Inhibition of allergen-specific tissue resident memory Th2 cells through blockade of CD3-mediated signaling ameliorates allergic lung inflammation

Abstract Allergic asthma remains a major public health concern, with more than 26 million Americans suffering from the disease. The secretion of cytokines such as IL-4, IL-5, and IL-13 and their ability to persist in the host long after the primary allergen encounter are a reason memory Th2 cells are a major driving force behind allergic asthma morbidity. The selective removal of pre-existing memory Th2 cells could be a key therapeutic venture to enhance tolerance. One such method could involve targeting CD3 through the use of inhibitory anti-CD3 antibodies which successfully induced tolerance in animal models of autoimmune diseases and also show promise in clinical trials. To determine if we could induce airway tolerance, we tested blocking CD3 complex signaling in a HDM model of allergic inflammation. Importantly, pre-sensitized C57BL/6J mice displayed strongly ablated lung inflammation and Th2 responses when treated at the time of memory T cell reactivation with F(ab′)2 anti-CD3 antibody. This treatment was found to inhibit HDM-specific CD4+ T cell proliferation and Th2 cytokine production. Interestingly, while mice treated with anti-CD3 also showed an increased frequency of Treg cells, protection to allergic inflammation was maintained even after Treg depletion. Anti-CD3 treatment was found to specifically inhibit eosinophilic lung inflammation driven by allergen-specific lung tissue resident memory (Trm) Th2 cells as determined by treatment of mice with fingolimod (FTY720), which prevents the recruitment and contribution of circulating memory T cells to the allergic response. These data suggest that blocking CD3 complex signaling could be employed to inhibit Trm recall responses to complex allergens thus promoting airway tolerance.</jats:p

Endoscopic Treatment of Upper Gastrointestinal Bleeding Using Haemoseal Spray: A Retrospective, Observational Study from a Tertiary Center in North India

Abstract Introduction United States Food and Drug Administration recently approved use of Hemospray for the management of gastrointestinal (GI) Bleeding. We report our experience with Haemoseal Spray (HS, Shaili Endoscopy) for the treatment of upper GI bleeding (UGIB). Methods Records of patients who received HS for UGIB from January 2013 to June 2018 were studied retrospectively. Patients with UGIB from focal lesions refractory to conventional endotherapy or those with diffuse/multiple lesions not amenable to conventional endotherapy received 5cc HS spray. Primary end-point studied was clinical success, defined as control of bleeding over 24 hours. Secondary end-points evaluated included recurrence of bleeding within 7 days, in-hospital mortality, and complications secondary to HS. Results Thirty-eight patients were treated with HS. The median age was 57 (range: 5–87) years with 27 males and 11 females. In 24 patients, HS was used as monotherapy, while it was combined with Injection/Clip/Argon Plasma Coagulation in 14. Etiology of bleeding was ulcers or erosions in 22, malignancy in 10, portal hypertensive gastropathy/gastric antral vascular ectasia in 4, and radiation gastropathy in 2. Clinical success was achieved in 32/38 (84%). All six nonresponders had coagulopathy related to chemotherapy/bone marrow transplant. Recurrent bleeding within 7 days was observed in four patients (gastric malignancy 2, radiation gastropathy 2). In-hospital mortality was seen in 8/38 (21%) of which 2(4.8%) were directly related to ongoing GI bleeding. There was no procedure-related complication. Conclusion HS is an effective and safe tool in the endoscopic management of UGIB due to diffuse or multiple focal lesions or focal lesions refractory to conventional endotherapy.</jats:p

