Th1 Activation Research Articles

Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes.

Patients with type 2 diabetes (T2D) are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that patients with T2D and coronavirus disease 2019 (COVID-19) infections, and influenza-infected T2D mice, exhibit defective T helper 1 (Th1) responses, which are an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4+ Tcells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4+ Tcells. These abnormalities promote lipid peroxidation (LPO), which drives carbonylation of signal transducer and activator of transcription 4 (STAT4), a crucial Th1-lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates Th1 defects in patients with T2D who have poor glycemic control and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications.

Prognostic value of IL-22 levels and the TH17 pathway in patients with acute myocardial infarction

Abstract Introduction Acute myocardial infarction (AMI) induces a surge in inflammatory cytokines and cells including T helper cells (TH). TH17 cells are activated by pro-inflammatory cytokines such as IL-1, IL-6, and IL-21; they secrete IL-17 and IL-22 to promote neutrophil chemotaxis and to induce pro-inflammatory cytokine secretion from macrophages. Purpose We aimed to explore the prognostic value of the TH17 pathway and its component cytokines in AMI patients. Methods Patients with AMI (STEMI and NSTEMI) were included from the SPUM-ACS cohort (total N=4,787) selecting a time window <24 h from symptom onset to blood sampling before PCI. Patients with malignancies or immunosuppressive therapies were excluded. 160 patients who experienced death (N=85) or recurrent AMI (N=75) within 1-year follow-up (AMI-case) were compared to 152 counterparts with favorable outcome matched for age, sex, AMI subtype, and onset time (AMI-control). 45 healthy blood donors (HD) without cardiovascular disease were added as a reference group. Cytokine levels were reported as median + IQR and were analyzed with multivariate linear regression. Group comparisons were made using the Mann-Whitney U test or Kruskal-Wallis test and multiple comparisons corrected with Dunn’s test. Kaplan-Meier curves were cut off at a median IL-22 level and tested with Log-rank test. Results Our measurement showed correlation among components in TH17 pathway. IL-22 was significantly associated with IL-1β (β=-3.027e-1, p=0.0164), IL-6 (β=5.413e-3, p<0.0001), and IL-21 (β=3.567e-2, p<0.0001), but not with IL-1α or IL-1RA. IL-22 was not correlated with IL-17. Age (median=71.45 vs 71.30 years, p>0.05), percentage of women (23.8% vs 19.7%, p>0.05), and percentage of STEMI (70.6% vs 69.7%, p>0.05) did not differ between AMI-case and AMI-control. AMI-case and AMI-control both showed higher plasma IL-22 levels than HD, whereas there was no difference between AMI groups (Figure 1A). AMI patients who died within 1-year follow-up had higher IL-22 levels than those with recurrent AMI (Figure 1B). Regarding TH17 activation, patients who died had higher IL-17 levels (Figure 1C). Median IL-22 (4.86 pg/mL) levels were tested for predicting outcome: Patients with higher IL-22 levels had more risk for death or recurrent AMI (p=0.0253, Figure 2A). The mortality of patients above median IL-22 levels was higher than those below (p=0.0126); The KM-curves diverged early in less than 1 month after the initial event (Figure 2B). Conclusions Upstream regulators (IL-1β, IL-6) correlated with downstream effectors (IL-22, IL-17) within the pathways involving TH17 cells. Both IL-22 and Il-17 were higher in AMI patients who died within one year than in similar patients who survived. Investigating TH-17- and IL-22-related pathways may be of interest for further investigation in patients with AMI.

