Extremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging.

There is a dramatic remodeling of the T cell compartment during aging. The most notorious changes are the reduction of the naive T cell pool and the accumulation of memory-like T cells. Memory-like T cells in older people acquire a phenotype of terminally differentiated cells, lose the expression of costimulatory molecules, and acquire properties of senescent cells. In this review, we focus on the different subsets of age-associated T cells that accumulate during aging. These subsets include extremely cytotoxic T cells with natural killer properties, exhausted T cells with altered cytokine production, and regulatory T cells that gain proinflammatory features. Importantly, all of these subsets lose their lymph node homing capacity and migrate preferentially to nonlymphoid tissues, where they contribute to tissue deterioration and inflammaging.

Nicotinamide adenine dinucleotide metabolism in the immune response, autoimmunity and inflammageing.

Metabolism is dynamically regulated to accompany immune cell function, and altered immunometabolism can result in impaired immune responses. Concomitantly, the pharmacological manipulation of metabolic processes offers an opportunity for therapeutic intervention in inflammatory disorders. The nicotinamide adenine dinucleotide (NAD+ ) is a critical metabolic intermediate that serves as enzyme cofactor in redox reactions, and is also used as a co-substrate by many enzymes such as sirtuins, adenosine diphosphate ribose transferases and synthases. Through these activities, NAD+ metabolism regulates a broad spectrum of cellular functions such as energy metabolism, DNA repair, regulation of the epigenetic landscape and inflammation. Thus, the manipulation of NAD+ availability using pharmacological compounds such as NAD+ precursors can have immune-modulatory properties in inflammation. Here, we discuss how the NAD+ metabolism contributes to the immune response and inflammatory conditions, with a special focus on multiple sclerosis, inflammatory bowel diseases and inflammageing. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

The role of T cells in age-related diseases.

Age-related T cell dysfunction can lead to failure of immune tolerance mechanisms, resulting in aberrant T cell-driven cytokine and cytotoxic responses that ultimately cause tissue damage. In this Review, we discuss the role of T cells in the onset and progression of age-associated conditions, focusing on cardiovascular disorders, metabolic dysfunction, neuroinflammation and defective tissue repair and regeneration. We present different mechanisms by which T cells contribute to inflammageing and might act as modulators of age-associated diseases, including through enhanced pro-inflammatory and cytotoxic activity, defective clearance of senescent cells or regulation of the gut microbiota. Finally, we propose that 'resetting' immune system tolerance or targeting pathogenic T cells could open up new therapeutic opportunities to boost resilience to age-related diseases.

2S albumins and nsLTP are involved in anaphylaxis to pizza sauce: IgE recognition before and after allergen processing.

Although pizza is one of the most popular foods in the world, allergic responses after ingesting pizza are relatively uncommon. However, precisely identifying the allergens responsible for these allergic reactions is challenging because of the high and diverse number of ingredients used in pizza preparation. In this report, we aim to identify the allergens responsible for systemic allergic reactions following ingestion of pizza in two patients. Using a skin prick by prick test (SPPT) and in vitro techniques, with natural and recombinant purified allergens from tomato and mustard seeds, we identified 2S albumin and non-specific lipid transfer proteins (nsLTP) as the proteins involved. However, IgE responses to the four nsLTPs differed before and after denaturation and reduction, thus suggesting additional complexity around nsLTP in food processing.

Glycolysis - a key player in the inflammatory response.

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria.

Mitochondrial metabolism and autophagy are two of the most metabolically active cellular processes, playing a crucial role in regulating organism longevity. In fact, both mitochondrial dysfunction or autophagy decline compromise cellular homeostasis and induce inflammation. Calorie restriction (CR) is the oldest strategy known to promote healthspan, and a plethora of CR mimetics have been used to emulate its beneficial effects. Herein, we discuss how CR and CR mimetics, by modulating mitochondrial metabolism or autophagic flux, prevent inflammatory processes, protect the intestinal barrier function, and dampen both inflammaging and neuroinflammation. We outline the effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade and how these anti-inflammatory properties could be involved in their ability to increase resilience to age-associated diseases.

Nut Allergy in Two Different Areas of Spain: Differences in Clinical and Molecular Pattern.

INTRODUCTION: Different clinical and molecular patterns of food allergy have been reported in different areas of the world. The aim of the study is to evaluate differences in allergen patterns among nut-allergic patients in two different areas of Spain. MATERIAL AND METHODS: A total of 77 patients with nut allergy from two different regions of Spain (Madrid and Asturias) were evaluated. RESULTS: Hazelnut, peanut, and walnut were the three most frequent nuts eliciting allergy in both regions, but in a different order. Patients from Madrid experienced systemic reactions more often than patients from Asturias (73.5% Madrid vs. 50.0%, p < 0.05). The percentage of sensitizations to LTP (Lipid Transfer Protein) was higher than Bet v 1 (p < 0.05) in the Madrid area. The percentage of sensitizations in Asturias area was similar to LTP than Bet v 1 (Pru p 3 46.4%, Bet v 1 42.9%, ns). Bet v 1 was the predominant allergen involved among hazelnut-allergic patients (56.2%), while LTP was more common in peanut-allergic patients (61.5%). CONCLUSION: Walnut, hazelnut, and peanut were the most frequent nuts eliciting allergy in Spain. Despite this, important differences in molecular pattern were appreciated not only between both regions, but also among nut-allergic patients in Asturias. The different molecular pattern was linked to the frequency of systemic symptoms.