Symptomatic Heterotopic Gastric Mucosa in Distal Esophagus

Abstract Introduction Heterotopic gastric mucosa (HGM) in esophagus is commonly noted as an inlet patch at endoscopy. We describe a rare patient with symptomatic distal esophageal HGM. Case Report A 40-year-old male presented with retrosternal pain and marked odynophagia for the last 4 weeks without any history of ingestion of antibiotics, foreign body, or corrosive. Endoscopy showed abrupt circumferential transition to salmon pink mucosa at 35 cm from incisors. From 35 to 41 cm, there were areas of polypoid edematous thickening with few superficial ulcers of 1 to 3 mm. Squamous epithelium was visualized at narrow band imaging from 41 cm to the Z-line at 43 cm with no hiatus hernia. Biopsy showed gastric-type mucosa with parietal cells without dysplasia. Serology for cytomegalovirus and human immunodeficiency virus was negative. He was managed with proton pump inhibitors (PPIs) and prokinetics and improved symptomatically. Follow-up endoscopy at 3 months demonstrated healing of ulcers with persistence of HGM and pseudopolyps. He remains well on maintenance with PPI at 1-year follow-up. Conclusion Symptomatic HGM in distal esophagus is rare and can be differentiated from Barrett’s esophagus histologically and by presence of squamous epithelium between HGM and stomach. Inflammatory mass lesions may develop and mimic esophageal malignancy. Symptoms are largely due to acid production and usually respond to PPI.</jats:p

Colonoscopic Instillation of Coca-Cola for Evacuation of Large Fecaloma: A Report of Two Cases and Review of Literature

Abstract Introduction Fecaloma is a large mass of organized hardened feces causing impaction, usually in rectum and sigmoid colon. Medical management usually entails digital evacuation, use of clearance enema, and oral laxatives. We report two patients managed successfully with colonoscopic instillation of Coca-Cola and review the literature. Case Report Patient 1: A 37-year-old male presented with firm, nontender, pitting mass over lower abdomen for 2 months and inability to pass stool for 1 month. Per-rectal examination and imaging confirmed presence of solid stool with gross distension of rectum and sigmoid colon. Attempts at clearance of stool with conventional methods were unsuccessful. At colonoscopy, 4 L of Coca-Cola was instilled into descending and sigmoid colon, leading to evacuation of 10 L of fragmented and liquid stool.Patient 2: A 72-year-old diabetic lady presented with constipation and tender, firm pelvic mass extending till mid-abdomen for 6 months. Per-rectal examination revealed presence of hard stool. Imaging confirmed large amount of fecal matter in dilated rectum, sigmoid, and descending colon. Attempts at evacuating stool with digital evacuation, sodium phosphate enema, and oral polyethylene glycol were unsuccessful. At colonoscopy, two sittings of instillation of 990 mL of Coca-Cola Light each were done into sigmoid colon over 2 days, resulting in clearance. Conclusion Colonoscopic instillation of Coca-Cola may be effective in evacuation of large fecaloma from rectum, sigmoid, and descending colon when refractory to use of conventional methods like digital disimpaction, rectal enema, and oral laxatives.</jats:p

Tumor necrosis factor like weak inducer of apoptosis (TWEAK) Promotes Inflammatory Activity in Keratinocytes with IL-17 and TNF to Drive Psoriasis

Abstract Psoriasis is an autoimmune skin disease caused by hyper-proliferation of keratinocytes driven by distinct inflammatory cells making cytokines such as IL-17 and TNF. Our previous studies with knockout animals revealed that the TNF-related cytokine TWEAK (TNFSF12) was also a critical contributor to skin inflammation and could be a potential therapeutic target in psoriasis. As Fn14, the receptor for TWEAK, is expressed by keratinocytes, we examined the inflammatory effects of TWEAK alone and with IL-17A and TNF in modulating psoriatic genes in human keratinocytes using RNA-seq. We found that TWEAK upregulated the expression of multiple chemokines and cytokines, such as IL-36G, IL-23A, IL-19, CCL5, CCL20, and other inflammation-associated genes, that have previously been found highly expressed in the skin of patients with psoriasis. TWEAK’s action was partially overlapping with IL-17 and TNF, but interestingly, in combination with IL-17 or TNF, TWEAK had strong synergistic effects in enhancing the expression of a number of these inflammatory genes. We then tested the impact of TWEAK neutralization on already existing skin inflammation in an imiquimod-induced psoriasis model. Mice treated therapeutically with anti-TWEAK showed significantly decreased numbers of immune cell infiltrates in the skin, with fewer γδ T cells, neutrophils and macrophages. These mice also exhibited a marked reduction in epidermal thickening, similar to mice treated with anti-IL-17 alone. Furthermore, co-neutralization of TWEAK and IL-17 demonstrated a greater effect in terms of reducing clinical symptoms. These data suggest that blocking TWEAK could be considered as a potential therapeutic avenue in humans to overcome the pathophysiology of psoriasis.</jats:p