Increased Cytokine Levels in Seronegative Myositis: Potential Th17 Immune Response Implications

Th17 cells are known for producing IL-17 and their role in the pathogenesis of various autoimmune diseases, including myositis. Likewise, the participation of the IL-23/IL-17 pathway in autoimmunity has been confirmed. In this study, we aimed to evaluate the behavior of cytokines in myositis, focusing on the autoantibodies profile and the myositis core set measures. Twenty-five myositis patients were enrolled in this cross-sectional study. An expert rheumatologist evaluated the myositis core set measures. Serum levels of cytokines and chemokines were quantified using the LEGENDplex Multi-Analyte Flow Assay Kit from BioLegend. The autoantibodies detection was carried out using the line-blot assay kit Euroline: Autoimmune Inflammatory Myopathies from EUROIMMUN. We found higher serum levels of IL-33, CXCL8, IL-6, IL-23, and IL-12p70 in seronegative patients. A multiple linear regression analysis revealed that MYOACT scores could be predicted by the increment of IL-23 and the decrement of CCL2, IL-10, and CXCL8 serum levels. These findings suggest that the immune response in seronegative myositis patients exhibits an IL-23-driven Th17 immune response. The relevance of this discovery lies in its potential therapeutic implications. Insights into the IL-23-driven Th17 immune response in seronegative patients highlight the potential for targeted therapies aimed at modulating Th17 activity.

Prospects of vaccination against pneumococcal infection based on the asthma phenotype

According to recent studies, bronchial asthma is characterized by a wide variability of the mechanisms of occurrence and progression. This heterogeneity is caused by patterns of predominant cells and inflammatory mediators, which determine differences in immunological parameters observed in patients with certain endotypes depending on the dominant type of mediators (high and low T2 inflammation). In long-term observations, a substantial research base has been accumulated justifying the effectiveness of vaccination against pneumococcal infection in patients with asthma. The vaccination decreases the frequency of exacerbations of the disease and hospitalizations in the short and medium term. However, these studies evaluated the asthma patients as a wholesome population, and it remains unexplored whether the effect of pneumococcal vaccines on asthma differs depending on the endotype of the disease and what are the mechanisms of such a differentiated effect.The aim of this work is to present the results of recent quality studies on changes in the profile of inflammatory asthma mediators under the action of immunobiological substances based on Streptococcus pneumoniae antigens, primarily from the vaccines.Conclusion. The asthma heterogeneity can lead to different clinical outcomes in pneumococcal infection and, respectively, the clinical effects of immunization in patients differentiate according to the nature of inflammation. In other words, the uniformity of the clinical effect of vaccination against pneumococcal infection in all patients in ongoing studies may represent the combined effect of molecular mechanisms regulating the specific activity of Th1-, Th2-, Th17-, NKT-, and Treg-cells. The results of studies proving the ability of pneumococcal vaccines to modulate the Th1-, Th2-, Th17-, Treg immune response in patients with asthma contributed to increased interest in developing new immunoregulatory therapeutic agents based on S. pneumoniae antigens.

Emergence of the B.1.214.2 SARS-CoV-2 lineage with an Omicron-like spike insertion and a unique upper airway immune signature

We investigate the emergence, mutation profile, and dissemination of SARS-CoV-2 lineage B.1.214.2, first identified in Belgium in January 2021. This variant, featuring a 3-amino acid insertion in the spike protein similar to the Omicron variant, was speculated to enhance transmissibility or immune evasion. Initially detected in international travelers, it substantially transmitted in Central Africa, Belgium, Switzerland, and France, peaking in April 2021. Our travel-aware phylogeographic analysis, incorporating travel history, estimated the origin to the Republic of the Congo, with primary European entry through France and Belgium, and multiple smaller introductions during the epidemic. We correlate its spread with human travel patterns and air passenger data. Further, upon reviewing national reports of SARS-CoV-2 outbreaks in Belgian nursing homes, we found this strain caused moderately severe outcomes (8.7% case fatality ratio). A distinct nasopharyngeal immune response was observed in elderly patients, characterized by 80% unique signatures, higher B- and T-cell activation, increased type I IFN signaling, and reduced NK, Th17, and complement system activation, compared to similar outbreaks. This unique immune response may explain the variant's epidemiological behavior and underscores the need for nasal vaccine strategies against emerging variants.

