95 research outputs found
3-Methylcholanthrene-induced transforming growth factor-β-producing carcinomas, but not sarcomas, are refractory to regulatory T cell-depletion therapy
No full textRegulatory T cell (Treg) is one of the major immunosuppressors in tumor-bearing hosts. Although Treg-depletion therapy has been shown to induce a complete cure in tumor-bearing mice, this is not always successful treatment. Using 3-methylcholanthrene (MCA)-induced primary mouse tumors, we examined the distinct regulation of Treg-mediated immunosuppression between carcinomas and sarcomas. We demonstrated that the numbers of Tregs were greatly increased in SCC-bearing mice compared with sarcoma-bearing mice. This appeared to be because SCC produced higher levels of active TGF-β, which is essential for inducing Tregs, compared with sarcoma. Moreover, SCC, but not sarcomas were refractory to Treg-depletion therapy by anti-CD25 mAb administration. The refractoriness of SCC against Treg-depletion therapy was due to the rapid recovery of Tregs in SCC-bearing mice compared with sarcoma-bearing mice. However, combination treatment of anti-TGF-β mAb with anti-CD25 mAb caused a significant reduction of Treg recovery and induced a complete cure in SCC-bearing mice. Thus, we first demonstrated the refractoriness of mouse carcinoma against Treg-depletion therapy using anti-CD25 mAb administration. We also proposed a novel Treg-blocking combination therapy using anti-CD25 mAb and anti-TGF-β mAb to induce a complete cure of tumor-bearing hosts
Th1 cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs.
No full textWe have previously described a method for adoptive immunotherapy of cancer based on antigen-specific Th1 cells. However, efficient induction of anti-tumor responses using Th1 cells remains a formidable challenge, especially for MHC class II-negative tumors. In the present study, we sought to develop a novel strategy to eradicate established tumors of the MHC class II-negative, ovalbumin (OVA)-expressing EG-7 cells. Tumor-bearing mice were intradermally treated with OVA-specific Th1 cells, combined with the model tumor antigen (OVA), near the tumor-draining lymph node (DLN). We found that tumor growth was significantly inhibited by this strategy and 50–60% of tumor-bearing mice were completely cured. Tumor eradication was crucially dependent on the generation of OVA/H-2Kb-specific CTLs in the tumor DLNs and tumor site. The injected Th1 cells were mainly distributed in tumor DLNs, where they vigorously proliferated and enhanced the activation of dendritic cells. Strikingly, we also found that the accumulation of CD4+CD25+ regulatory T cells (Tregs) was significantly inhibited in tumor DLNs by Th1 cell adjuvant therapy and this abrogation was associated with IFN secreted by Th1 cells. These results identify Th1 cell adjuvant therapy combined with tumor vaccination as a novel approach to the treatment of human cancer
Characterization of the critical Sobolev space on the optimal singularity at the origin
No full textIn the present paper, we investigate the optimal singularity at the origin for the functions belonging to the critical Sobolev space H^[n/p, p] (ℝ^[n]), 1 < p < ∞. With this purpose, we shall show the weighted Gagliardo-Nirenberg type inequality: ||u|| _[Lq(ℝ^[n] ; dx/|x|s)] ≤ C(1/[n-s])^[1/q + 1/p'] q^[1/p'] ||u|| ^[(n-s)p/nq] _[Lp(ℝ^[n]] ||(-Δ)^[n/2p] u||^[1-[(n-s)p]/nq] _[Lp(ℝ^[n]], (GN) where C depends only on n and p. Here, 0 ≤ s < n and p~ ≤ q < ∞ with some p~ ∈ (p, ∞) determined only by n and p. Additionally, in the case n ≥ 2 and n/[n-1] ≤ p < ∞, we can prove the growth orders for s as s ↑ n and for q as q → ∞ are both optimal. (GN) allows us to prove the Trudinger type estimate with the homogeneous weight. Furthermore, it is obvious that (GN) can not hold with the weight |x|^[n] itself. However, with a help of the logarithmic weight of the type (log 1/|x|)^[r] |x|^[n] at the origin, we cover this critical weight. Simultaneously, we shall give the minimal exponent r = [q+p']/p' so that the continuous embedding can hold
STAT1-mediated induction of Ly6c-expressing macrophages are involved in the pathogenesis of an acute colitis model
No full textBackground
The development of inflammatory bowel diseases is thought to be multifactorial, but the exact steps in pathogenesis are poorly understood. In this study, we investigated involvement of the activation of STAT1 signal pathway in the pathogenesis of an acute colitis model.
Methods
A dextran sulfate sodium-induced acute colitis model was established by using wild-type C57BL/6 mice and STAT1-deficient mice. Disease indicators such as body weight loss and clinical score, induction of cytokines, chemokines, and inflammatory cells were evaluated in the acute colitis model.
Results
Disease state was significantly improved in the acute colitis model using STAT1-deficient mice compared with wild-type mice. The induction of Ly6c-highly expressing cells in colorectal tissues was attenuated in STAT1-deficient mice. IL-6, CCL2, and CCR2 gene expressions in Ly6c-highly expressing cells accumulated in the inflamed colon tissues and were significantly higher than in Ly6c-intermediate-expressing cells, whereas TNF-α and IFN-α/β gene expression was higher in Ly6c-intermediate-expressing cells. Blockade of CCR2-mediated signaling significantly reduced the disease state in the acute colitis model.
