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Showing results for tags 'intraepithelial lymphocytes'.
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Celiac.com 08/14/2024 - Refractory celiac disease type II, commonly referred to as RCDII, is a rare and severe form of celiac disease. Unlike typical celiac disease, RCDII does not respond to a gluten-free diet. This condition is marked by the clonal expansion of abnormal intraepithelial lymphocytes, which can lead to high mortality rates due to the lack of effective treatment options. One promising treatment involves the use of tofacitinib, a small-molecule inhibitor targeting specific enzymes known as JAK1 and JAK3. This study explores the potential of tofacitinib to induce clinical remission in patients with RCDII. Study Overview and Methodology This open-label clinical study involved six patients diagnosed with RCDII, who had not responded to previous treatments, including the drug cladribine. Four patients were treated according to the study protocol in the Netherlands, while two patients in Germany received similar treatment outside the protocol. The patients were given 10 mg of tofacitinib twice daily for 12 weeks. The study aimed to assess both the clinical and immunologic responses to the treatment. Baseline Characteristics of Patients At the beginning of the study, all patients exhibited significant symptoms of malabsorption, such as weight loss, diarrhea, abdominal pain, and low levels of albumin in the blood. Small intestine biopsies showed a high percentage of abnormal intraepithelial lymphocytes, ranging from 70% to 90%. Two patients also had ulcerative jejunitis, a severe condition causing ulcers in the small intestine. Histological examinations revealed varying degrees of villous atrophy, a condition where the finger-like projections in the small intestine are damaged, affecting nutrient absorption. Clinical Response to Tofacitinib Treatment All patients completed the 12-week treatment course with tofacitinib. Within a span of two to fourteen days, patients experienced a noticeable resolution of diarrhea and abdominal pain. Additionally, they showed significant weight gain, with a median increase of over 12% by the end of the 12 weeks. One patient with severe ulcerative jejunitis was even able to discontinue total parenteral nutrition by week nine. However, upon discontinuation of tofacitinib, all patients quickly relapsed, experiencing weight loss and a return of symptoms. When tofacitinib treatment was resumed, patients again showed rapid and complete clinical improvement. Immunologic and Histologic Findings The primary immunologic endpoint was to achieve a reduction of at least 20% in the number of abnormal intraepithelial lymphocytes. This goal was not met by any patient. The median percentage of abnormal cells remained relatively unchanged from baseline to the end of the 12-week treatment period. Despite this, four out of six patients showed significant improvement in the histology of their small intestine, indicating mucosal healing. This improvement was particularly evident in patients with ulcerative jejunitis. Adverse Events and Safety Throughout the study, all patients experienced adverse events. The most common was lymphopenia, a condition characterized by low levels of lymphocytes in the blood. One patient suffered a serious adverse event, developing a pulmonary embolism associated with a line sepsis caused by a bacterial infection. This patient continued to receive tofacitinib at a reduced dose of 5 mg twice daily, with continued clinical improvement. No other serious infections were reported, and there was no progression to enteropathy-associated T-cell lymphoma in any patient. Extended Follow-Up and Long-Term Outcomes During an extended follow-up period of up to two years, the patients continued to show persistent clinical remission while on a reduced dose of tofacitinib. The median weight gain further increased, and duodenal biopsies indicated ongoing histologic improvement. Capsule endoscopy revealed complete or near-complete resolution of intestinal ulcerations in patients with ulcerative jejunitis. These findings suggest that tofacitinib not only provides short-term relief but also contributes to long-term clinical remission in patients with RCDII. Implications for Future Treatment of Celiac Disease This study is significant for several reasons. First, it demonstrates that tofacitinib can induce rapid and sustained clinical remission in patients with refractory celiac disease type II, a condition that has been notoriously difficult to treat. Second, the study's findings suggest that while tofacitinib may not reduce the number of abnormal intraepithelial lymphocytes, it effectively mitigates their harmful activity. This functional impact is crucial for improving patient outcomes. For those with celiac disease, particularly the rare and severe RCDII, this study offers hope for a viable treatment option where none previously existed. It also underscores the importance of continued research and clinical trials to explore and refine new therapies. The potential for tofacitinib to change the treatment landscape for RCDII patients is substantial, offering a path to better management and improved quality of life. Read more at: cghjournal.org
