Signaling via LTbetaR on the lamina propria stromal cells of the gut is required for IgA production

Peyer's patches (PPs) and/or mesenteric lymph nodes (MLNs) are thought to be essential for immunoglobulin A (IgA) production. We found that the severe IgA deficiency in lymphotoxin-deficient (LT(-/-)) mice could be fully reversed by reconstitution with LT-expressing bone marrow, despite the absence of both LNs and PPs. The number of IgA precursors from LT(-/-) mice was not reduced, and they were able to migrate into the lamina propria (LP) of wild-type mice but not of LTbetaR(-/-) mice. Consistently, lymphoid tissue chemokines and adhesion molecules were reduced within the LP of LTalpha(-/-) and LTbetaR(-/-) mice. IgA deficiency in LTalpha(-/-) mice was reversed by the transplantation of a segment of RAG-1 (recombination-activating gene 1) deficient intestine, which confirmed the dispensability of the MLNs and PPs and the sufficiency of the LT-mediated gut microenvironment for IgA production.     

Loss of claudin-1 expression induces epithelial-mesenchymal transition through nuclear factor-κB activation in colorectal cancer

Objective

The aim of this study was to elucidate the clinicopathological significance and prognostic role of loss of claudin-1 in colorectal cancer (CRC).

IMMUNOHISTOCHEMICAL DISTRIBUTION OF CANNABINOID CB 1 RECEPTOR IN THE RAT CENTRAL NERVOUS SYSTEM

IMMUNOHISTOCHEMICAL DISTRIBUTION OF CANNABINOID CB 1 RECEPTOR IN THE RAT CENTRAL NERVOUS SYSTEM@邹冈     

Comparison of Different Types of Oral Adsorbent Therapy in Patients with Chronic Kidney Disease: A Multicenter,Randomized, Phase IV Clinical Trial

PurposeOral adsorbents delay disease progression and improve uremic symptoms in patients with chronic kidney disease (CKD). DW-7202 is a newly developed oral adsorbent with high adsorptive selectivity for uremic toxins. We evaluated patient preference for and adherence to DW-7202 versus AST-120 therapy and compared treatment efficacy and safety in patients with pre-dialysis CKD.Materials and MethodsA seven-center, randomized, open-label, two-way crossover, active-controlled, phase IV clinical trial was conducted. Patients with stable CKD were randomly assigned to receive DW-7202 (capsule type) or AST-120 (granule type) for 12 weeks. The groups then switched to the other adsorbent and took it for the next 12 weeks. Patient preference was the primary outcome. Secondary outcomes included changes in estimated glomerular filtration rate (eGFR) and serum creatinine, cystatin C, and indoxyl sulfate (IS) levels.ResultsSignificantly more patients preferred DW-7202 than AST-120 (p<0.001). Patient adherence improved after switching from AST-120 to DW-7202; there was no apparent change in adherence after switching from DW-7202 to AST-120. Changes in eGFR and serum creatinine, cystatin C, and IS levels were not significantly different according to adsorbent type. There was also no significant difference in the incidences of adverse events during treatment with DW-7202 and AST-120.ConclusionDW-7202 can be considered as an alternative to AST-120 in patients who cannot tolerate or show poor adherence to granule type adsorbents. Further studies to evaluate factors affecting patient preferences and improved adherence are warranted (Clinical trial registration No. {"type":"clinical-trial","attrs":{"text":"NCT02681952","term_id":"NCT02681952"}}NCT02681952).     

Immunity to type IX collagen in rodents: a study of type IX collagen for autoimmune and arthritogenic activities

Type IX collagen (CIX), a cartilage-specific glycoprotein, constitutes ≤ 10% of cartilage collagen. To ascertain whether CIX can induce arthritis as shown for type II and XI collagen (CII and CXI), outbred rats were sensitized with bovine, chick and human CIX; inbred rats, mice, and guinea pigs were sensitized with bovine CIX. Mice and guinea pigs proved resistant to arthritis, as did rats sensitized with CIX/Freund's incomplete adjuvant (FIA). Arthritis was seen in rats when 100 μg of Mycobacterium tuberculosis (Mtb) were added to FIA, but seldom with smaller doses of Mtb, suggesting the arthritis was adjuvant-induced. High levels of antibodies to rat CIX, containing complement-fixing subclasses, were detected in rat sera in addition to DTH and lymphocyte proliferation responses to rat CIX. Given the potential for CIX-induced disease, CIX-sensitized rats were injected intraperitoneally with lipopolysaccharide (LPS) to stimulate proinflammatory cytokine release, and intra-articularly with rat CIX to stimulate arthritis. LPS stimulation was ineffective; however, intra-articularly injected CIX produced transient synovitis. When rats with stable adjuvant arthritis were sensitized with CIX/FIA, significant increases in paw volume were measured compared with controls given CI/FIA. Immunohistochemical studies of actively and passively sensitized rats revealed deposits of CIX antibody, but not C3, at the joint margins where proteoglycan staining was weak. Together, these findings suggest that autoimmunity to CIX, in contrast to CII and CXI, is not directly pathogenic but may contribute to joint injury provided arthritis is initiated by an independent disease process.     

