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Use of the Tissue Common Rejection Module Score in Kidney Transplant as an Objective Measure of Allograft Inflammation.
Zarinsefat, A, Guerra, JMA, Sigdel, T, Damm, I, Sarwal, R, Chan-On, C, Szabo, G, Aguilar-Frasco, JL, Ixtlapale-Carmona, X, Salinas-Ramos, C, et al
Frontiers in immunology. 2020;:614343
Abstract
Long-term kidney transplant (KT) allograft outcomes have not improved as expected despite a better understanding of rejection and improved immunosuppression. Previous work had validated a computed rejection score, the tissue common rejection module (tCRM), measured by amplification-based assessment of 11 genes from formalin-fixed paraffin-embedded (FFPE) biopsy specimens, which allows for quantitative, unbiased assessment of immune injury. We applied tCRM in a prospective trial of 124 KT recipients, and contrasted assessment by tCRM and histology reads from 2 independent pathologists on protocol and cause biopsies post-transplant. Four 10-μm shaves from FFPE biopsy specimens were used for RNA extraction and amplification by qPCR of the 11 tCRM genes, from which the tCRM score was calculated. Biopsy diagnoses of either acute rejection (AR) or borderline rejection (BL) were considered to have inflammation present, while stable biopsies had no inflammation. Of the 77 biopsies that were read by both pathologists, a total of 40 mismatches in the diagnosis were present. The median tCRM scores for AR, BL, and stable diagnoses were 4.87, 1.85, and 1.27, respectively, with an overall significant difference among all histologic groups (Kruskal-Wallis, p < 0.0001). There were significant differences in tCRM scores between pathologists both finding inflammation vs. disagreement (p = 0.003), and both finding inflammation vs. both finding no inflammation (p < 0.001), along with overall significance between all scores (Kruskal-Wallis, p < 0.001). A logistic regression model predicting graft inflammation using various clinical predictor variables and tCRM revealed the tCRM score as the only significant predictor of graft inflammation (OR: 1.90, 95% CI: 1.40-2.68, p < 0.0001). Accurate, quantitative, and unbiased assessment of rejection of the clinical sample is critical. Given the discrepant diagnoses between pathologists on the same samples, individuals could utilize the tCRM score as a tiebreaker in unclear situations. We propose that the tCRM quantitative score can provide unbiased quantification of graft inflammation, and its rapid evaluation by PCR on the FFPE shave can become a critical adjunct to help drive clinical decision making and immunosuppression delivery.
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[Therapeutic effects of target artery infusion of verapamil and chemotherapy drugs on advanced non-small cell lung cancer].
Tan, YF, Ma, HX, Zhao, B, Zhang, HR
Zhonghua zhong liu za zhi [Chinese journal of oncology]. 2020;(6):486-490
Abstract
Objective: To investigate the effects of targeted artery perfusion of verapamil and chemotherapy drugs on advanced non-small cell lung cancer (NSCLC). Methods: Sixty patients with advanced NSCLC who were admitted to the Central Hospital of Zhumadian from April 2016 to April 2018 were selected as the research subjects. They were divided into the observation group (26 cases) and the control group (34 cases) according to the treatment method. Patients in the observation group were treated with targeted artery perfusion of verapamil and chemotherapy drugs while the control group were treated with target artery perfusion of chemotherapy drugs alone.Both groups were treated continuously for more than 2 months. The short-term curative effect, adverse reactions, changes in immune function, levels of serum tumor markers and Karnofsky Performance Scale (KPS) scores before and after treatment as well as the prognosis were compared between the two groups. Results: The response rate and control rate in the observation group were 80.8% and 96.2%, higher than 55.9% and 76.5% in the control group (P<0.05). After treatment, CD4(+) levels and CD4(+) /CD8(+) in the observation group were (25.43±2.76)% and (0.88±0.11), lower than (27.56±2.79)% and (0.95±0.13) in the control group (P<0.05). After treatment, serum levels of CEA and CA50 in the observation group were (11.57±2.32)ng/ml and (16.62±3.28)U/ml, also lower than (15.87±2.66)ng/ml and (20.31±3.42)U/ml in the control group (P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). After treatment, KPS score of the observation group was (81.44±2.76) points, higher than (79.62±2.38) points of the control group (P<0.05). The median survival time and progression-free median survival time of the observation group were 16.0 months and 7.5 months, respectively, significantly better than 10.0 months and 5.0 months of the control group (P<0.05). Conclusions: The treatment with target arterial perfusion of verapamil and chemotherapy drugs for advanced NSCLC can effectively improve the short-term curative effect, reduce serum levels of tumor markers, improve life quality and prolong the survival time. However, it has a certain inhibitory effect on the patient's immune function.
