Joseph C Maranville1, Dejan Micic2, Stephen B Hanauer3, Anna Di Rienzo4, Sonia S Kupfer5. 1. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA; Department of Medicine, The University of Chicago, Chicago, IL, USA; Department of Human Genetics, The University of Chicago, Chicago, IL, USA. 2. Department of Medicine, The University of Chicago, Chicago, IL, USA. 3. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA; Department of Medicine, The University of Chicago, Chicago, IL, USA. 4. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA; Department of Human Genetics, The University of Chicago, Chicago, IL, USA. Electronic address: dirienzo@uchicago.edu. 5. Department of Medicine, The University of Chicago, Chicago, IL, USA. Electronic address: Sonia.Kupfer@uchospitals.edu.
Abstract
BACKGROUND: Glucocorticoids (GCs) are steroid hormones used to induce remission in moderate-to-severe inflammatory bowel disease (IBD). A substantial fraction of patients do not respond to GC treatment and require alternate therapies or surgery. At present, non-response can only be assessed empirically by observing continued disease activity. METHODS: To identify potential biomarkers of GC response, we retrospectively identified and recruited 18 GC-responsive and 18 GC-nonresponsive IBD patients. This sample included 14 patients with ulcerative colitis (UC) and 22 patients with Crohn's disease (CD), all previously treated with steroids. In peripheral blood mononuclear cells from each patient, we performed in vitro assays to measure GC inhibition of three different immune stimulants (phytohemagglutinin [PHA], α-CD3/α-CD28, and lipopolysaccharide [LPS]). RESULTS: In both diseases, we found that inhibition of PHA-mediated T cell proliferation was significantly associated with clinical GC response (P=0.04). Inhibition of proliferation due to direct T cell receptor stimulation using α-CD3/α-CD28 was also significantly associated with clinical GC response in UC patients (P=0.009), but not in CD patients (P=0.78). Interestingly, inhibition of LPS-mediated cytokine secretion showed the strongest association with clinical GC response across both diseases (P=0.005). CONCLUSIONS: We show that inhibition of LPS stimulation is more strongly associated with clinical GC response in IBD patients than inhibition of PHA and α-CD3/α-CD28-mediated proliferation. These results support an important role of bacterial recognition and innate immunity in the etiology of IBD. This assay could be a powerful predictor of clinical response to GCs.
BACKGROUND: Glucocorticoids (GCs) are steroid hormones used to induce remission in moderate-to-severe inflammatory bowel disease (IBD). A substantial fraction of patients do not respond to GC treatment and require alternate therapies or surgery. At present, non-response can only be assessed empirically by observing continued disease activity. METHODS: To identify potential biomarkers of GC response, we retrospectively identified and recruited 18 GC-responsive and 18 GC-nonresponsive IBDpatients. This sample included 14 patients with ulcerative colitis (UC) and 22 patients with Crohn's disease (CD), all previously treated with steroids. In peripheral blood mononuclear cells from each patient, we performed in vitro assays to measure GC inhibition of three different immune stimulants (phytohemagglutinin [PHA], α-CD3/α-CD28, and lipopolysaccharide [LPS]). RESULTS: In both diseases, we found that inhibition of PHA-mediated T cell proliferation was significantly associated with clinical GC response (P=0.04). Inhibition of proliferation due to direct T cell receptor stimulation using α-CD3/α-CD28 was also significantly associated with clinical GC response in UC patients (P=0.009), but not in CDpatients (P=0.78). Interestingly, inhibition of LPS-mediated cytokine secretion showed the strongest association with clinical GC response across both diseases (P=0.005). CONCLUSIONS: We show that inhibition of LPS stimulation is more strongly associated with clinical GC response in IBDpatients than inhibition of PHA and α-CD3/α-CD28-mediated proliferation. These results support an important role of bacterial recognition and innate immunity in the etiology of IBD. This assay could be a powerful predictor of clinical response to GCs.
Authors: Helioswilton Sales-Campos; Patrícia R de Souza; Paulo J Basso; Viviani Nardini; Angelica Silva; Fernanda Banquieri; Vanessa B F Alves; Javier E L Chica; Auro Nomizo; Cristina R B Cardoso Journal: Immunology Date: 2016-10-07 Impact factor: 7.397
Authors: Mark M T J Broekman; Hennie M J Roelofs; Frank Hoentjen; Renske Wiegertjes; Nicole Stoel; Leo A Joosten; Dirk J de Jong; Geert J A Wanten Journal: PLoS One Date: 2015-07-24 Impact factor: 3.240
Authors: Emily L Williams; Madeleine L Stimpson; Peter L Collins; Doyo G Enki; Ashish Sinha; Richard W Lee; Ashwin D Dhanda Journal: Biomark Res Date: 2016-12-15