinical trials to discover in vivo eQTL interactions with therapeutically relevant environmental variables.

Activation of Cytotoxic Lymphocytes Through CD6 Enhances Killing of Cancer Cells.

Immune checkpoint inhibitors (ICIs) have demonstrated efficacy and improved survival in a growing number of cancers. Despite their success, ICIs are associated with immune-related adverse events that can interfere with their use. Therefore, safer approaches are needed. CD6, expressed by T-lymphocytes and human NK cells, engages in cell-cell interactions by binding to its ligands CD166 (ALCAM) and CD318 (CDCP1). CD6 is a target protein for regulating immune responses and is required for the development of several mouse models of autoimmunity. Interestingly, CD6 is exclusively expressed on immune cells while CD318 is strongly expressed on most cancers. Here we demonstrate that disrupting the CD6-CD318 axis with UMCD6, an anti-CD6 monoclonal antibody, prolongs survival of mice in xenograft models of human breast and prostate cancer, treated with infusions of human lymphocytes. Analysis of tumor-infiltrating immune cells showed that augmentation of lymphocyte cytotoxicity by UMCD6 is due to effects of this antibody on NK, NKT and CD8+ T cells. Tumor-infiltrating cytotoxic lymphocytes were found in higher proportions and were activated in UMCD6-treated mice compared to controls. Similar changes in gene expression were observed by RNA-seq analysis of NK cells treated with UMCD6. Particularly, UMCD6 up-regulated the NKG2D-DAP10 complex and activated PI3K. Thus, the CD6-CD318 axis can regulate the activation state of cytotoxic lymphocytes and their positioning within the tumor microenvironment.

Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

OBJECTIVE: Previous studies showed that inhibiting lymphocyte costimulation reduces declining ß-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. RESEARCH DESIGN AND METHODS: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. RESULTS: A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. CONCLUSIONS: Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.