Preventive and therapeutic effects of oral tolerance in a murine model of asthma

Allergic asthma is an inflammatory disease of the airways, and Th2 cells secreting IL-4 and IL-5 play a pivotal role in its pathogenesis. We have previously demonstrated that oral tolerance can be induced and maintained more profoundly in a Th2-related immune response, and that an ongoing immune response can be suppressed by the oral administration of antigen combined with an appropriate feeding regimen. In the present study, we examined the preventive and therapeutic effects of the oral administration of allergen on a Th2-mediated immune disorder using a murine model of asthma. Our results show that the development of asthma can be blocked completely by orally administering allergen. Airway hyperreactivity, allergen-specific IgE production, Th2-derived cytokines, allergen-induced T cell proliferation and the infiltration of inflammatory effector cells into the lung were prevented by such oral administration. To assess the therapeutic effects of oral administration on the progression of asthma, we tested the effects of oral tolerance in an established asthma model, and found that a multiple high dose-feeding regimen was effective at suppressing the progression of mild asthma. In the high dose-feeding group, the number of eosinophils in bronchoalveolar lavage fluid was reduced and airway reactivity also decreased. However, this was insufficient to reduce airway reactivity and eosinophilia in bronchoalveolar lavage fluid in cases of severe asthma. These results demonstrate that allergic asthma may be ameliorated by feeding allergen; there is hope that these results will provide a new immunotherapeutic strategy for allergic asthma.     

Loss of heterozygosity on chromosomes 3p,8p,9p and 17p in the progression of squamous cell carcinoma of the larynx

Previous molecular genetic studies of laryngeal squamous cell carcinoma (SCC)have shown certain chromosomal regions with recurring alterations. But studies of sequential molecular alterations and genetic progression model of laryngeal SCC have not been clearly defined. To identify the chromosomal alterations associated with the carcinogenesis of laryngeal SCC, we analyzed genomic DNA from microdissected squamous metaplasia, squamous dysplasia, invasive SCC, and metastatic carcinoma samples from 22 laryngeal SCC patients for loss of heterozygosity (LOH) at microsatellite loci. Ten microsatellite markers on chromosome 3p, 8p, 9p, and 17p were used. LOH at 9p21 was observed in the all stages including squamous metaplasia, squamous dysplasia, invasive SCC and metastatic carcinoma. LOH at 17p13.1, 3p25 and 3p14.2 was observed from the squamous dysplasia, invasive SCC and metastatic carcinoma. LOH at 8p21.3-p22 was observed mainly from the invasive SCC and metastatic carcinoma. The results suggest that 9p21 in the early event, 17p13.1, 3p25 and 3p14.2 in the intermediate event and 8p21.3- p22 in the late event may be involved in the laryngeal carcinogenesis.     

Cell physiology of cAMP sensor Epac

Many animal studies and human epidemiological findings have shown that impaired growth in utero is associated with physiological abnormalities in later life and have linked this to tissue programming during suboptimal intrauterine conditions at critical periods of development. However, few of these studies have considered the contribution of the placenta to the ensuing adult phenotype. In mammals, the major determinant of intrauterine growth is the placental nutrient supply, which, in turn, depends on the size, morphology, blood supply and transporter abundance of the placenta and on synthesis and metabolism of nutrients and hormones by the uteroplacental tissues. This review examines the regulation of placental nutrient transfer capacity and the potential programming effects of nutrition and glucocorticoid over-exposure on placental phenotype with particular emphasis on the role of the Igf2 gene in these processes.     

Methods for derivation of human embryonic stem cells

The expanded blastocysts, developed from 2PN-stage embryos, are generally divided into three categories: a good blastocyst containing a large and distinguishable inner cell mass (ICM), a blastocyst with a small and distinct ICM, and a blastocyst with a poorly defined ICM. In this study, we introduce methods for the derivation of human embryonic stem cells (hESCs) depending on the quality of the blastocysts. An immunosurgical method was used for the good expanded blastocysts. This method, however, raises the probability of ICM loss in cases of hESC derivation from blastocysts with smaller or indistinct ICMs. Furthermore, this method is also associated with a risk of the contamination of the hESCs with animal pathogens. To overcome these shortcomings, the partial- or whole-embryo culture method was used. For blastocysts with no visible ICM, the whole-embryo culture method was used to establish hESCs via the seeding of the entire blastocyst without its zona pellucida directly on a STO feeder layer. However, trophectodermal overgrowth tends to hinder the expansion of the ICM during the initial steps of hESC derivation. Therefore, the partial-embryo culture method was developed to establish hESCs from blastocysts with smaller ICMs. The surgical isolation of the region containing the ICM with an ultra-fine glass pipette alleviates trophectoderm overgrowth. This method is also applicable to blastocysts with large and distinct ICMs, and the efficiency of this method is comparable to that of the immunosurgical method.