Age-related differences in mRNA vaccine immunogenicity and adjuvancy.

Selective 5-Lipoxygenase Expression in Langerhans Cells and Impaired Dendritic Cell Migration in 5-LO-Deficient Mice Reveal Leukotriene Action in Skin

Cardiovascular diseases (CVDs) are one of the leading causes of mortality worldwide.1 It has been so for decades, notwithstanding a wide array of – mostly preventive – treatment modalities targeting known risk factors, such as hyperlipidemia, type 2 diabetes mellitus, hypertension, or obesity. Recent technical and conceptual advances have unveiled important contributions of the immune system in the pathophysiology of a variety of CVDs such as atherosclerosis, ischemic stroke, chronic heart failure, and other myocardial conditions like myocardial ischemia and reperfusion, viral myocarditis, and cardiac transplantation.2–4 In many of these disorders, so-called danger-associated molecular patterns (DAMPs), released from necrotic tissue and dying cells, can lead to the activation of certain immune cell populations such as monocytes/ macrophages, granulocytes, and T cells, thus aggravating ongoing inflammatory processes at the lesion site. Dendritic cells (DCs) are key modulators of immunity, pivotal in directing innate and adaptive immune responses against microbial, viral, but also modified self-antigens present at the sites of injury. Given the tissue trauma underlying various CVDs, it is not surprising that recent observations have allocated a regulatory role for DCs in CVD-associated immune responses. Interestingly, nondiseased arteries of young individuals were seen to host a network of resident vascular DCs (CD1a+ S100+ lag+ CD31− CD83− CD86−),5 representing a phenotype related to Langerhans cells in the skin. In agreement, monocyte-derived CD11c+ CD68+ dendritic cells could be detected in the atherosclerosis-prone lesser curvature and aortic sinus in inbred atherosclerosis-susceptible (C57Bl/6), but not resistant mouse strains (balb/c).6 Murine vascular resident DCs express an immature phenotype with low expression of costimulatory molecules, and are present in the subendothelial space with occasional probing into the vascular lumen. DCs have …

[Background] Promising efficacy of the immunotherapy with anti-PD-1 antibody for esophageal squamous cell carcinoma (ESCC) is expected. Tumor-infiltrating lymphocytes (TILs)have been found to be associated with favorable outcome of patients in many cancers including ESCC. However, the contributing factor of TILs in the primary tumor remains unclear. Dendritic cells (DCs) are the most potent antigen-presenting cells to induce cytotoxic T lymphocytes. [Purpose] The aim of this study was to examine the correlation of mature dendritic cells with CD8+ cells in the tumor in order to clarify the impact of DCs on locally infiltrated lymphocytes in ESCC. [Object and Methods] Formalin-fixed, paraffin-embedded blocks of primary lesions were collected from 80 patients with ESCC who underwent surgical treatment at Osaka City University Hospital. Immunohistochemical analysis using anti-LAMP-3 antibody and CD8 antibody was used to evaluate intratumoral DCs and TILs. The number of LAMP-3+DCs and TILs were counted at ×400 magnification. We divided the 80 cases into two groups according to the median number of intratumoral DCs and TILs to examine the clinicopathological features. [Results] LAMP-3+DCs were predominantly observed in peritumoral area and sparsely found in intratumoral area, whereas CD8+T cells distributed between both peritumoral and intratumoral areas. The number of DCs was significantly associated with increasing TNM stage. For example, the median number of DCs was 59.9 in pathological T1, 34.2 in T2/3, 62.4 in pN1, 34.1 in pN1/2/3. In addition, many patients with high infiltaraion of DCs had positive lymphatic invasion (Ly). The number of intratumoral DCs was significantly correlated with the number of TILs which were observed in intratumoral regions. Patients in the high infiltration of DCs group showed a significant better prognosis than patients in the low infiltration group. Double staining showed that LAMP3+DC-CD8+T cell clusters were seen in peritumoral area. Citation Format: Junya Nishimura, Hiroaki Tanaka, Yuichiro Miki, Tatsuro Tamura, Tatsunari Fukuoka, Go Ohira, Masatsune Shibutani, Sadaaki Yamazoe, Kenjiro Kimura, Takahiro Toyokawa, Hisashi Nagahara, Ryosuke Amano, Kazuya Muguruma, Kiyoshi Maeda, Kosei Hirakawa, Masaichi Ohira. Impact of intratumoral mature dendritic cells on prognosis of the patients with esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2945. doi:10.1158/1538-7445.AM2017-2945

Durable cell‐mediated immune responses require efficient innate immune signaling and the release of pro‐inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS‐CoV‐2 mRNA vaccination primes human monocyte‐derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed macrophages undergo NLRP3‐driven pyroptotic cell death and subsequently secrete mature interleukin‐1β. These effects depend on activation of spleen tyrosine kinase (SYK) coupled to C‐type lectin receptors. Using autologous cocultures, we show that SYK and NLRP3 orchestrate macrophage‐driven activation of effector memory T cells. Furthermore, vaccination‐induced macrophage priming can be enhanced with repetitive antigen exposure providing a rationale for prime‐boost concepts to augment innate immune signaling in SARS‐CoV‐2 vaccination. Collectively, these findings identify SYK as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein‐specific T cell responses.