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Administration of Intravenous Iron Formulations Induces Complement Activation in-vivo.
Faria, B, Gaya da Costa, M, Poppelaars, F, Franssen, CFM, Pestana, M, Berger, SP, Daha, MR, Gaillard, CAJM, Seelen, MA
Frontiers in immunology. 2019;:1885
Abstract
Background: Intravenous (IV) iron is widely used to treat anemia in chronic kidney disease patients. Previously, iron formulations were shown to induce immune activation in-vitro. The current study aimed to investigate the effect of IV iron on complement activation in-vivo, and whether this subsequently induces inflammation and/or oxidative stress. Methods: Two distinct patient groups were included: 51 non-dialysis and 32 dialysis patients. The non-dialysis group received iron sucrose or ferric carboxymaltose, based on physicians' choice. Plasma samples were collected prior to and 1 h after completion of IV iron infusion. The dialysis group received iron sucrose exclusively. Plasma samples were collected at the start and end of two consecutive hemodialysis sessions, one with and one without IV iron. Finally, plasma levels of MBL, C1q, properdin, factor D, sC5b-9, MPO, PTX3 were assessed by ELISA. Results: In the non-dialysis group, sC5b-9 levels significantly increased after IV iron by 32%, while levels of factor D and MBL significantly dropped. Subgroup analysis demonstrated that iron sucrose induced complement activation whereas ferric carboxymaltose did not. In the dialysis group, levels of sC5b-9 significantly increased by 46% during the dialysis session with IV iron, while factor D levels significantly fell. Furthermore, the relative decrease in factor D by IV iron correlated significantly with the relative increase in sC5b-9 by IV iron. MPO levels rose significantly during the dialysis session with IV iron, but not in the session without iron. Moreover, the relative increase in MPO and sC5b-9 by IV iron correlated significantly. PTX3 levels were not affected by IV iron. Conclusions: Iron sucrose but not ferric carboxymaltose, results in complement activation possibly via the lectin and alternative pathway partially mediating oxidative stress but not inflammation.
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Effect of preoperative immunonutrition on complications after salvage surgery in head and neck cancer.
Mueller, SA, Mayer, C, Bojaxhiu, B, Aeberhard, C, Schuetz, P, Stanga, Z, Giger, R
Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale. 2019;48(1):25
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Surgery, radiotherapy (RT) and chemo-radiotherapy (CRT) are the main treatments for head and neck cancer, but (C)RT has significant side effects on local tissues due to impaired wound healing. Malnutrition is also common in these patients and may add to poor wound healing and recovery. Immunonutrition (IN) are medical dietary formulas designed to provide the essential nutrients for an adequate immune reaction during medical treatment. The aim of this study was to evaluate the effect of preoperative IN on postoperative complications after salvage surgery in head and neck cancer. Patients in the intervention group received 3 IN units per day for 5 days before surgery. The IN units contained 300 kcal and were enriched with omega-3 fatty acids, arginine, RNA-nucleotides and soluble guar fibre. The control group, who did not receive IN, included consecutive patients treated prior to the intervention group. 96 patients were evaluated, of which 51 received IN. The total number of patients suffering any complications was significantly lower in the group receiving IN (35% vs. 58%). There was also a significant reduction in length of hospital stay in the IN group compared to the control group (6 days vs. 17 days). Limitations of this study include the use of a historical control group, and the limited number of patients.