Molecular and immunological characterization of the first allergenic lipocalin in hamster: the major allergen from Siberian hamster (Phodopus sungorus).

The most frequent pet allergy is to cat and dog, but in recent years, it has become increasingly popular to have other pets, and the risk of exposure to new allergens is more prevalent. The list of new pets includes hamsters, and one of the most popular hamsters is the Siberian hamster (Phodopus sungorus). The aim of this study was the characterization and cloning of the major allergen from this hamster. The study of its allergenicity and cross-reactivity could improve the specific diagnosis and treatment for hamster-allergic patients. Thirteen Siberian hamster-allergic patients were recruited at the outpatient clinic. Protein extracts were prepared from the hair, urine, and salivary glands of four hamster species (European, golden, Siberian, and Roborovski). IgE-binding proteins were detected by immunoblotting and identified by mass spectrometry. The recombinant protein was produced in Escherichia coli and then purified by metal chelate affinity chromatography. The allergenic properties of the recombinant protein were tested by ELISA and immunoblotting, and biological activity was tested according to capacity for basophil activation. Three IgE-binding proteins were identified in extracts obtained from Siberian hamster hair, urine, and salivary glands. All proteins corresponded to the same protein, which was identified as a lipocalin. This lipocalin had no cross-reactivity with common and golden hamsters. The recombinant allergen was cloned and purified, showing similar IgE reactivity in vitro to Siberian hamster protein extracts. Also, the recombinant allergen was capable of producing biological activation in vivo. The major Siberian hamster allergen was cloned, and allergenic properties were characterized, providing a new tool for specific diagnosis of allergy to Siberian hamster.

Multicenter phase II clinical trial of preoperative capecitabine with concurrent radiotherapy in patients with locally advanced rectal cancer.

INTRODUCTION: To assess pathologic complete response, sphincter preservation rates and toxicity profile of preoperative chemoradiation with capecitabine in resectable locally advanced rectal cancer. MATERIALS AND METHODS: Fifty-eight patients from six Spanish centers were included (March 2004 to June 2005) with histological/cytological diagnosis of locally advanced rectal cancer, age between 18 and 80 years, ECOG 0-2, adequate bone marrow, renal and hepatic functions. Prior chemotherapy/radiotherapy was not allowed. Preoperative treatment was capecitabine 825 mg/m(2) bid concomitant to radiotherapy (45 + 5.4 Gy boost over 5.5 weeks). Surgery was performed 4-8 weeks after completion of chemoradiotherapy. RESULTS: Fifty-eight patients were enrolled in this study: 60.3 % males, median age of 64.5 (30.9-78.7) years, 28.6 % with ECOG 0 and 71.4 % with ECOG 1. Median distance of tumor from the anal verge was 7 (1-12) cm. Fifty-two (89.6. %) patients completed preoperative chemoradiotherapy. Primary tumor and node downstaging occurred in 61.1 and 69.6 % of patients, respectively. Surgery was performed in 55 patients (94.8 %): 80 % had negative lymph nodes and 72.7 % underwent sphincter-preserving procedures. A pathologic complete response was observed in 10.5 % (95 % CI 2.5-18.5) of the patients. Main grade I-II toxicities were leucopenia (43.1 %), neutropenia (24.1 %), anemia (36.2 %), diarrhea (32.8 %) and skin disorders (5.1 %), from which diarrhea (6.9 %), leucopenia (1.7 %) and skin disorders (1.7 %) reached grade III. There were no grade IV toxicities. CONCLUSIONS: Preoperative capecitabine-based chemoradiation is a well-tolerated and effective neoadjuvant treatment for locally advanced rectal cancer that achieves encouraging rates of tumor downstaging.

Clinical and technological transition in breast cancer.

This article is a summary of the conference "Clinical and technological transition in breast cancer" that took place in the Congress of the Spanish Society of Radiation Oncology, placed in Vigo (Spain) on June 21, 2013. Hugo Marsiglia and Philip Poortmanns were the speakers, the first discussed about "Clinical and technological transition" and the second about "EORTC clinical trials and protocols".

Long-term changes in pulmonary function after incidental lung irradiation for breast cancer: a prospective study with 7-year follow-up.

