Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.

The interleukin-12 (IL-12) family is a class of heterodimeric cytokines that play crucial roles in pro-inflammatory and pro-stimulatory responses. Although some IL-12 and IL-23 paralogues have been found in fish, their functional activity in fish remains poorly understood. In this study, Pf_IL-12p35a/b, Pf_IL-23p19 and Pf_IL-12p40a/b/c genes were cloned from yellow catfish (Pelteobagrus fulvidraco), four α-helices were found in Pf_IL-12p35a/b and Pf_IL-23p19. The transcripts of these six genes were relatively high in mucus and immune tissues of healthy individuals, and in gill leukocytes. Following Edwardsiella ictaluri infection, Pf_IL-12p35a/b and Pf_IL-23p19 mRNAs were induced in brain and kidney (or head kidney), Pf_IL-12p40a mRNA was induced in gill, and Pf_IL-12p40b/c mRNAs were induced in brain and liver (or skin). The mRNA expression of these genes in PBLs was induced by phytohaemagglutinin (PHA) and polyinosinic-polycytidylic acid (poly I:C), while lipopolysaccharides (LPS) induced the mRNA expression of Pf_IL-12p35a and Pf_IL-12p40b/c in PBLs. After stimulation with recombinant (r) Pf_IL-12 and rPf_IL-23 subunit proteins, either alone or in combination, mRNA expression patterns of genes related to T helper cell development exhibited distinct differences. The results suggest that Pf_IL-12 and Pf_IL-23 subunits may play important roles in regulating immune responses to pathogens and T helper cell development.

Inflammatory bowel diseases (IBDs) pose significant challenges in terms of treatment non-response, necessitating the development of novel therapeutic approaches. Although biological medicines that target TNF-α (tumour necrosis factor-α) have shown clinical success in some IBD patients, a substantial proportion still fails to respond.
We designed bispecific nanobodies (BsNbs) with the ability to simultaneously target human macrophage-expressed membrane TNF-α (hmTNF-α) and IL-23. Additionally, we fused the constant region of human IgG1 Fc (hIgG1 Fc) to BsNb to create BsNb-Fc.  Our study encompassed in vitro and in vivo characterization of BsNb and BsNb-Fc.
BsNb-Fc exhibited an improved serum half-life, targeting capability and effector function than BsNb. It\'s demonstrated that BsNb-Fc exhibited superior anti-inflammatory effects compared to the anti-TNF-α mAb (infliximab, IFX) combined with anti-IL-12/IL-23p40 mAb (ustekinumab, UST) by Transwell co-culture assays. Notably, in murine models of acute colitis brought on by 2,4,6-trinitrobenzene sulfonic acid（TNBS) and dextran sulphate sodium (DSS), BsNb-Fc effectively alleviated colitis severity. Additionally, BsNb-Fc outperformed the IFX&UST combination in TNBS-induced colitis, significantly reducing colon inflammation in mice with colitis produced by TNBS and DSS.
These findings highlight an enhanced efficacy and improved biostability of BsNb-Fc, suggesting its potential as a promising therapeutic option for IBD patients with insufficient response to TNF-α inhibition.
A bispecific nanobody (BsNb) was created to target TNF-α and IL-23p19, exhibiting high affinity and remarkable stability. BsNb-Fc inhibited the release of cytokines in CD4+T cells during co-culture experiments. BsNb-Fc effectively alleviated colitis severity in mouse model with acute colitis induced by DSS or TNBS, outperforming the IFX&UST combination.

