Mediators of the homeostasis and effector functions of memory Th2 cells as novel drug targets in intractable chronic allergic diseases.

Allergic patients have life-long chronic inflammatory diseases with repeated relapses and exacerbations. Currently used allergy therapeutics have some limitations, which warrants a search for novel drug targets for allergy treatment. The studies on conventional allergic disease therapeutics have been focused on the pathology of allergy involving effector type 2 helper T cells (Th2). However, it has been suggested that allergen-specific memory Th2 cells are developed after the initial allergen exposure, which may play a critical role in the allergic relapses. Here, we discuss the contribution of memory Th2 cells to allergic diseases and the microenvironmental factors for chronic allergic disease persistence. Since most allergy drugs are prescribed to suppress symptoms of the diseases, targeting the different types of cells or factors contributing to allergic diseases persistence may cure the disease.

Prevention of Adjacent Segmental Disease after Fusion in Degenerative Spinal Disorder: Correlation between Segmental Lumbar Lordosis Ratio and Pelvic Incidence–Lumbar Lordosis Mismatch for a Minimum 5-Year Follow-up

STUDY DESIGN: Retrospective study. PURPOSE: Associations among risk factors related to adjacent segmental disease (ASD) remain unclear. We evaluated the risk factors and segmental lordosis ratio to prevent ASD developing after lumbar spinal fusion. OVERVIEW OF LITERATURE: Risk factors related to ASD development are age, sex, obesity, pre-existing degeneration, number of fusion segments, and decreased postoperative lumbar lordosis (LL). However, the associations among these factors are still unclear and should be clearly identified. METHODS: We retrospectively reviewed data on 274 patients who underwent lumbar spinal fusion of three segments or below for lumbar degenerative disease from January 2010 to December 2012, with over 5 years of follow-up. Patients with preoperative sagittal vertical axis (SVA) >5 cm were excluded due to sagittal imbalance. A total of 37 patients with ASD and 40 control patients (CTRL) were randomly selected in a similar distribution of matching variables: age, sex, and preoperative degenerative changes. Sex, age, number of fusion segments, radiologic measurements, L4–5–S1/L1–S1 LL ratio, and spinopelvic parameters (pelvic incidence [PI], pelvic tilt [PT], sacral slope [SS], and SVA) were analyzed. Logistic regression was used to analyze the correlation between PI–LL mismatch and L4–5–S1 segmental lordosis rate. RESULTS: No significant difference was found between ASDs and CTRL groups regarding age, sex, number of fusion segments, fusion method, and preoperative and postoperative spinopelvic parameters (PI, SS, PT, and LL). However, regarding the L4–5–S1/L1–S1 lordosis ratio, 50% (p=0.045), 60% (p=0.031), 70% (p=0.042), 80% (p=0.023), and 90% (p=0.023) were statistically significant; 10 group, and the difference was statistically significant (p=0.048). CONCLUSIONS: Patients with a postoperative L4–5–S1/L1–S1 lordosis ratio >50% had less occurrence of ASD. Correcting LL according to PI and physiologic segmental lordosis ratio is important in preventing ASD.

Perioperative Fresh Red Blood Cell Transfusion May Negatively Affect Recipient Survival After Liver Transplantation.

OBJECTIVE: The aim of this study is to evaluate the association between fresh red blood cell (RBC) transfusion and recipient survival after liver transplantation. BACKGROUND: Fresh RBC products contain many viable leukocytes. Allogeneic leukocytes are responsible for adverse transfusion reactions in the immunocompromised host. METHODS: Among 343 liver transplant recipients who underwent perioperative RBC transfusion, 91 of 226 who did not receive fresh RBCs were matched with 91 of 117 who received fresh RBCs with 1:1 matching ratio using the propensity score based on the amount of transfused blood products and others. Survival analysis was performed using the Cox model. RESULTS: All transfused 3230 RBCs were leukoreduced and irradiated. Before matching, recipients in fresh RBC group received 3 U (2-6 U) of fresh RBCs. After a median follow-up of 60 months, 60 of 343 recipients (17.5%) died. Survival probability at 1/2/5 years after transplantation was 94.7%/92.0%/85.8% for nonfresh RBC group and 82.9%/76.0%/72.0% for fresh RBC group [death hazard ratio (HR) = 2.37 (1.43-3.94), P = 0.001]. In multivariable analysis, fresh RBC transfusion was significantly associated with increased death risk [HR = 2.33 (1.35-4.01), P = 0.002]. After matching, recipients in fresh RBC group received 3 U (2-5 U) of fresh RBCs. After a median follow-up of 56 months, 35 of 182 recipients (19.2%) died. Survival probability at 1/2/5 years was 95.6%/93.2%/86.0% for nonfresh RBC group and 85.7%/78.0%/73.0% for fresh RBC group [HR = 2.23 (1.43-3.94), P = 0.028]. Multivariable analysis confirmed a significance of fresh RBC transfusion [HR = 3.20 (1.51-6.78), P = 0.002]. CONCLUSION: Our findings suggest a potential negative impact of fresh RBC transfusion on the survival of patients undergoing liver transplantation.