PURPOSE: To evaluate late pulmonary function changes after incidental pulmonary irradiation for breast cancer. METHODS AND MATERIALS: Forty-three consecutive female patients diagnosed with breast carcinoma and treated with postoperative radiation therapy (RT) at the same dose (50 Gy) and fractionation (2 Gy/fraction, 5 days/week) were enrolled. Pulmonary function tests (PFT) and ventilation/perfusion scans were performed before RT and 6, 12, 24, and 84 months afterward. RESULTS: Forty-one patients, mean age 55 years, were eligible for the analysis. No differences were found in the baseline PFT values for age, smoking status and previous chemotherapy; women undergoing mastectomy showed baseline spirometric PFT values lower than did women treated with conservative surgery. The mean pulmonary dose was 10.9 Gy, being higher in women who also received lymph node RT (15.8 vs 8.6, P<.01). Only 1 patient experienced symptomatic pneumonitis. All PFT values showed a reduction at 6 months. From then on, the forced vital capacity and forced expiratory volume in 1 second began their recovery until reaching, and even exceeding, their baseline values at 7 years. Diffusing capacity of the lungs for carbon monoxide and ventilation/perfusion scans continued to reduce for 24 months and then partially recovered their baseline values (-3.5%, -3.8%, and -5.5%, respectively). Only the percentage difference at 7 years in the ventilation scan correlated with the dosimetric parameters studied. Other variables, such as age, smoking status, previous chemotherapy, and concomitant tamoxifen showed no significant relation with changes in PFT (ΔPFT) values at 7 years. CONCLUSIONS: The study of reproducible subclinical parameters, such as PFT values, shows how their figures decrease in the first 2 years but practically recover their baseline values in the long term. The extent of the reduction in PFT values was small, and there was no clear association with several dosimetric and clinical parameters.

Risk-adapted adjuvant chemotherapy after concomitant fluoropyrimidine-radiotherapy neoadjuvant treatment for patients with resectable cT3-4 or N+ rectal cancer.

Adjuvant chemotherapy in rectal cancer is not well defined.After neoadjuvant chemoradiation and surgery, at least a short period of treatment with 5-fluorouracil is recommended, and some investigators claim a more aggressive approach, in particular, for those patients with a high risk of systemic relapse. Nevertheless, there are few studies about adjuvant combination therapy tolerance and efficacy, and no randomized trials have been conducted comparing fluoropyrimidines versus combination therapy such as folinic acid plus 5-fluorouracil plus oxaliplatin(FOLFOX), considered the standard of care in stage IIIcolon cancer. We present an institutional series of risk adapted adjuvant therapy. Sixty evaluable patients who had received treatment with neoadjuvant fluoropyrimidine radiotherapy and surgery now received adjuvant fluoropyrimidines in the case of pT0-2N0 or oxaliplatin based combination in the case of pT3-4 or N+ . Overall, 33 patients experienced downstaging to pT2-0N0 (55%) and27 patients were restaged as pT3-4 or N+ (45%) after surgery. Local recurrence rate was 5% (three patients), one local and one local plus systemic in the adjuvant single agent group and one local plus systemic in the adjuvant FOLFOX group. Systemic relapse occurred in 14 patients(23.3%), five (15%) in the single-agent group and nine(33.3%) in the FOLFOX group. Disease-free survival at 3 years for patients in the good prognostic group(pT0-2N0) and poor prognostic group (pT3-4 or N+ ) were 78.7 and 62.2%, respectively. Severe diarrhoea was more frequent with fluoropyrimidines and neutropenia, mucositis and peripheral neuropathy were more common with FOLFOX. There were no toxic deaths. A risk-adapted adjuvant therapeutic decision is feasible with an acceptable safety profile even with the use of oxaliplatin based combinations. Three-year disease-free survival compares favourably with historical controls, especially in those patients with high risk factors for relapse.Phase III controlled trials are needed.

Watermelon profilin: characterization of a major allergen as a model for plant-derived food profilins.

BACKGROUND: Plant profilins have been reported as minor allergens. They are a well-known pan-allergen family responsible for cross-reactivity between plant-derived foods and pollens. Watermelon profilin has been reported to be a major allergen in watermelon (Citrullus lanatus).The aim of this study was to characterize recombinant watermelon profilin, confirming its reactivity for diagnostic purposes and the development of immunotherapy. METHODS: Native profilin was purified from watermelon extract by affinity chromatography using poly-L-proline. Recombinant His-tagged profilin was produced in Pichia pastoris yeast using pPICZαA vector and purified by metal chelate affinity chromatography. ELISA and immunoblot were carried out with sera from 17 watermelon-allergic patients. Biological activity was tested by the basophil activation test. RESULTS: Native profilin and recombinant profilin were purified and identified by mass spectrometry. Both show similar IgE reactivity in vitro and are biologically active. CONCLUSIONS: Similarities were found in the IgE-binding patterns and biological activity of recombinant profilin and native profilin. Recombinant profilin may be a powerful tool for specific diagnosis.