BACKGROUND: Interleukin-23p19 (IL-23p19) has been demonstrated to be involved in the occurrence and development of cardiovascular diseases such as myocardial infarction and atherosclerosis. This study aimed to examine whether IL-23p19 regulates cardiac remodeling processes and explore its possible mechanisms.
RESULTS: Transverse aortic constriction was performed to construct a mouse cardiac remodeling model, and sham surgery was used as a control. The results showed that IL-23p19 expression was increased in the heart after surgery and may be mainly produced by cardiac macrophages. Knockout of IL-23p19 attenuated M1 macrophage polarization, reduced ferroptosis, improved the process of cardiac remodeling and alleviated cardiac dysfunction in TAC mice. Cell culture experiments found that macrophages were the main cause of ferroptosis when phenylephrine (PE) was added, and blocking ferroptosis with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, significantly inhibited M1 macrophage polarization. Treatment with Fer-1 also improved cardiac remodeling and alleviated cardiac dysfunction in IL-23p19-/- mice subjected to TAC surgery. Finally, TAC IL-23p19-/- mice that were administered macrophages isolated from WT mice exhibited an increased proportion of M1 macrophages and aggravated cardiac remodeling, and these effects were reversed when Fer-1 was administered.
CONCLUSIONS: Knockout of IL-23p19 may attenuate M1 macrophage polarization to improve the cardiac remodeling process by reducing macrophage ferroptosis, and IL-23p19 may be a potential target for the prevention and treatment of cardiac remodeling.

UNASSIGNED: Interleukin (IL) 23p19 monoclonal antibodies were efficacious and safe in the treatment of psoriasis. A first-in-human (FIH) study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of IBI112, a novel IL-23p19 monoclonal antibody.
UNASSIGNED: In this FIH, randomized, double-blind, placebo-controlled, single-ascending-dose study, a subcutaneous (SC, 5-600 mg) or intravenous (IV, 100 and 600 mg) or placebo was administered to eligible healthy subjects. Safety was assessed by physical examinations, vital signs, laboratory tests, and electrocardiograms. Furthermore, non-compartment analysis and population PK modeling were conducted to characterize PK, and model-based simulation was applied to justify dose selection for psoriasis patients.
UNASSIGNED: A total of 46 subjects were enrolled, with 35 receiving IBI112 and 11 receiving placebo. No serious adverse events (SAEs) and no clinically significant adverse events were identified. After a single SC of IBI112, the median Tmax was 4-10.5 days, and the half-life (t1/2) ranged from 21.8 to 35.8 days. IBI112 exposures (Cmax and AUCinf) approached dose proportionality across 5-300 mg range.
UNASSIGNED: IBI112 was well tolerated and safe at SC or IV dose up to 600 mg and showed a linear PK characteristics at SC dose from 5 to 300 mg.
UNASSIGNED: ClinicalTrial.gov NCT04511624.

The interleukin-23 (IL-23)/IL-17 immune axis has been linked to the pathology of psoriasis, but how this axis contributes to skin inflammation in this disease remains unclear. We measured inflammatory cytokines associated with the IL-23/IL-17 immune axis in the serum of patients with psoriasis using enzyme-linked immunosorbent assays. Psoriasis was induced in male C57BL/6J mice using imiquimod (IMQ) cream, and animals received intraperitoneal injections of recombinant mouse anti-IL-23A or anti-IL-17A antibodies for 7 days. The potential effects of the IL-23/IL-17 immune axis on skin inflammation were assessed based on pathology scoring, hematoxylin-eosin staining of skin samples, and quantitation of inflammatory cytokines. Western blotting was used to evaluate levels of the following factors in skin: ACT1, TRAF6, TAK1, NF-κB, and pNF-κB. The serum of psoriasis patients showed elevated levels of several cytokines involved in the IL-23/IL-17 immune axis: IL-2, IL-4, IL-8, IL-12, IL-17, IL-22, IL-23, and interferon-γ. Levels of IL-23p19 and IL-17 were increased in serum and skin of IMQ-treated mice, while ACT1, TRAF6, TAK1, NF-κB, and pNF-κB were upregulated in the skin. A large proportion of NF-κB p65 localized in nucleus of involucrin+ cells in the epidermis and in F4/80+ cells of the dermis of psoriatic lesional skin. Treating these animals with anti-IL-23 or anti-IL-17 antibodies improved pathological score and immune imbalance, mitigated skin inflammation and downregulated ACT1, TRAF6, TAK1, NF-κB, and pNF-κB in skin. Our results suggest that skin inflammation mediated by the IL-23/IL-17 immune axis in psoriasis involves activation of the ACT1/TRAF6/TAK1/NF-κB pathway in keratinocytes and macrophage.