Qingchang suppository ameliorates mucosal inflammation in ulcerative colitis by inhibiting the differentiation and effector functions of Th1 and Th17 cells

Ethnopharmacological relevanceQing Chang Suppository (QCS), a traditional Chinese medicine formula, has been shown to effectively alleviate mucosal inflammation in patients with ulcerative colitis (UC). While the mechanism of QCS appears to be related to the regulation of CD4+T cell subset responses, direct evidence demonstrating that QCS inhibits Th1 and Th17 cell activation in UC (particularly based on human data) remains lacking. Additionally, the precise mechanisms through which QCS affects these cells have yet to be fully elucidated. Aim of studyThis study aimed to investigate the effects of QCS on Th1 and Th17 cell responses in UC and to explore the underlying mechanisms. Materials and methodsTwenty-eight patients with mild-to-moderate UC were recruited and treated with QCS for 12 weeks. Symptoms were assessed every two weeks, with sigmoidoscopies performed at baseline and at week 12. Intestinal mucosal biopsies and peripheral blood (PB) were collected at these time points. At the end of the trial, patients were categorized into responder and non-responder groups based on a modified Mayo disease activity index score. Healthy controls (HCs) were defined as subjects without IBD or colorectal carcinoma but with colon polyps. The frequencies of IFN-γ+CD4+T cells and IL-17A+CD4+T cells in PB and colonic mucosa were measured using flow cytometry. The expression levels and localization of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A were determined via immunofluorescence, and JNK signaling activation was assessed through immunoblotting and immunohistochemistry. All parameters were compared across the three groups. ResultsAt week 12, responders showed a significant reduction in colonic mucosal inflammation compared to baseline, accompanied by decreased frequencies of IFN-γ+CD4+T and IL-17A+CD4+ T cells in both PB and the colonic epithelial layer. Notably, Th1 and Th17 cell activity around intestinal epithelial cells (IECs) was nearly undetectable, as evidenced by the diminished expression of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A. Additionally, JNK phosphorylation in these cells was significantly reduced. In contrast, non-responders exhibited no meaningful improvement; colonic pathology remained unchanged, and elevated levels of IFN-γ+CD4+T and IL-17A+CD 4+T cells persisted in both the PB and colonic epithelial layer. The presence of Th1 and Th17 cells and their associated cytokines around IECs remained substantial, and there was no significant change in JNK activation. ConclusionQCS attenuates mucosal inflammation in UC patients by inhibiting the differentiation and effector functions of Th1 and Th17 cells, primarily through the regulation of the JNK signaling pathway.

Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation

Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial. Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD. Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment. These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor. This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital.

HIF-2α-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis

Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation.

Adaptive and innate immune response of Leishmania infantum infection in Cirneco dell’Etna dog breed

Leishmania spp. are an intracellular protozoa present in many countries around the world. In Europe, both the parasite and the disease it causes, leishmaniasis, are endemic in the Mediterranean basin. Clinical signs and severity of disease are highly variable depending on the host in both humans and dogs, traditionally considered the main reservoir of the parasite. The reason for these differences is not known, but it has been speculated that some hosts present immune response, related to activation of Th1 and Th17, capable of controlling the spread of the parasite, and that these immune responses are related to the genetic background of the host. The Ibizan hound, an autochthonous canine breed of the Mediterranean basin, has been postulated as a breed resistant to infection, but other canine breeds evolutionarily close to it and native to this region have not been studied. One of them is the Cirneco dell’Etna, native to the island of Sicily in southern Italy. In this study, the immune response against L. infantum infection in this canine breed was analysed. The results showed that infected dogs of this breed present high levels of several cytokines related to Th1 and Th17 immune response, and significant correlation between serum levels of cytokines related to disease resistance. Further studies are necessary in this canine breed to determine the mechanisms of immune response and genetic background related to L. infantum infection control.

