Low-Dose JAK3 Inhibition Improves Antitumor T-Cell Immunity and Immunotherapy Efficacy.

Terminal T-cell exhaustion poses a significant barrier to effective anticancer immunotherapy efficacy, with current drugs aimed at reversing exhaustion being limited. Recent investigations into the molecular drivers of T-cell exhaustion have led to the identification of chronic IL2 receptor (IL2R)-STAT5 pathway signaling in mediating T-cell exhaustion. We targeted the key downstream IL2R-intermediate JAK 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) that potently inhibited STAT5-phosphorylation in vitro.

Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis.

Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy.

Exome sequencing in patient-parent trios suggests new candidate genes for early-onset primary sclerosing cholangitis.

Background & Aims: Primary sclerosing cholangitis (PSC) is a rare bile duct disease strongly associated with inflammatory bowel disease (IBD). Whole-exome sequencing (WES) has contributed to understanding the molecular basis of very early-onset IBD, but rare protein-altering genetic variants have not been identified for early-onset PSC. We performed WES in patients diagnosed with PSC ≤ 12 years to investigate the contribution of rare genetic variants to early-onset PSC.

Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Infliximab in Pediatric Inflammatory Bowel Disease: A Systematic Review and Revised Dosing Considerations.

Objectives: Infliximab (IFX), a monoclonal antibody directed against tumor necrosis factor alpha is a potent treatment option for inflammatory bowel disease (IBD). Dosing regimens in children are extrapolated from adult data using a fixed, weight-based dose, which is often not adequate. While clinical trials have focused on safety and efficacy, there is limited data on pharmacokinetic characteristics and immunogenicity of IFX in children.

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD.

Infiltration of the lamina propria by inflammatory CD4 T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4 T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4 T-cell populations is crucial to prevent uncontrolled CD4 T-cell responses and subsequent intestinal tissue damage.

Deletion of IL-6 Exacerbates Colitis and Induces Systemic Inflammation in IL-10-Deficient Mice.

Background And Aims: Interleukin 6 [IL-6] or its receptor is currently a candidate for targeted biological therapy of inflammatory bowel disease [IBD]. Thus, a comprehensive understanding of the consequences of blocking IL-6 is imperative. We investigated this by evaluating the effects of IL-6 deletion on the spontaneous colitis of IL-10-deficient mice [IL-10-/-].

Disease progression in paediatric- and adult-onset sclerosing cholangitis: Results from two independent Dutch registries.

Background & Aims: Sclerosing cholangitis (SC) is a severe liver disease leading to destruction of bile ducts. It is believed to run a milder course in children than in adults. To test this assumption, we evaluated time-to-complication curves in two independent paediatric-onset cohorts from the same geographical area.

Tipping the balance: inhibitory checkpoints in intestinal homeostasis.

The small intestinal and colonic lamina propria are populated with forkhead box P3 (FOXP3)CD4 regulatory T cells (Tregs) and interleukin-10-producing T cells that orchestrate intestinal tolerance to harmless microbial and food antigens. Expression of co-inhibitory receptors such as CTLA-4 and PD-1 serve as checkpoints to these cells controlling their T-cell receptor (TCR)-mediated and CD28-mediated activation and modulating the phenotype of neighboring antigen presenting cells. Recent discoveries on the diversity of co-inhibitory receptors and their selective cellular expression has shed new light on their tissue-dependent function.

Frequencies of circulating regulatory TIGITCD38 effector T cells correlate with the course of inflammatory bowel disease.

Disease heterogeneity hampers achieving long-term disease remission in inflammatory bowel disease (IBD). Monitoring ongoing tissue-localized regulatory and inflammatory T-cell responses in peripheral blood would empower disease classification. We determined whether regulatory and inflammatory phenotypes of circulating CD38 effector (CD62LCD4) T cells, a population enriched for cells with mucosal antigen specificity, classify disease course in pediatric IBD patients.

Malignancy and Mortality in Pediatric-onset Inflammatory Bowel Disease: A Systematic Review.

Background: Cancer and death are the most severe outcomes that affect patients with inflammatory bowel disease (IBD). These outcomes are even more severe if they occur at a young age but are rare, even in the general population. We conducted a systematic review to provide an overview of all reported pediatric (PIBD) patients with severe outcome.

The Pathogenic Role of NLRP3 Inflammasome Activation in Inflammatory Bowel Diseases of Both Mice and Humans.

Background And Aims: NLRP3 inflammasome is known to be involved in inflammatory bowel diseases. However, it is controversial whether it is pathogenic or beneficial. This study evaluated the roles of NLRP3 inflammasome in the pathogenesis of inflammatory bowel disease in IL-10-/- mice and humans.

The Role of Therapeutic Drug Monitoring of Anti-Tumor Necrosis Factor Alpha Agents in Children and Adolescents with Inflammatory Bowel Disease.

Background: Anti-tumor necrosis factor alpha (TNFα) therapy is effective in pediatric patients with inflammatory bowel disease (IBD) but associated with a risk of developing anti-drug antibodies (ADA) which lower the efficacy. Incorporating measurement of trough levels and ADA (therapeutic drug monitoring) may prevent the development of neutralizing ADA or could contribute to more optimal treatment strategies if ADA are already formed. The aim of this review was to investigate the role of therapeutic drug monitoring in children and adolescents with IBD exposed to anti-TNFα agents.