Abstract
BACKGROUND Patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma are at high risk of postoperative complications due to the adverse effects of radiotherapy on wound healing. Malnutrition is an additional risk factor and we tested the hypothesis that preoperative administration of immunonutrition would decrease complications in this high risk population. METHODS This single armed study with historical control included consecutive patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma. We compared outcomes before and after implementation of preoperative immunonutrition and adjusted the regression analysis for gender, age, body mass index, Nutritional Risk Screening (NRS 2002), tobacco and alcohol consumption, tumor localization, tumor stage, and type of surgery. The primary endpoint was overall complications from surgery within a follow-up of 30 days. RESULTS Ninety-six patients were included (intervention group: 51, control group: 45). Use of preoperative immunonutrition was associated with a significant reduction in overall complications (35% vs. 58%, fully-adjusted odds ratio 0.30 (95%CI 0.10-0.91, p = 0.034). Length of hospital stay was also significantly reduced (17 days vs. 6 days, p = < 0.001). No differences in mortality and hospital readmission were found. These results remained robust in multivariate analysis. CONCLUSIONS In patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma, preoperative immunonutrition exhibited favorable effects on the complication rate and consequently reduced the length of hospital stay. By improving both tissue regeneration and immune response, immunonutrition may help to improve surgical outcomes in this high-risk population.
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Oral administration of 5-aminolevulinic acid induces heme oxygenase-1 expression in peripheral blood mononuclear cells of healthy human subjects in combination with ferrous iron.
Ito, H, Nishio, Y, Hara, T, Sugihara, H, Tanaka, T, Li, XK
European journal of pharmacology. 2018;:25-33
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Heme oxygenase-1 (HO-1) is a major anti-inflammatory enzyme and a key regulator that induces immune tolerance through affecting the differentiation of dendritic cells. The aim of this study is to determine whether the combination of 5-aminolevulinic acid (ALA) and iron induces HO-1 expression in healthy human peripheral blood mononuclear cells (PBMC). The study was an open labeled, non-randomized, non-placebo-controlled trial using healthy male adults and consisted of three parts. Study A aimed to find the peak HO-1 expression at 0, 1, 2, 3, 4, 6, 8, 12, 16, and 24 h after administration. Study B aimed to examine HO-1 dose dependency at 150, 300, and 600 mg of ALA and the need for iron supplementation. Study C aimed to investigate HO-1 changes during a three-day, repetitive administration of ALA and iron. The combination of ALA 600 mg and sodium ferrous citrate (SFC) 942 mg upregulated HO-1 in PBMC at 8 h after administration while sole administration of ALA or SFC was unable to induce HO-1. HO-1 in blood myeloid and plasmacytoid dendritic cells was also upregulated with ALA+SFC. Clear dose dependency of ALA+SFC was not detected, and a slight tendency towards a cumulative effect of HO-1 after three-day, repetitive administration was observed. ALA, which is already approved for use in several countries as a diagnosis agent for cancer, has the potential to become a novel therapeutic drug for diseases stemming from unwanted immune response such as autoimmune diseases and the rejection response following organ transplantation.
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Food-specific IgGs Are Highly Increased in the Sera of Patients with Inflammatory Bowel Disease and Are Clinically Relevant to the Pathogenesis.
Xiao, N, Liu, F, Zhou, G, Sun, M, Ai, F, Liu, Z
Internal medicine (Tokyo, Japan). 2018;57(19):2787-2798
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Inflammatory bowel disease (IBD) is an umbrella term incorporating ulcerative colitis (UC) and Crohn’s disease (CD). The exact reasons for the development of IBD are still being debated, however food allergy has been implicated. Diagnosis of food allergy is normally performed looking at the body’s immediate immune response, however the delayed immune response may be of importance in IBD. This study of 301 patients with IBD and 178 healthy controls aimed to look at the delayed immune response of individuals with IBD following the introduction of certain foods. It also looked at the efficacy of a drug treatment, infliximab (IFX) on this immune response. The results showed that the delayed immune response to egg, milk, wheat, corn, rice, tomato, codfish, and soya was increased in those with CD compared to those with UC and healthy control. Infliximab treatment was effective in suppressing this immune response in individuals with CD. It was concluded that in individuals with IBD, measuring the delayed immune response to foods may be an important diagnosis and management tool. This study could be used by healthcare professionals to understand that measuring the immediate immune response to certain foods in individuals with IBD, may not be sufficient. Measuring the delayed immune response in combination with the immediate immune response may give a better picture of foods which should be avoided in those with IBD. Infliximab treatment may be an effective treatment in patients with IBD and a delayed immune response to certain foods.