Therapeutic effects of chamomile volatile oil nanoemulsion/Bletilla striata polysaccharides gels on atopic dermatitis

Atopic dermatitis (AD) is a prevalent chronic skin condition characterized by complex immune responses. Chamomile possesses potent anti-inflammatory properties and has been widely used in treating various skin diseases. This study aimed to assess the therapeutic benefits of chamomile volatile oil nanoemulsion gels (CVO-NEGs) for the treatment of AD. Chamomile volatile oil nanoemulsions (CVO-NEs) were prepared using the phase transition method, yielding spherical nanoparticles with a particle size of 19.07 nm. Subsequently, Bletilla striata polysaccharides were employed to encapsulate CVO-NEs, resulting in the formation of CVO-NEGs. In vivo studies demonstrated that the preparation of CVO-NEGs enhanced the biological activity of volatile oil in AD therapy. Histopathological results indicated that CVO-NEGs reduced skin damage, epidermal thickness, and mast cell infiltration. CVO-NEGs suppressed IgG production and reduced the levels of cytokines, including TNF-α, IL-4, and IFN-γ, in AD mice. Furthermore, flow cytometry revealed that CVO-NEGs were involved in regulating the differentiation of CD4+ T cell subsets. The immune imbalance of Th1/Th2 in AD mice can be controlled, resulting in a reduction in the hypersensitivity reaction caused by excessive Th2 activation. In conclusion, the present study confirms that CVO-NEGs have the potential to serve as an effective alternative treatment for AD.

Spatial transcriptomics reveals organized and distinct immune activation in cutaneous granulomatous disorders

BackgroundNon-infectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear. ObjectiveTo understand spatial gene expression characteristics in these disorders. MethodsWe performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion. ResultsCS is characterized by a polarized, spatially organized T helper (Th) 1 predominant response with classical macrophage activation. GA is characterized by a mixed, but spatially organized pattern of Th1 and Th2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of Th1, Th2, and Th17 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation. ConclusionsInflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes.

IL-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma

BackgroundAsthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by TH2 lymphocytes or type 2 innate lymphoid cells (ILC2s). Interleukin-2 family cytokines play a key role in the differentiation, homeostasis and effector function of innate and adaptive lymphocytes. ObjectiveIL-9 and IL-21 boost the activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown. MethodsUsing newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination, in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups. ResultsIL-9 played a central role in controlling innate IL-33 induced lung inflammation by promoting proliferation and activation of ILC2s, in an IL-21 independent manner. Conversely, chronic house dust mite induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, that controlled TH2 activation, eosinophilia, total serum IgE and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) samples we measured elevated IL-21 protein within the allergic asthmatic group, compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets. ConclusionIL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.

Serum Biomarkers in Bullous Pemphigoid: A Systematic Review.

Bullous pemphigoid (BP) is the most common type of subepidermal blistering disease, usually observed in the elderly population, with a mean age of presentation between 66 and 83 years. BP is a psychosocially ladened disease, with many patients experiencing negative body image, social isolation, and depression. The identification and validation of biomarkers in BP may further the understanding of disease pathogenesis, provide objective measures in assessing efficacy in clinical trials, and identify new targets for targeted therapy. Two databases (Medline and Embase) were searched from database inception to September 2023. All published articles reporting on biomarker levels of BP patients in serum compared to healthy controls were included. A total of 877 unique articles were identified, resulting in the inclusion of 62 case-control studies reporting on a total of 1837 patients and 140 unique biomarkers. Biomarkers were categorized into T-cell mediated, B-cell mediated, innate immune system, and coagulation cascade pathway. The most notable biomarkers identified include increases in anti-BP180/230 immunoglobulin (Ig)G/E, total IgE, TNF-α, B-cell activating factor, interleukin-31, eosinophil cationic protein, MMP-9, and coagulation cascade biomarker levels. The results of this review provide the greatest support for a role of anti-BP180/230 autoantibodies, Th2 cells, eosinophils, and the coagulation cascade in the pathogenesis of BP. The pathogenesis of BP has an underlying autoimmune etiology centred around the production of autoantibodies against BP180/230, but increased Th2, eosinophil and coagulation cascade activity may be contributory.

Biomarkers in Pemphigus Vulgaris: A Systematic Review.