IL-7 plays a critical role for the homeostasis of allergen-specific memory CD4 T cells in the lung and airways.

Memory T cells respond rapidly to repeated antigen exposure and can maintain their population for extended periods through self-renewal. These characteristics of memory T cells have mainly been studied during viral infections, whereas their existence and functions in allergic diseases have been studied incompletely. Since allergic patients can suffer repeated relapses caused by intermittent allergen exposure, we hypothesized that allergen- specific memory Th2 cells are present and the factors necessary for the maintenance of these cells are provided by the lung and airways. Using a murine model of airway inflammation, we found that allergen-specific CD4 T cells survived longer than 70 days in the lung and airways in an IL-7 dependent fashion. These T cells showing homeostatic proliferation were largely found in the mediastinal lymph node (mLN), rather than the airways; however, cells residing in the lung and airways developed recall responses successfully. We also found that CD4 T cells exhibited differential phenotypes in the mLN and in the lung. Altogether, we believe that allergen-specific memory T cells reside and function in the lung and airways, while their numbers are replenished through homeostatic turnover in the mLNs. Furthermore, we determined that IL-7 signaling is important for the homeostasis of these cells.

A cytokine study of pediatric Tourette's disorder without obsessive compulsive disorder.

It has been suggested that post-infectious inflammation in central nervous system is a cause of tic disorder including Tourette's disorder (TD). Since pro-inflammatory cytokines are important mediators inducing inflammation, the cytokine levels are regarded as one of the important indicators of inflammation. Several studies have investigated the relationship of autoimmunity and the pathogenesis of TD by measuring the inflammatory cytokine levels of blood. However, when using human samples, the experimental results can be affected by the factors like size of sample, comorbidity, medication that patients take and the severity of the diseases. Thus, it is important to exclude the possibility that comorbidity and medication affects the level of inflammatory cytokines in the serum of TD patients. In our experiment, we recruited 29 patients without obsessive compulsive disorder (OCD) comorbidity and the majority of these patients did not take medication. The six pro-inflammatory cytokine levels of blood between patient and healthy groups were compared, considering the factors above, to determine more accurate results. Of the cytokines we investigated, the interleukin 12 p70 (IL-12p70) and tumor necrosis factor α (TNFα) levels increased in patient group compared to healthy controls and the patient group which have anti-streptolysin O (ASO) score under the 200 or YTGSS score from 10 to 19 also showed higher IL-12p70 or TNFα levels. In addition, the patients who did not take medication showed higher TNFα levels compared to healthy controls. In conclusion, we suggest that inflammatory pathways that involve IL-12p70 or TNFα are important to the pathogenesis of TD.

The Quantified Level of Circulating Prostate Stem Cell Antigen mRNA relative to GAPDH Level Is a Clinically Significant Indictor for Predicting Biochemical Recurrence in Prostate Cancer Patients after Radical Prostatectomy.