Abstract
Objective Dietary antigens are common luminal antigens in the gastrointestinal tract and have been considered to contribute to the pathogenesis of inflammatory bowel disease (IBD). We analyzed the levels of food-specific IgGs against a variety of dietary antigens, explored the clinical relevance of food allergy to the pathogenesis of IBD, and investigated whether or not infliximab (IFX) treatment could regulate the immune responses induced by dietary antigens. Methods A total of 301 IBD patients, including 201 patients with Crohn's disease (CD) and 100 patients with ulcerative colitis (UC), were recruited, and their serum food-specific IgGs against 14 food antigens were detected by a semi-quantitative enzyme linked immunosorbent assay (ELISA). Total serum IgG and IgE levels were measured by immunonephelometry and fluorescent enzyme immunoassay, respectively. Simultaneously, the relevant medical records and clinical data were collected for further analyses. Results Food-specific IgGs against egg, milk, wheat, corn, rice, tomato, codfish, and soybean antigens were found to be significantly increased in the sera of CD patients compared with UC patients and healthy controls (p<0.01). The levels of total serum IgG and IgE were also significantly higher in CD patients than in healthy controls (p<0.01). The titers of corn- and tomato-specific IgGs were found to be significantly correlated with total serum IgG in CD patients (p<0.05), while the titers of egg-, milk-, and wheat-specific IgGs were correlated with total serum IgE (p<0.05). Interestingly, IFX therapy was able to down-regulate the food-specific IgG-mediated immune response markedly in active CD patients. Conclusion Food-specific IgGs against egg, milk, wheat, corn, rice, tomato, codfish, and soybean are highly increased in the sera of CD patients. IFX treatment was able to down-regulate the levels of food-specific IgGs by suppressing intestinal inflammation and promoting mucosal healing. Therefore, food-specific IgGs may serve as an important approach in the diagnosis and management of food allergy in IBD.
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Effect of lactoferrin on taste and smell abnormalities induced by chemotherapy: a proteome analysis.
Wang, A, Duncan, SE, Lesser, GJ, Ray, WK, Dietrich, AM
Food & function. 2018;(9):4948-4958
Abstract
Cancer patients receiving chemotherapy often experience taste and smell abnormalities (TSA). To date, the underlying molecular mechanisms of this frequent side-effect have not been determined and effective treatments are not available. This study assessed the feasibility of lactoferrin (LF) supplementation as a treatment for TSA and investigate the related mechanisms through salivary proteome analysis. Nineteen cancer patients with established TSA following chemotherapy administration were enrolled in this study. Cancer patients and additional 12 healthy subjects took LF supplements, 3 tablets per day (250 mg per tablet), for 30 days. Saliva was collected at three timepoints: baseline, 30-day LF supplementation, and 30-day post-LF supplementation. Patient's TSA level, salivary proteome, and salivary minerals at each LF treatment stage were analyzed. High TSA level was associated with high concentration of salivary Fe and loss of critical salivary immune proteins. LF supplementation significantly decreased the concentration of salivary Fe (P = 0.025), increased the abundance (P < 0.05) of salivary α-amylase and Zn-α-2-GP, and led to an overall increase of expression (≥2-fold changes) of immune proteins including immunoglobulin heavy chain, annexin A1, and proteinase inhibitor. Abundance of α-amylase and SPLUNC2 were further increased (P < 0.05) at 30-day post-LF supplementation in cancer patients. At the same time, total TSA score was significantly reduced (P < 0.001) in chemotherapy patients. This study demonstrated the feasibility of developing lactoferrin supplementation as a treatment to reduce TSA caused by chemotherapy and improve cancer patient's oral immunity.
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Proteomic Analysis of Peripheral Blood Mononuclear Cells after a High-Fat, High-Carbohydrate Meal with Orange Juice.
