Biology subjects

Hudesman, D.

Publications and source records attributed to Hudesman, D..

3 recordsLinked to original sources

bioRxiv2024

Tofacitinib uptake by patient-derived intestinal organoids predicts individual clinical responsiveness

Background & AimsDespite increasing therapeutic options in the treatment of ulcerative colitis (UC), achieving disease remission remains a major clinical challenge. Nonresponse to therapy is common and clinicians have little guidance in selecting the optimal therapy for an individual patient. This study examined whether patient-derived materials could predict individual clinical responsiveness to the Janus kinase (JAK) inhibitor, tofacitinib, prior to treatment initiation. MethodIn 48 patients with UC initiating tofacitinib, we longitudinally collected clinical covariates, stool, and colonic biopsies to analyze the microbiota, transcriptome, and exome variations associated with clinical responsiveness at week 24. We established patient-derived organoids (n = 23) to determine how their viability upon stimulation with proinflammatory cytokines in the presence of tofacitinib related to drug responsiveness in patients. We performed additional biochemical analyses of organoids and primary tissues to identify the mechanism underlying differential tofacitinib sensitivity. ResultsThe composition of the gut microbiota, rectal transcriptome, inflammatory biomarkers, and exome variations were indistinguishable among UC patients prior to tofacitinib treatment. However, a subset of patient-derived organoids displayed reduced sensitivity to tofacitinib as determined by the ability of the drug to inhibit STAT1 phosphorylation and loss of viability upon cytokine stimulation. Remarkably, sensitivity of organoids to tofacitinib predicted individual clinical patient responsiveness. Reduced responsiveness to tofacitinib was associated with decreased levels of the cationic transporter MATE1, which mediates tofacitinib uptake. ConclusionsPatient-derived intestinal organoids predict and identify mechanisms of individual tofacitinib responsiveness in UC. Specifically, MATE1 expression predicted clinical response to tofacitinib.

cell biology↗

bioRxiv2020

Transcriptional Atlas of Ileal-Anal Pouch Immune Cells from Ulcerative Colitis Patients

How the human intestinal immune system is distinctly organized to respond to inflammation is still poorly understood. Here, we used single-cell RNA-sequencing to examine lamina propria CD45+ hematopoietic cells from patients with inflammatory bowel disease that have undergone ileal pouch-anal anastomosis, or the colon mucosa of ulcerative colitis patients. We identified a population of IL1B+ antimicrobial macrophages and FOXP3/+BATF+ T cells that are associated and expanded in inflamed tissues, which we further validated in other scRNA-seq datasets from IBD patients. CD8+ T cells were unexpectedly more abundant in the pouch than colon. Cell type specific markers obtained from single-cell RNA-sequencing was used to infer representation from bulk RNA sequencing datasets, which further implicated antimicrobial macrophages expressing IL1B with S100A8/A9 calprotectin as being associated with inflammation, as well as Bacteroides and Escherichia bacterial species. Finally, we find that non-responsiveness to anti-integrin biologic therapies in UC patients is associated with the signature of this antimicrobial macrophage population in a subset of patients. This study identified conserved and distinct features of intestinal inflammation between parts of the small and large intestine undergoing similar inflammation conditions.

immunology↗

bioRxiv2019

Serum Amyloid A Proteins Induce Pathogenic TH17 Cells and Promote Inflammatory Disease

Lymphoid cells that produce IL-17 cytokines protect barrier tissues from pathogenic microbes, but are also prominent effectors of inflammation and autoimmune disease. T-helper (TH17) cells, defined by ROR{gamma}t-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, TH17 cell behaviors vary markedly according to their environment. Here we show that SAAs additionally direct a pathogenic pro-inflammatory TH17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting TH17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.

immunology↗