Schnell Alexander, Aicher Carmen, Schnegelsberg Philipp A, Schwarz Benedikt, Schmidt Hannah, Allabauer Ida, Rueckel Aline, Regensburger Adrian P, Woelfle Joachim, Hoerning André
Pediatric Gastroenterology, Hepatology and Endoscopy, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Bavaria, Germany.
Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Bavaria, Germany.
Clin Exp Immunol. 2025 Jan 21;219(1). doi: 10.1093/cei/uxae066.
T cells are one of the main drivers of inflammatory bowel diseases (IBD). Infliximab (IFX) is used in the treatment of IBD as an anti-inflammatory drug to induce remission by neutralizing TNFα. We determined the individual chemokine/homing receptor and cytokine profile in pediatric IBD patients before and during IFX therapy to identify predictive biomarkers for therapy success. Peripheral blood CD4+ cells from pediatric patients with IBD were immunomagnetically isolated and either directly analyzed by FACS for cell distribution and chemokine/homing receptor expression or evaluated for cytokine production after in-vitro-stimulation. Twenty-one responders (RS) and 21 non-responders (NRS) were recruited. Before IFX therapy, flow cytometry revealed decreased percentages of naïve conventional T cells in pediatric IBD patients. The proportions of CD62-L+ T cells were decreased in both CD and UC therapy responders. The cytokine profile of T cells was highly altered in IBD patients compared to healthy controls (HC). During IFX therapy, the frequencies of conventional memory and regulatory memory T cells expanded in both cohorts. IFX response was marked by a decrease of α4β7+ and IFNγ+ memory T cells in both CD and UC. In contrast, frequencies of Lag-3+ T cells proved to be significantly increased in NRS. These observations were irrespective of the underlying disease. T cells of pediatric IBD patients display an activated and rather Th1/Th17-shifted phenotype. The increased expression of the checkpoint molecule Lag-3 on T cells of NRS resembles a more exhausted phenotype than in RS and HC which appeared to be a relevant predictive marker for therapy failure.
T细胞是炎症性肠病（IBD）的主要驱动因素之一。英夫利昔单抗（IFX）作为一种抗炎药物用于治疗IBD，通过中和TNFα诱导缓解。我们测定了儿科IBD患者在IFX治疗前和治疗期间的个体趋化因子/归巢受体及细胞因子谱，以确定治疗成功的预测生物标志物。通过免疫磁珠法分离儿科IBD患者外周血CD4+细胞，要么直接用流式细胞术分析细胞分布和趋化因子/归巢受体表达，要么在体外刺激后评估细胞因子产生情况。招募了21名应答者（RS）和21名无应答者（NRS）。在IFX治疗前，流式细胞术显示儿科IBD患者中幼稚常规T细胞百分比降低。在克罗恩病（CD）和溃疡性结肠炎（UC）治疗应答者中，CD62-L+ T细胞比例均降低。与健康对照（HC）相比，IBD患者T细胞的细胞因子谱发生了高度改变。在IFX治疗期间，两个队列中常规记忆T细胞和调节性记忆T细胞的频率均增加。IFX应答的特征是CD和UC中α4β7+和IFNγ+记忆T细胞减少。相反，Lag-3+ T细胞频率在NRS中显著增加。这些观察结果与潜在疾病无关。儿科IBD患者的T细胞表现出活化且偏向Th1/Th17的表型。NRS的T细胞上检查点分子Lag-3表达增加，与RS和HC相比表现出更耗竭的表型，这似乎是治疗失败的一个相关预测标志物。