Pemphigus vulgaris (PV) is a rare intraepidermal blistering disease that is potentially life-threatening due to risk of infection and failure of skin barrier function. The identification of biomarkers has the potential to provide diagnostic utility and identify new therapeutic targets. The objective of this systematic review is to identify all potentially relevant PV biomarkers, categorize them, and identify trends to determine the involvement of T-cell-mediated, B-cell-1mediated, and innate immune-mediated pathways in PV pathogenesis. Medline and Embase databases were searched according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, resulting in the inclusion of 66 studies that reported on a total of 2463 patients and 146 unique biomarkers. Biomarkers were categorized into T-cell-mediated, B-cell-mediated, and innate immune system pathways. The most notable biomarkers trends include elevations in IL-4, IL-6, IL-17A, anti-Dsg1/3 autoantibodies, and a reduction in Treg cells and FOXP3. The results of this review support current theories of PV pathogenesis, with increased Th2 activity, increased Th17 activity, decreased Treg activity, and production of anti-Dsg1/3 autoantibodies being observed. Targeting of IL-4 and IL-6 may provide therapeutic benefit. However, more research is required to validate biomarkers for clinical utility and assess viability as therapeutic targets.

Card9 and MyD88 differentially regulate Th17 immunity to the commensal yeast Malassezia in the murine skin.

The fungal community of the skin microbiome is dominated by a single genus, Malassezia. Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity. The mechanisms driving Th17 responses to Malassezia remain, however, unclear. Here, we show that the C-type lectin receptors Mincle, Dectin-1, and Dectin-2 recognize conserved patterns in the cell wall of Malassezia and induce dendritic cell activation in vitro, while only Dectin-2 is required for Th17 activation during experimental skin colonization in vivo. In contrast, Toll-like receptor recognition was redundant in this context. Instead, inflammatory IL-1 family cytokines signaling via MyD88 were also implicated in Th17 activation in a T cell-intrinsic manner. Taken together, we characterized the pathways contributing to protective immunity against the most abundant member of the skin mycobiome. This knowledge contributes to the understanding of barrier immunity and its regulation by commensals and is relevant considering how aberrant immune responses are associated with severe skin pathologies.

PERIO-02: Phase 1b pressure enabled regional immuno-oncology trial of nelitolimod (SD-101), a class C TLR9 agonist, delivered via hepatic artery infusion +/- checkpoint inhibition in intrahepatic cholangiocarcinoma and hepatocellular carcinoma.

2622 Background: Immunotherapy (ICI) has shown limited survival benefit in patients (pts) with advanced HCC and intrahepatic cholangiocarcinoma (ICC). Nelitolimod (SD-101), a Class C toll-like receptor-9 (TLR-9 agonist), depletes MDSCs while broadly stimulating the tumor microenvironment. Given safety challenges with IV infusion and distribution limitations of needle injection, we studied hepatic arterial infusion (HAI) of nelitolimod with Pressure-Enabled Drug Delivery (PEDD) to enhance ICI responsiveness. Methods: Pts with advanced HCC or ICC were enrolled. Nelitolimod was dose-escalated without ICI (Cohort A), with pembrolizumab (Cohort B), or with nivolumab + ipilimumab (Cohort C). Nelitolimod administered with HAI for 2 cycles, with 3 weekly doses per cycle using the TriNav device. Primary endpoints included safety and optimal dose determination. Immune cells were examined in blood and tumor tissue using multiplex IF, flow cytometry, and Nanostring. Results: At data cutoff, 29 pts [70% ICC, 30% HCC] were enrolled, 23 received at least one dose of nelitolimod: 3 in Cohort A (4 mg), 8 in Cohort B (2 and 4 mg) and 12 in Cohort C (2 and 4 mg). Median age was 64.5. Only 1 pt was treatment-naïve; 4, 2L (17%); 5, 3L (22%); 14, > 4L (61%). 26% pts had > 10 liver tumors. 3 pts (13%) experienced serious treatment-related adverse events (AE); 1 pt dose-limiting toxicity. Five pts experienced LFT elevations, most G1 with 2 reported as G3. In cohort A, 1 of 3 evaluable pts had SD as best on-treatment response. In cohort B, 1 of 4 evaluable pts had SD as best on-treatment response, others experienced PD by RECIST 1.1. In cohort C 2 mg, 2 of 5 had SD reported at Day 53. At 4 mg dose in cohort C, 3 of 3 pts had disease control, with one CR in the liver (5L ICC) and 2 SD. Decreases were noted in the target liver lesion (31.3 to 17.5 mm), non-target liver lesion, and extra-hepatic lymph nodes on days 53 and 84 with complete response of target liver lesions and stability of extra hepatic nodal lesions reported on Day 154. Median PFS in the Cohort C 4 mg dose level is >120 days. Median OS for this group has not reached (range 120-170 days). Immune effects in cohort C 4 mg pts included increases in liver tumor CD4+ and CD8+ T cells, along with a decrease in the MDSC:CD8+ T cell ratio. Gene expression changes in cohort C 4 mg pts revealed increased Th1 programming in tumor tissue, with increased interferon, cytokine, TLR, Th1, and lymphocyte activation signals in surrounding normal liver. Changes among blood immune cells included increased IFNg and IL2-R expression, with decreased IL17A and VEGFA. Conclusions: HAI of nelitolimod has been well tolerated and associated with encouraging immunologic activity in HCC and ICC. Clinical and biologic activity in cohort C at 4mg is supportive of further enrollment in this cohort. Clinical trial information: NCT05220722 .

