Highlights • VISTA blockade increases T cell recruitment in the tumor microenvironment. • VISTA blockade converts CD8+ T cells to finally differentiated effector T cells. • VISTA blockade enhances ...multifuntionality of CD8+ T cells. • Combined CTLA-4 and VISTA blockade is more efficacious. • Inhibition of regulatory T cell recruitment within tumors is critical.
Interleukin-33 (IL-33) is a member of the IL-1 cytokine family, which includes IL-1 and IL-18. IL-33 is considered to be crucial for induction of Th2-type cytokine-associated immune responses such as ...host defense against nematodes and allergic diseases by inducing production of such Th2-type cytokines as IL-5 and IL-13 by Th2 cells, mast cells, basophils and eosinophils. In addition, IL-33 is involved in the induction of non-Th2-type acute and chronic inflammation as a proinflammatory cytokine, similar to IL-1 and IL-18. In this review, we summarize and discuss the current knowledge regarding the roles of IL-33 and IL-33 receptors in host defense and disease development.
IL-33, a member of the IL-1-related cytokines, is considered to be a proallergic cytokine that is especially involved in Th2-type immune responses. Moreover, like IL-1α, IL-33 has been suggested to ...act as an “alarmin” that amplifies immune responses during tissue injury. In contrast to IL-1, however, the precise roles of IL-33 in those settings are poorly understood. Using IL-1- and IL-33-deficient mice, we found that IL-1, but not IL-33, played a substantial role in induction of T cell-mediated type IV hypersensitivity such as contact and delayed-type hypersensitivity and autoimmune diseases such as experimental autoimmune encephalomyelitis. Most notably, however, IL-33 was important for innate-type mucosal immunity in the lungs and gut. That is, IL-33 was essential for manifestation of T cell-independent protease allergen-induced airway inflammation as well as OVA-induced allergic topical airway inflammation, without affecting acquisition of antigen-specific memory T cells. IL-33 was significantly involved in the development of dextran-induced colitis accompanied by T cell-independent epithelial cell damage, but not in streptozocin-induced diabetes or Con A-induced hepatitis characterized by T cell-mediated apoptotic tissue destruction. In addition, IL-33-deficient mice showed a substantially diminished LPS-induced systemic inflammatory response. These observations indicate that IL-33 is a crucial amplifier of mucosal and systemic innate, rather than acquired, immune responses.
B7-H3 is a member of the B7 family of immune-regulatory ligands and is a costimulatory molecule promoting the T cell response in vitro. We herein investigated the clinical utility of serum soluble ...B7-H3 (sB7-H3) in patients with non-muscle invasive bladder cancer (NMIBC).
We analyzed 555 patients in whom NMIBC was diagnosed at Tokyo Metropolitan Tama Medical Center between 2008 and 2013. We measured the serum sB7-H3 (sB7-H3) level using the enzyme-linked immunosorbent assay (ELISA) and evaluated the utility of sB7-H3 as a prognostic biomarker for NMIBC. We used the Cox proportional hazards regression model to assess recurrence-free survival (RFS) and progression-free survival (PFS) with the sB7-H3 level.
We detected high levels of sB7-H3 in the sera of 47% of patients with NMIBC versus only 8% in healthy donors. The increase of sB7-H3 was significantly associated with poor RFS and PFS. Multivariate analysis showed that elevated sB7-H3 was an independent prognostic factor of RFS and PFS. According to the European Organization for Research and Treatment of Cancer (EORTC), in intermediate-low and intermediate-high risk groups, the presence of sB7-H3 significantly determined the rate of recurrence and progression.
Our data suggested that evaluating serum sB7-H3 expression is a useful tool for predicting the prognosis of patients with NMIBC.
Interleukin-33 in allergy Ohno, Tatsukuni; Morita, Hideaki; Arae, Ken ...
Allergy,
October 2012, Letnik:
67, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Interleukin‐33 (IL‐33) is a member of the IL‐1 cytokine family, which includes IL‐1 and IL‐18, and is considered to be important for host defense against nematodes by inducing Th2 cytokine production ...via the IL‐33 receptor. IL‐33 receptor is a heterodimer of IL‐1 receptor‐like 1 (IL‐1RL1; also called ST2, T1, Der4, and fit‐1) and IL‐1 receptor accessory protein (IL‐1RAcP). On the other hand, excessive and/or inappropriate production of IL‐33 is considered to be involved in the development of various disorders, such as allergic and autoimmune diseases. Unlike IL‐1β and IL‐18, IL‐33 does not seem to be secreted through the activation of inflammasomes in events such as apoptosis. However, IL‐33 is localized in the nucleus of cells and is released during tissue injury associated with necrosis. This suggests that it acts as an alarmin, like IL‐1α and high‐mobility group box chromosomal protein‐1 (HMGB‐1). This review summarizes current knowledge regarding the roles of IL‐33 in the functions of various cell types and the pathogenesis of allergy.
Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant manifestation of a congenital genetic disorder caused by a mutation in the NOTCH2 gene. NOTCH signaling has variations from NOTCH 1 to 4 and ...maintains homeostasis by determining and regulating the proliferation and differentiation of various cells. In HCS, the over-accumulated NOTCH2 causes abnormal bone resorption due to its continuous excessive signaling. HCS is characterized by progressive bone destruction, has complex wide-range clinical manifestations, and significantly impacts the patient’s quality of life. However, no effective treatment has been established for HCS to date. There are genetic variants of NOTCH2 that have been reported in the ClinVar database of the U.S. National Institutes of Health. In total, 26 mutant variants were detected based on the American College of Medical Genetics and Genomics (ACMC). To date, there has been no comprehensive compilation of HCS mutations. In this review, we provide the most comprehensive list possible of HCS variants, nucleotide changes, amino acid definitions, and molecular consequences reported to date, following the ACMC guidelines.