OBJECTIVE: To observe the expression of helper T cells 17(Th17), interleukin 23 (IL-23) in peripheral blood in patients with acute myeloid leukemia (AML), to analyze the relationship between Th17, IL-23 in peripheral blood and immunophenotype.
METHODS: 105 patients with AML in the hospital from January 2019 to January 2021 were prospectively selected as the research subjects, the expression of Th17 and IL-23 in peripheral blood of patients with AML was detected by flow cytometry; immunophenotype was detected and counted. The relationship between the expression of Th17, IL-23 in peripheral blood and immunophenotype of AML patients was analyzed. Draw ROC curve and analyze the predictive value of Th17 and IL-23 expression in peripheral blood to immunophenotype.
RESULTS: The immunophenotype results of AML patients showed that myeloid antigen, lymphoid antigen and hematopoietic stem/progenitor cell marker antigen were positive expressed for various antigens in 105 AML patients, in myeloid antigens, CD13+ accounted for the highest proportion (93.33%), in lymphoid antigens, CD56+ accounted for the highest proportion (32.38%), and in hematopoietic stem/progenitor cell marker antigens, CD38+ accounted for the highest proportion (68.57%). The expression of Th17 in peripheral blood of AML patients with CD56+, CD7+, CD34+ and human leukocyte antigen DR+(HLA-DR+) were higher than that of AML patients with CD56-, CD7-, CD34-, HLA-DR-, the expression of IL-23 in peripheral blood of AML patients with CD56+, CD34+ and HLA-DR+ were higher than that of AML patients with CD56-, CD34-, HLA-DR-, the differences were statistically significant (P<0.05); compared the expression of Th17 and IL-23 in peripheral blood between other antibody positive and negative patients, there was no statistical significant difference (P>0.05). Logistic regression analysis showed that the high expression of Th17 in patients with AML was related to the positive expression of CD56, CD7, CD34 and HLA-DR in the detection of immunophenotype, the high expression of IL-23 was related to the positive expression of CD56, CD34 and HLA-DR in the detection of immunophenotype. The ROC curve showed that the AUC of expression levels of Th17 and IL-23 in peripheral blood alone and in combination for predicting CD56+, CD34+, HLA-DR+ and Th17 in peripheral blood for predicting CD7+ were mostly 0.5-0.7, which had certain predictive value, but the predictive performance was low.
CONCLUSIONS: Myeloid antigen, lymphoid antigen and hematopoietic hematopoietic stem/progenitor cell marker antigen are positive expressed for various antigens in AML patients, the high expression of Th17 in peripheral blood of AML patients is related to the positive expression of CD56, CD7, CD34 and HLA-DR in detection of immunophenotyping, the high expression of IL-23 is related to the positive expression of CD56, CD34 and HLA-DR in the detection of immunophenotype.
UNASSIGNED: 外周血Th17、IL-23的表达及其与急性髓细胞白血病患者免疫表型的关系分析.
UNASSIGNED: 观察急性髓细胞白血病（AML）患者外周血辅助性T细胞17（Th17）和白细胞介素23（IL-23）的表达，分析外周血Th17、IL-23与免疫表型的关系.
UNASSIGNED: 前瞻性选择2019年1月-2021年1月医院105例AML患者作为研究对象，经流式细胞术检测AML患者外周血Th17、IL-23的表达，检测并统计AML患者免疫表型；分析AML患者外周血Th17、IL-23表达与免疫表型的关系。绘制ROC曲线，分析外周血Th17、IL-23表达对免疫表型的预测价值.
UNASSIGNED: AML患者免疫表型检测结果显示，105例AML患者髓系抗原、淋系抗原、造血干/祖细胞标记抗原均有多种抗原呈阳性表达，髓系抗原中，CD13+占比最高（93.33%），淋系抗原中，CD56+占比最高（32.38%），造血干/祖细胞标记抗原中，CD38+占比最高（68.57%）。CD56+、CD7+、CD34+、人类白细胞抗原DR+(HLA-DR+)的AML患者外周血Th17表达高于CD56-、CD7-、CD34-、HLA-DR-的患者，CD56+、CD34+、HLA-DR+的AML患者外周血IL-23表达高于CD56-、CD34-、HLA-DR-的患者，差异有统计学意义（P＜0.05）；其他抗体阳性与阴性患者外周血Th17、IL-23表达比较差异无统计学意义（P＞0.05）。经Logistic回归分析显示，AML患者外周血Th17高表达与免疫表型检查中CD56、CD7、CD34、HLA-DR阳性表达有关，IL-23高表达与免疫表型检查中CD56、CD34、HLA-DR阳性表达有关。绘制ROC曲线发现，外周血Th17、IL-23表达水平单独及联合预测CD56+、CD34+、HLA-DR+的AUC及外周血Th17预测CD7+的AUC多数在0.5-0.7，有一定预测价值，但预测性能较低.
UNASSIGNED: AML患者髓系抗原、淋系抗原、造血干/祖细胞标记抗原均有多种抗原呈阳性表达，AML患者外周血Th17高表达与免疫表型检查中CD56、CD7、CD34、HLA-DR阳性表达有关，IL-23高表达与免疫表型检查中CD56、CD34、HLA-DR阳性表达有关.