Conclusions
Two different types of Ly6c-expressing macrophages are induced in the inflamed tissues through the IFN-α/β-STAT1-mediated CCL2/CCR2 cascade and this is associated with the pathogenesis such as onset, exacerbation, and subsequent chronicity of acute colitis
Robust bonding and one-step facile synthesis of tough hydrogels with desirable shape by virtue of the double network structure
No full textRobust bonding of a hydrogel in aqueous environment, either to another hydrogel or to a solid, is one of the major unsolved issues for the practical applications of hydrogels in various fields. Here we report robust bonding between a pair of hydrogel sheets, containing over 90 wt% of water, by 10 applying the double-network (DN) structure. In the optimal condition, the peeling energy of the united gel sheets reaches 1200 J/m2, which is comparable to the bulk fracture energy of a normal type of tough DN gels. This hydrogel bonding technique is also applied to form tough bonding between hydrogel and plastic plates. Furthermore, based on this technique, we have developed a facile method to synthesize robust double network hydrogels with any desirable free-shape from 15 micro-gel precursors. These novel techniques will substantially merit the applications of the tough hydrogels in various fields, such as an artifical meniscus
IL6 modulates the immune status of the tumor microenvironment to facilitate metastatic colonization of colorectal cancer cells
No full textIt is unknown as to how liver metastases are correlated with host immune status in colorectal cancer. In this study, we found that IL-6, a proinflammatory cytokine produced in tumor-bearing states, promotes the metastatic colonization of colon cancer cells in association with dysfunctional anti-tumor immunity. In IL-6-deficient mice, metastatic colonization of CT26 cells in the liver was reduced, and the anti-tumor effector function of CD8+ T cells as well as IL-12 production by CD11c+ dendritic cells were augmented in vivo. Furthermore, IL-6-deficient mice exhibited enhanced IFNAR1- mediated type I interferon signaling, which upregulated PD-L1 and MHC class I expression on CT26 cells. In vivo injection of anti-PD-L1 antibody effectively suppressed the metastatic colonization of CT26 cells in Il6-/- but not Il6+/+ mice. Finally, we confirmed that colorectal cancer patients with low IL-6 levels in their primary tumors showed prolonged disease-free survival. These findings suggest IL-6 may be a promising target for the treatment of metastasis in colorectal cancers by improving host immunity
Epidemiological study of the prevalence of rheumatic disorders in rural districts in Tottori Prefecture, Japan
No full textEpidemiological evaluation of rural population samples of Misasa, Tomari and Kofu villages in Tottori Prefecture, Japan (Fig. 1), for occurance of rheumatic disorders was performed. This region has an annual rainfall of about 80 inches. The principal occupations are farming, and fishery in part. 1. One thousand six hundreds and twenty-seven persons, age 30 and over were investigated by clinical and serological means. In this preliminary communication the prevalence of probable and definite rheumatoid arthritis, accoding to defined by the A.R.A. criteria, was 1.04% and low back pain-sciatic pain, arthralgia and painful shoulder (cervical spondylosis and so on) were 8.4, 8.9 and 7.1% respectively (Table 2 and 4). 2. Serum samples from residents in Misasa- and Tomari-districts were obtained and rheumatoid factor was tested by means of RA-test (Hyland Laboratories). The incidence of positive test was 3.2% in 407 males and 5.0% in 715 females, but there is no significant difference between the two. Concerning the effect of age, there was a general tendency for the proportion of positive test to be greatest in the older age groups (Fig. 2). 3. Serum uric acid concentrations of 230 males and 395 females were measured by the modified method of Folin-Wu (latron-kit-method). The mean serum uric acid concentration (with standard deviation) was found to be 4.02±0.18mg. per 100ml. for males and 3.38±0.13mg. per 100ml. for females (Fig. 3 and 4), and the differecne between the two was significant. The author found no gouty patient in this papulation survey
Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling
No full textEsophageal cancer-related gene 4 (Ecrg4), a hormone-like peptide, is thought to be a tumor suppressor, however, little is known about the mechanism of how Ecrg4 suppresses tumorigenesis. Here, we show that the ecrg4 null glioma-initiating cell (GIC) line, which was generated from neural stem cells of ecrg4 knockout (KO) mice, effectively formed tumors in the brains of immunocompetent mice, whereas the transplanted ecrg4 wild type-GIC line GIC(+/+) was frequently eliminated. This was caused by host immune system including adaptive T cell responses, since depletion of CD4+, CD8+, or NK cells by specific antibodies in vivo recovered tumorigenicity of GIC(+/+). We demonstrate that Ecrg4 fragments, amino acid residues 71-132 and 133-148, which are produced by the proteolitic cleavage, induced the expression of pro-inflammatory cytokines in microglia in vitro. Moreover, blockades of type-I interferon (IFN) signaling in vivo, either depleting IFN-α/β receptor 1 or using stat1 KO mice, abrogated the Ecrg4-dependent antitumor activity. Together, our findings indicate a major antitumor function of Ecrg4 in enhancing host immunity via type-I IFN signaling, and suggest its potential as a clinical candidate for cancer immunotherapy
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