The role of dendritic cells in asthma

Chronic Ethanol Consumption Impairs Cellular Immune Responses Against HCV NS5 Protein Due to Dendritic Cell Dysfunction

Macroporous hydrogel-based mRNA cancer vaccine for in situ recruitment and modulation of dendritic cells.

Tissues accommodate defined numbers of dendritic cells (DCs) in highly specific niches where different intrinsic and environmental stimuli control DC life span and numbers. DC homeostasis in tissues is important, because experimental changes in DC numbers influence immunity and tolerance toward various immune catastrophes and inflammation. However, the precise molecular mechanisms regulating DC life span and homeostasis are unclear. We report that the GTPase RhoA controls homeostatic proliferation, cytokinesis, survival, and turnover of cDCs. Deletion of RhoA strongly decreased the numbers of CD11b(-)CD8(+) and CD11b(+)Esam(hi) DC subsets, whereas CD11b(+)Esam(lo) DCs were not affected in conditional RhoA-deficient mice. Proteome analyses revealed a defective prosurvival pathway via PI3K/protein kinase B (Akt1)/Bcl-2-associated death promoter in the absence of RhoA. Taken together, our findings identify RhoA as a central regulator of DC homeostasis, and its deletion decreases DC numbers below critical thresholds for immune protection and homeostasis, causing aberrant compensatory DC proliferation.

Objective To investigate the changes in the number and function of peripheral blood dendritic cells (DCs) in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI).Methods Thirty-six SPF C57BL/6 mice,aged 6-8 weeks,weighing 18-22 g,were randomly divided into 2 groups (n =18 each):control group and ALI group.ALI was induced by intra-tracheal injection of LPS 2 mg/kg in 30μl of PBS in group ALI,while group C received the equal volume of PBS.Six mice were chosen at 6,12 and 24 h after LPS or PBS administration (T1-3) and anesthetized.The chest was opened and venous blood samples were collected from the right ventricle for measurement of the number of DCs and the phenotype of DCs (CD80,MHC Ⅱ) in the peripheral blood by flow cytometry.The mice were then sacrificed and lungs were removed for microscopic examination and for determination of IL-6 content in lung tissues (by ELISA).The pathological changes of the lung were scored.Wet lung weight/body weight ratio was calculated.Results Microscopic examination showed widened alveolar septum,congestion,bleeding and massive inflammatory cell infiltration in ALI group.Compared with group C,wet lung weight/body weight ratio,IL-6 content and lung injury scores were significantly increased at each time point,the number of peripheral blood DCs was decreased at T1,while enlarged at T3,and the expression of MHC Ⅱ was up-regulated at T2,3 in group ALI (P ＜ 0.05).IL-6 content was significantly higher at T2,and the number of peripheral blood DCs was larger and the expression of MHC Ⅱ was up-regulated at T2,3 than at T1 in group ALI (P ＜0.05).The number of peripheral blood DCs was significantly larger at T3 than at T2 in group ALI (P ＜ 0.05).There was no significant change in CD80 expression at each time point between the two groups (P ＞ 0.05).Conclusion The number of peripheral blood DCs is decreased at the early period and then increased gradually and the function becomes gradually mature. Key words: Respiratory distress syndrome, adult; Dendritic cells

Expression of retinoic acid receptors in intestinal mucosa and the effect of vitamin A on mucosal immunity

Cutaneous lupus erythematosus flare with vitiligo-like depigmentation following the AstraZeneca COVID vaccine