Leprosy is an infectious disease caused by non-cultivable bacteria Mycobacterium leprae. Th17 cells play vital roles during pathogenesis of leprosy reactions and IL-23 is involved in Th17 cell differentiation. Although previous studies have reported the participation of IL-23 in leprosy patients in peripheral blood, the role of this cytokine in skin has not yet been described for the disease. In this study, we first evaluated IL-23 expression in the skin of patients with leprosy. Data showed that in keratinocytes, endothelial cells, and macrophages, IL-23 expression was markedly higher in patients compared to that in the normal skin controls. Also, leprosy patients presented higher percentage of IL-17A-producing IL-23R + CD4 T cells than healthy donors. IL-23R blocking induced markedly downregulated IL-17A secretion in leprosy patients but not in healthy donors. Furthermore, TGF-β expression was significantly elevated after IL-23R blocking. Overall, this study establishes that Th17 cells produce IL-17A in an IL-23 dependent manner in the skin of leprosy patients and provides more focused treatment strategies for Mycobacterium leprae.

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)-mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.

OBJECTIVE: Guillain-Barré syndrome (GBS) results from autoimmune attack on the peripheral nerves, causing sensory, motor and autonomic abnormalities. Emerging evidence suggests that there might be an association between COVID-19 and GBS. Nevertheless, the underlying pathophysiological mechanism remains unclear.
METHODS: We performed bioinformatic analyses to delineate the potential genetic crosstalk between COVID-19 and GBS.
RESULTS: COVID-19 and GBS were associated with a similar subset of immune/inflammation regulatory genes, including TNF, CSF2, IL2RA, IL1B, IL4, IL6 and IL10. Protein-protein interaction network analysis revealed that the combined gene set showed an increased connectivity as compared to COVID-19 or GBS alone, particularly the potentiated interactions with CD86, IL23A, IL27, ISG20, PTGS2, HLA-DRB1, HLA-DQB1 and ITGAM, and these genes are related to Th17 cell differentiation. Transcriptome analysis of peripheral blood mononuclear cells from patients with COVID-19 and GBS further demonstrated the activation of interleukin-17 signalling in both conditions.
CONCLUSIONS: Augmented Th17 cell differentiation and cytokine response was identified in both COVID-19 and GBS. PBMC transcriptome analysis also suggested the pivotal involvement of Th17 signalling pathway. In conclusion, our data suggested aberrant Th17 cell differentiation as a possible mechanism by which COVID-19 can increase the risk of GBS.