Osteoimmune Interaction and TH-1/TH-2 Ratio in Jawbone Marrow Defects: An Underestimated Association - Original Research.

Osteoimmunology recognizes the relationship between bone cells and immune cells. Chronic osteoimmune dysregulation is present in bone marrow defects of the jaw (BMDJ) as fatty-degenerative osteonecrosis (FDOJ). In comparison to samples from healthy jaw bone, the cytokine analysis of samples of BMDJ/FDOJ from 128 patients showed downregulated TNF-α and IL-6 expression and the singular overexpression of the chemokine RANTES/CCL5. This paper raises the question of whether the osteoimmune defects due to incomplete wound healing in BMDJ/FDOJ in 128 patients are related to dysregulation of the Th1/Th2 ratio and regulatory T cell (T-reg) expression in a control group of 197 BMDJ/FDOJ patients, each presenting with BMDJ/FJOD and one of seven different immune disorders. In the control group, serum concentrations of the cytokines IFN-y and IL-4 were determined after stimulated cytokine release and displayed as Th1/Th2 ratios. Data show a shift in Th2 in more than 80% (n = 167) of the control cohort of 197 chronically ill patients with concomitant BMDJ/FDOJ. In these 167 subjects, the Th1/Th2 ratio was <6.1 demonstrating impaired immune regulation. Forty-seven subjects or 30% showed not only a shift in Th2 but also excessive T-reg overactivation with levels of >1.900 pg/mL, indicating strongly downregulated immune activity. BMDJ/FDOJ is characterized by a lack of Th1 cytokines and an excessive expression of RANTES/CCL5 and IL-1ra and, thus, the inversion of an acute inflammatory cytokine pattern. In contrast, abdominal fat contains a very high proportion of regulatory Th1 cells and produces an inflammatory immune response through the high overexpression of TNF-α and IL-6. The lack of Th1 activation in BMDJ/FDOJ areas inhibits normal wound healing and supports the persistence of BMDJ/FDOJ. The Th1/Th2 ratio requires greater consideration, especially with respect to wound healing following dental surgical interventions, such as jaw surgery, implantation and augmentation, to avoid the emergence of the osteoimmune situation that is characteristic of BMDJ/FDOJ.

Mild Disease Course of Experimental Autoimmune Encephalomyelitis without Pertussis Toxin: Brain Transcriptome Analysis Reveals Similar Signaling to Active Lesions in Multiple Sclerosis.

Experimental autoimmune encephalomyelitis (EAE) is a powerful model to study multiple sclerosis (MS). One of the approaches for EAE is to actively immunize with myelin-derived peptides with immune adjuvants. One of the commonly used immune adjuvants is pertussis toxin (PTx), without which EAE disease is mild with relatively longer onset. However, pertussis toxin can also inhibit G protein-coupled receptor (GPCR) signaling so it can confound investigations into the role of GPCRs in EAE or therapies designed to target GPCRs. Since EAE via active immunization without PTx results in a relatively mild disease state, we wanted to confirm that appropriate signaling molecules for the disease were being induced in one target tissue (i.e., brain). RNA-Seq analysis of whole brain tissue demonstrated that the MS signaling pathway was strongly activated in symptomatic mice. In addition, there was activation of Th1 (IFN signaling), Th2 (IL-4 signaling), and Th17 (IL-17 signaling). In comparing canonical pathways from our mouse mild EAE brains with a human MS atlas, EAE shared the most pathways with active and inactive lesions. An advantage of this approach is that disease induction is slower to develop and results in modest clinical signs, which likely more closely mimic human disease onset.