Dendritic cells (DC) have an increasingly important role in vaccination therapy; therefore, this study sought to determine the migratory capacity and immunogenic function of murine bone-marrow (BM)-derived DC following subcutaneous (s.c.) and intravenous (i.v.) injection in vivo. DC were enriched from BM cultures using metrizamide. Following centrifugation, the low-buoyant density cells, referred to throughout as DC, were CD11c(high), Iab(high), B7-1(high) and B7-2(high) and potently activated alloreactive T cells in mixed lymphocyte reactions (MLR). In contrast, the high-density cells expressed low levels of the above markers, comprised mostly of granulocytes based on GR1 expression, and were poor stimulators in MLR. Following s.c. injection of fluorescently labelled cells into syngeneic recipient mice, DC but not granulocytes migrated to the T-dependent areas of draining lymph nodes (LN). DC numbers in LN were quantified by flow-cytometric analysis, on 1, 2, 3, 5 and 7 days following DC transfer. Peak numbers of around 90 DC per draining LN were found at 2 days. There was very little migration of DC to non-draining LN, thymus or spleen at any of the time-points studied. In contrast, following i.v. injection, DC accumulated mainly in the spleen, liver and lungs of recipient mice but were largely absent from peripheral LN and thymus. The ability of DC to induce T-cell-mediated immune responses was examined using trinitrobenzenesulphate (TNBS)-derivatized DC (TNBS-DC) to sensitize for contact hypersensitivity responses (CHS) in naive syngeneic recipients. Following s.c. injection, as few as 105 TNBS-DC, but not TNBS-granulocytes, sensitized for CHS responses. However, the same number of TNBS-DC failed to induce CHS following i.v. injection. In summary, this study provides new and quantitative data on the organ specific migration of murine BM-derived DC following s.c. and i.v. injection. The demonstration that the route of DC administration determines the potency of CHS induction, strongly suggests that the route of immunization should be considered in the design of vaccine protocols using DC.

Food allergy affects approximately 6% of children and is the leading cause of hospitalization for anaphylactic reactions in westernized countries. Crucial in the establishment of allergy is the activation of dendritic cells (DC) leading to T helper 2-mediated responses. We, therefore, investigated whether changes in DC subsets precede the establishment of food allergy, and which DC subsets have functional relevance during allergic sensitization in a mouse model. Changes in DC populations in the intestine were analysed after exposure to cholera toxin alone and in combination with peanut extract (PE) as an allergen. To study the functional role of DC subsets in relation to food allergy, we used expansion of DC in vivo by treatment with Flt3L. Sensitization to PE in this mouse model was accompanied by a shift in DC subsets in intestinal tissues towards more CD11b(+) DC and less CD103(+) DC. No significant changes in the plasmacytoid DC (pDC) numbers were observed. Flt3L treatment, resulting in the expansion of all DC subtypes, inhibited allergic manifestations in our model, including Th2 cytokine production, PE-specific IgE and PE-induced mast cell degranulation. pDC depletion reversed Flt3L-induced inhibition of IgE responses and mast cell degranulation. conclusions and clinical relevance: The establishment of food allergy is accompanied by profound changes in DC subsets in the intestine towards more inflammatory CD11b(+) DC. In addition, expansion of DC numbers by Flt3L, in particular pDC, inhibits the establishment of allergic manifestations in the intestine. These findings are of relevance for understanding the role of DC subsets early during the process of allergic sensitization, and may lead to new therapeutic or prophylactic opportunities to prevent food allergy.

Dendritic cells (DCs) are antigen-presenting cells with a unique ability to cross prime T cells and generate strong antitumor responses. This study evaluates the presence and prognostic significance of DCs as well as functional T cells, which accumulate in the microenvironment in patients with oral squamous cell carcinoma (OSCC). Immunohistochemistry for S-100 positive or p55 positive DCs and for T-cell receptor (TcR)-associated zeta-chain expression in tumor-infiltrating lymphocytes (TILs) was performed in 132 paraffin embedded specimens from patients with primary OSCC. The median clinical follow-up for the patients was 50 months. The numbers of intratumoral DCs or TILs expressing the zeta chain were determined microscopically and compared with clinical and pathohistologic prognostic parameters, including disease stage, T stage or tumor grade, lymph node involvement, as well as disease free survival and overall survival. Immunostaining identified DCs in the epithelial compartment of the tumors (S-100 positive) as well as interdigitating reticular DCs (p55 positive) in peritumoral areas. Based on S-100 staining, intratumoral DC infiltrates were low (<10 DCs per high-power field [HPF]) in 20% of OSCC specimens, intermediate (10-20 DCs per HPF) in 42% of OSCC specimens, and high (>20 DCs per HPF) in 37% of OSCC specimens. The number of S-100 positive DCs was positively and significantly correlated with that of p55 and of TILs with normal zeta-chain expression. A low number of infiltrating S-100 positive DCs was more predictive of poor survival (hazard ratio, 7.95) than lymph node involvement (hazard ratio, 3.36) or late T stage (hazard ratio, 2.92). A significant but weaker association of p55 positive DC infiltration with survival was observed. Low density of DCs and low or absent expression of the zeta chain in TILs correlated with each other and predicted the poorest survival and the greatest risk. The number of DCs infiltrating the tumor is a highly significant prognostic parameter in patients with OSCC. Furthermore, the absence or paucity of DCs is strongly linked to abnormalities in the TcR-associated zeta chain in TILs. The two biomarkers, zeta-chain expression in TILs and the number of S-100+ DCs in the tumor, independently predict overall survival, disease free survival, and time to disease recurrence in patients with OSCC.

An Optimized, Ex Vivo Log-Scale Expansion of UCB-Derived Myeloid Dcs, Towards Efficient Cancer Immunotherapy