The study quantified the relative absolute PSCA level in relation to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) level in the peripheral blood of 478 hormone-naive prostate cancer (PC) patients who underwent radical prostatectomy from 2005 to 2012 and evaluated its prognostic significance as a risk factor for predicting biochemical recurrence (BCR), compared to known parameters. Nested real-time polymerase chain reaction (RT-PCR) and gel electrophoresis detected PSCA levels and measured the PSCA/GAPDH ratio. Clinicopathological data from the institutional database were examined to determine the adequate cut-off level to predict postoperative BCR. A total of 110 patients had a positive PSCA result (23.0%) via RT-PCR (mean blood ratio 1.1 ± 0.4). The BCR was significantly higher in the PSCA-positive detection group (p = 0.009). A multivariate model was created to show that a PSCA/GAPDH ratio between 1.0 and 1.5 (HR 12.722), clinical T2c stage (HR 0.104), preoperative PSA (HR 1.225), extraprostatic capsule extension (HR 0.006), lymph node dissection (HR 16.437), and positive resection margin (HR 27.453) were significant predictive factors for BCR (p < 0.05). The study showed successful quantification of PSCA with its significance for BCR-related risk factor; however, further studies are needed to confirm its clinical predictive value.

Estrogenic endocrine-disrupting chemicals modulate the production of inflammatory mediators and cell viability of lipopolysaccharide-stimulated macrophages.

Estrogenic endocrine-disrupting chemicals (EDCs) are exogenous substances that act as competitive inhibitors of estrogen in the endocrine system. By disrupting the endocrine system, EDCs can cause severe disabilities and diseases, including cancers and altered sexual development. Although the influence of these molecules in the endocrine system is evident, the effects of EDCs on the immune system as well as their cytotoxicity have been poorly examined. Therefore, we selected 21 EDCs that are commonly found in Korean ecosystems, such as surface waters and effluents, and studied their immunologic effects by comparing nitric oxide (NO) production and cytotoxicity in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (RAW cells), a macrophage cell line. Among the EDCs tested, fenitrothion (FTH) inhibited the messenger RNA (mRNA) expression of inducible NO synthase (iNOS), resulting in reduced NO production, while treatment with andostenedione (AD), diethyl phthalate, di-n-butyl phthalate (DBP), estriol, or molinate decreased production of NO in an iNOS-independent fashion. In contrast, benzo(a)pyrene (B(a)P) increased the production of NO in RAW cells. In addition, AD, DBP, or FTH inhibited the mRNA expression of tumor necrosis factor alpha or interleukin-1 beta. Treatment with 17-α-ethynylestradiol, 17-ß-estradiol, 4-n-butyl phenol, or alachlor induced apoptosis of RAW cells, while dicyclohexyl phthalate and B(a)P caused cell death in an apoptosis-independent manner. These data suggest that EDCs can influence the immune response to pathogens by modulating the functions of macrophages.

Single-walled carbon nanotubes induce cell death and transcription of TNF-α in macrophages without affecting nitric oxide production.

Single-walled carbon nanotubes (SWCNTs) are potent nanomaterials that have diverse shapes and features. The utilization of these molecules for drug delivery is being investigated; thus, it is important to determine whether they alter immune responses against pathogens. In this study, we show that macrophages treated with a mixture of lipopolysaccharide and SWCNTs produced normal levels of nitric oxide and inducible nitric oxide synthase mRNA. However, these treatments induced cell death, presumably via necrosis. In addition, treating cells with SWCNTs induced the expression of tumor necrosis factor-α mRNA, a potent pro-inflammatory cytokine. These results suggest that SWCNTs may influence immune responses, which could result in unexpected effects following their administration for the purpose of drug delivery.

Diverse influences of androgen-disrupting chemicals on immune responses mounted by macrophages.

Androgen-disrupting chemicals (ADCs) can alter male sexual development. Although the effects of ADCs on hormone disruption have been studied, their influence on the immune response is not fully understood. To investigate the effects of ADCs on innate immunity, we tested eight candidate ADCs for their influence on macrophages by measuring nitric oxide (NO) production and cell viability. Our results showed that treatment with a mixture of lipopolysaccharide and hexachlorobenzene increased NO production in RAW 264.7 cells, a murine macrophage cell line. In contrast, compared to exposure to a negative control, exposure to di-2-ethylhexyl adipate (DEHA), benzylbutyl phthalate (BBP), testosterone (TTT), or permethrin decreased NO production. DEHA, BBP, and TTT inhibited NO production in an inducible nitric oxide synthase-dependent manner. Treatment with bisphenol A (BPA), nonylphenol (NNP), or tributyltin chloride (TBTC) reduced NO production and induced cell death. While BPA induced RAW 264.7 cell death through apoptosis, NNP and TBTC caused cell death through necrosis. These results offer insights into the influences of ADCs on the innate immune system.