Impaired autophagy in myeloid cells aggravates psoriasis-like skin inflammation through the IL-1β/CXCL2/neutrophil axis

BackgroundPsoriasis is an inflammatory skin disease characterized by the hyperproliferative epidermal keratinocytes and significant immune cells infiltration, leading to cytokines production such as IL-1β, TNF-α, IL-23, and IL-17. Recent study highlights the critical role of IL-1β in the induction and activation of pathogenic Th17 and IL-17-producing γδ T cells, contributing to psoriasis. However, the mechanism underlying IL-1β dysregulation in psoriasis pathogenesis is unclear. Autophagy regulates IL-1β production and has a pleiotropic effect on inflammatory disorders. Previous studies showed controversial role of autophagy in psoriasis pathogenesis, either pro-inflammatory in autophagy-deficient keratinocyte or anti-inflammatory in pharmacologically autophagy-promoting macrophages. Thus, the direct role of autophagy and its therapeutic potential in psoriasis remains unclear.MethodsWe used myeloid cell-specific autophagy-related gene 7 (Atg7)-deficient mice and determined the effect of autophagy deficiency in myeloid cells on neutrophilia and disease pathogenesis in an imiquimod-induced psoriasis mouse model. We then assessed the pathogenic mechanism focusing on immune cells producing IL-1β and IL-17 along with gene expression profiles associated with psoriasis in mouse model and public database on patients. Moreover, therapeutic potential of IL-1β blocking in such context was assessed.ResultsWe found that autophagy deficiency in myeloid cells exacerbated neutrophilic inflammation and disease pathogenesis in mice with psoriasis. This autophagy-dependent effect was associated with a significant increase in IL-1β production from myeloid cells, particularly macrophages, Cxcl2 expression, and IL-17 A producing T cells including γδ T cells. Supporting this, treatment with systemic IL-1 receptor blocking antibody or topical saccharin, a disaccharide suppressing pro-IL-1β expression, led to the alleviation of neutrophilia and psoriatic skin inflammation linked to autophagy deficiency. The pathophysiological relevance of this finding was supported by dysregulation of autophagy-related genes and their correlation with Th17 cytokines in psoriatic skin lesion from patients with psoriasis.ConclusionsOur results suggest that autophagy dysfunction in myeloid cells, especially macrophages, along with IL-1β dysregulation has a causal role in neutrophilic inflammation and psoriasis pathogenesis.

The Role of OX40-OX40L Axis in the Pathogenesis of Atopic Dermatitis.

OX40 is a co-stimulatory immune checkpoint molecule that promotes the activation and the effector function of T lymphocytes through interaction with its ligand (OX40L) on antigen-presenting cells. OX40-OX40L axis plays a crucial role in Th1 and Th2 cell expansion, particularly during the late phases or long-lasting response. Atopic dermatitis is characterized by an immune dysregulation of Th2 activity and by an overproduction of proinflammatory cytokines such as interleukin (IL)-4 and IL-13. Other molecules involved in its pathogenesis include thymic stromal lymphopoietin, IL-33, and IL-25, which contribute to the promotion of OX40L expression on dendritic cells. Lesional skin in atopic dermatitis exhibits a higher level of OX40L+-presenting cells compared with other dermatologic diseases or normal skin. Recent clinical trials using antagonizing anti-OX40 or anti-OX40L antibodies have shown symptom improvement and cutaneous manifestation alleviation in patients with atopic dermatitis. These findings suggest the relevance of the OX40-OX40L axis in atopic dermatitis pathogenesis.