The identification of novel helper T (Th) cell subsets, i.e., IL-17-producing Th cells (Th17 cells) and regulatory T cells (Treg cells), provided new insight into our understanding of the molecular ...mechanisms involved in the development of infectious and autoimmune diseases as well as immune responses, and thus led to revision of the classic Th1/Th2 paradigm. Several current lines of evidence from gene-deficient mice indicate that IL-17 and Th17 cells, but not IFN-y and Th1 cells, are responsible for the development of autoimmune diseases such as murine arthritis and encephalomyelitis, which have classically been considered to be Th1-mediated disorders. Th17 cells may also contribute to the pathogenesis of classically recognized Th2-mediated allergic disorders. In this review, we summarize the current knowledge regarding iL-17 and Th17 cells and discuss their potential roles in the pathogenesis of allergic disorders.
Background
The immune checkpoint programmed cell death 1 (PD‐1): PD‐1 ligand 1 (PD‐L1) pathway plays a crucial role in maintaining immune tolerance and preventing tissue damages by excessive immune ...responses. PD‐L1 is physiologically expressed and upregulated in keratinocytes (KCs) in the oral cavity. We here investigated the contribution of PD‐L1 that was overexpressed in gingival basal KCs in a ligature‐induced periodontitis model.
Methods
Wild‐type (WT) BALB/c and K14/PD‐L1 transgenic (tg) mice, in which PD‐L1 was overexpressed in basal KCs under control of the keratin 14 promoter, were used. To induce periodontitis, a 9‐0 silk ligature was placed around the upper right second molar, and lipopolysaccharide from Porphyromonas gingivalis was applied on the suture. Gingival tissues were collected on day 7, after which histological analyses were performed, including by hematoxylin and eosin and tartrate‐resistant acid phosphate staining (TRAP) and quantitative PCR for proinflammatory cytokines and bone metabolism‐related genes. Alveolar bone loss at 7 weeks after ligature placement was assessed by micro‐computed tomography analysis.
Results
PD‐L1 was overexpressed in the basal KCs of all gingival epithelia in K14/PD‐L1tg mice. Early ligature‐induced periodontal inflammation, as assessed based on histological changes, elevation of proinflammatory cytokine (IL‐1β, IL‐6, TNF‐α) expression, periodontal ligament degeneration, and osteoclastogenesis as assessed by Rankl and Opg expression and TRAP+ cells, was markedly impaired in K14/PD‐L1tg mice. Alveolar bone resorption at a late time point was also clearly minimized in K14/PD‐L1tg mice.
Conclusion
Overexpression of PD‐L1 in gingival basal keratinocytes in K14/PD‐L1tg mice reduces periodontal inflammation and alveolar bone resorption in a ligature‐induced periodontitis model.
Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is preferentially and constitutively expressed in epithelial cells, and it is especially localized in the cells' nucleus. The nuclear ...IL-33 is released by necrotic cells after tissue injury and/or trauma, and subsequently provokes local inflammation as an alarmin, like high-mobility group box protein-1 (HMGB-1) and IL-1α. IL-33 mainly activates Th2 cells and such innate-type immune cells as mast cells, basophils, eosinophils and natural helper cells that express IL-33R (a heterodimer of IL-1 receptor-like 1 IL-1RL1; also called ST2, T1, Der4, fit-1 and IL-1 receptor accessory protein IL-1RAcP). That activation causes the cells to produce Th2 cytokines, which contribute to host defense against nematodes. On the other hand, excessive and/or inappropriate production of IL-33 is also considered to be involved in the development of such disorders as allergy. In this review, we summarize current knowledge regarding the pathogenic roles of IL-33 in the development of allergic inflammation by focusing on its effects on innate-type immune cells.
How the innate and adaptive immune systems cooperate in the natural history of allergic diseases has been largely unknown. Plant-derived allergen, papain, and mite allergens, Der f 1 and Der p 1, ...belong to the same family of cysteine proteases. We examined the role of protease allergens in the induction of Ab production and airway inflammation after repeated intranasal administration without adjuvants and that in basophil/mast cell stimulation in vitro. Papain induced papain-specific IgE/IgG1 and lung eosinophilia. Der f 1 induced Der f 1-specific IgG1 and eosinophilia. Although papain-, Der f 1-, and Der p 1-stimulated basophils expressed allergy-inducing cytokines, including IL-4 in vitro, basophil-depleting Ab and mast cell deficiency did not suppress the papain-induced in vivo responses. Protease inhibitor-treated allergens and a catalytic site mutant did not induce the responses. These results indicate that protease activity is essential to Ab production and eosinophilia in vivo and basophil activation in vitro. IL-33-deficient mice lacked eosinophilia and had reduced papain-specific IgE/IgG1. Coadministration of OVA with papain induced OVA-specific IgE/IgG1, which was reduced in IL-33-deficient mice. We demonstrated IL-33 release, subsequent IL-33-dependent IL-5/IL-13 release, and activation of T1/ST2-expressing lineage(-)CD25(+)CD44(+) innate lymphoid cells in the lung after papain inhalation, suggesting the contribution of the IL-33-type 2 innate lymphoid cell-IL-5/IL-13 axis to the papain-induced airway eosinophilia. Rag2-deficient mice, which lack adaptive immune cells, showed significant, but less severe, eosinophilia. Collectively, these results suggest cooperation of adaptive immune cells and IL-33-responsive innate cells in protease-dependent allergic airway inflammation.
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