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Celiac.com 04/14/2020 - Non-celiac wheat sensitivity (NCWS) most frequently presents clinically with irritable bowel syndrome (IBS)-like symptoms, although many extra-intestinal manifestations have also been attributed to it. No studies to date have evaluated the presence and frequency of gynecological symptoms in NCWS. A team of researchers recently set out to assess the frequency of gynecological disorders in patients with NCWS. The research team included Maurizio Soresi, Salvatore Incandela, Pasquale Mansueto, Giuseppe Incandela, Francesco La Blasca, Francesca Fayer, Alberto D’Alcamo, Ada Maria Florena & Antonio Carroccio. They are variously affiliated with the Gynecology Unit, Giovanni Paolo II Hospital, Sciacca, Italy, and with the Internal Medicine Unit, and the Pathology Unit of the Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo in Palermo, Italy. The team surveyed gynecological symptoms and recurrent cystitis in sixty-eight women with NCWS. They referred all patients with symptoms to specialists. The study used three different control groups. The first included 52 patients with IBS not related to NCWS, the second included 56 patients with celiac disease, and the third included 71 healthy control subjects. Nearly sixty percent of NCWS patients had more frequent gynecological symptoms, than did healthy control subjects, IBS control subjects or controls with celiac disease. More than twenty-five percent of patients with NCWS experienced more frequent changes to the menstrual cycle, compared with just over eleven percent of healthy controls. Sixteen percent patients with NCWS suffered from recurrent vaginitis (16%) and dyspareunia (6%) significantly more frequently than healthy controls. Nearly thirty percent of NCWS patients reported recurrent cystitis, far more than in healthy, IBS, and celiac control groups. Most patients with NCWS and recurrent vaginitis or cystitis had negative microbiological exam results. Gluten-Free Diet Resolves Symptoms Over a one-year follow-up period, nearly half of patients with menstrual disorders and nearly forty percent with recurrent vaginitis reported that their symptoms had resolved on a wheat-free diet. Gynecological symptoms and recurrent cystitis were substantially more frequent in patients with NCWS than in IBS patients. Further study will likely help to shed light on the reasons for this difference, and help to reveal other important differences between these conditions. Read more in Digestive Diseases and Sciences (2020)
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Celiac.com 03/04/2019 - Tissue-resident lymphocytes play a key role in immune surveillance, but there’s not much data on how these cells respond to chronic inflammation. A team of researchers recently set out to assess how well tissue-resident lymphocytes respond to chronic inflammation. The research team included Toufic Mayassi; Kristin Ladell; Herman Gudjonson; Jamie Rossjohn; David A. Price; and Bana Jabri. In celiac disease, the team found that gluten-induced inflammation substantially reduced levels of naturally occurring Vγ4 +/Vδ1 + intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4 +/Vδ1 + IELs occurred together with the expansion of gluten-sensitive, interferon-γ-producing Vδ1 + IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Eliminating dietary gluten normalized BTNL8 expression, but was not enough to restore the physiological Vγ4 +/Vδ1 + subset among TCRγδ + IELs. Together, the data show that long-term inflammation permanently changes the tissue-resident TCRγδ + IEL compartment in celiac disease. What exactly does that mean? Some of the takeaways include: • Innate-like Vδ1 + IELs are superseded by interferon-γ-producing Vδ1 + IELs in celiac disease • The Vδ1 + IEL TCR repertoire is permanently reshaped in celiac disease • A molecular signature defines Vδ1 + IEL expansions in active celiac disease • Loss of BTNL8 expression coincides with permanent loss of BTNL3/8-reactive γδ + IELs in celiac disease Even on a gluten-free diet, chronic inflammation causes permanent changes to the tissue-resident TCRγδ + IEL compartment in celiac patients. Further study is needed to determine the full significance of these findings. Read more in: CELL
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