Chaves, DFS, Carvalho, PC, Brasili, E, Rogero, MM, Hassimotto, NA, Diedrich, JK, Moresco, JJ, Yates, JR, Lajolo, FM
Journal of proteome research. 2017;(11):4086-4092
Abstract
Oxidative stress and inflammation play a role in the physiopathology of insulin resistance, diabetes and cardiovascular disease. A single high-fat, high-carbohydrate (HFHC) meal induces an increase in inflammatory and oxidative stress markers in peripheral blood mononuclear cells (PBMC). Previous studies have shown that orange juice is able to prevent this response by inhibiting toll like receptors (TLR) expression and endotoxemia. Our goal was to study the proteome response in PBMC after the consumption of a HFHC meal consumed with water, orange juice or an isocaloric beverage (water with glucose). Twelve healthy individuals completed the protocol in a crossover design, and blood samples were obtained before and 1, 3, and 5 h after consumption. Proteomic profile, glucose, insulin, lipid and cytokines levels were investigated. The glycemic and insulinemic response was higher when the meal was consumed with glucose, while there was no difference in the response between water and orange juice. Proteome analysis in PBMC was carried out using TMT ten-plex. A total of 3813 proteins, originating from 15 662 peptides were identified. Three proteins showed significantly altered expression in the three treatments: apolipoprotein A-II, ceruloplasmin and hemopexin. When the HFHC meal was consumed with water there was an increase in some inflammatory pathways such as the Fc-gamma receptor dependent phagocytosis and the complement cascade, but the immune system as a whole was not significantly altered. However, when the meal was consumed with glucose, the immune system was up regulated. Among the pathways induced after 3 h were those of the adaptive immune system and cytokine signaling. Five hours after the meal, pathways of the complement cascade and classical antibody mediated complement activation were up regulated. When the meal was consumed with orange juice there was an up regulation of proteins involved in signal transduction, DNA replication and cell cycle. The promyelocytic leukemia protein (PML) showed a 28.2-fold increase. This protein was down regulated when the meal was consumed with water. Regarding the immune system, several of the pathways induced by glucose were down regulated when the meal was consumed with orange juice: proteins involved with the adaptive immune system and cytokine signaling. Therefore, we have shown that orange juice can not only suppress diet induced inflammation, but also regulate the expression of proteins such as PML, which may play a key role in the regulation of metabolism.
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Effects of Short-Term Probiotic Ingestion on Immune Profiles and Microbial Translocation among HIV-1-Infected Vietnamese Children.
Ishizaki, A, Bi, X, Nguyen, LV, Matsuda, K, Pham, HV, Phan, CTT, Khu, DTK, Ichimura, H
International journal of molecular sciences. 2017;(10)
Abstract
Here, we investigated the effects of the probiotic strain Lactobacillus casei Shirota (LcS) on immune profiles and intestinal microbial translocation among children infected with human immunodeficiency virus (HIV). This prospective study included 60 HIV-infected children-including 31 without antiretroviral therapy (ART) (HIV(+)) and 29 who received ART for a median of 3.5 years (ART(+)) and 20 children without HIV infection (HIV(-)). Participants were recruited in Vietnam. All children were given fermented milk containing LcS (6.5 × 10⁸ cfu) daily for 8 weeks. Before and after LcS ingestion, blood samples were collected for virological, immunological, and bacteriological analyses. After LcS ingestion, peripheral CD4⁺ T-cell and Th2 (CXCR3-CCR6-CD4⁺) counts significantly increased in both HIV-infected groups; Th17 (CXCR3-CCR6⁺CD4⁺) counts increased in all three groups; regulatory T-cell (CD25highCD4⁺) counts decreased in the ART(+) and HIV(-) groups; activated CD8⁺ cells (CD38⁺HLA-DR⁺CD8⁺) decreased from 27.5% to 13.2% (p < 0.001) in HIV(+) children; and plasma HIV load decreased slightly but significantly among HIV(+) children. No group showed a significantly altered frequency of bacterial 16S/23S rRNA gene detection in the plasma. No serious adverse events occurred. These findings suggest that short-term LcS ingestion is a safe supportive approach with immunological and virological benefits in HIV-infected children.
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Higher DHEAS Levels Associated with Long-Term Practicing of Tai Chi.
Lai, HM, Liu, MSY, Lin, TJ, Tsai, YL, Chien, EJ
The Chinese journal of physiology. 2017;(2):124-130
Abstract
Tai Chi has many benefits for middle-aged/older individuals including improvements to muscle strength and various body lipid components. DHEAS and testosterone have anti-obesity/anti-aging characteristics and also improve libido, vitality and immunity levels. Thus, the aim of the present study was to investigate the differences between middle-aged Tai Chi practitioners (n = 17) and sedentary individuals (n = 17) in terms of leg strength, blood levels of cholesterol, triglyceride, HDL, as well as DHEAS, testosterone and cortisol. Unpaired t-tests were used to identify significant differences between the two groups. There were no significant differences in body composition, leg strength, blood lipid components and testosterone. However, the Tai Chi practitioners had higher levels of DHEAS (P < 0.01) and lower levels of cortisol (P < 0.05). Thus, Tai Chi practitioners have a higher ratio of DHEAS to cortisol, which might have potential benefits in terms of improving an individual’s health-related quality of life during the aging.