In vitro sensitivity assays and clinical response to glucocorticoids in patients with inflammatory bowel disease

J Crohns Colitis. 2014 Nov;8(11):1539-47. doi: 10.1016/j.crohns.2014.06.013. Epub 2014 Jul 19.

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.

Keywords: Crohn's disease;; Cytokines;; Pharmacology;; Precision medicine; Ulcerative colitis;.

MeSH terms

  • Adaptive Immunity
  • Adult
  • Biomarkers
  • CD28 Antigens / metabolism
  • CD3 Complex / pharmacology
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Colitis, Ulcerative / drug therapy*
  • Colitis, Ulcerative / immunology
  • Crohn Disease / drug therapy*
  • Crohn Disease / immunology
  • Drug Resistance
  • Female
  • Glucocorticoids / pharmacology*
  • Humans
  • Immunity, Innate
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / pharmacology
  • Male
  • Middle Aged
  • Phytohemagglutinins / pharmacology
  • Retrospective Studies
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / physiology*
  • Young Adult

Substances

  • Biomarkers
  • CD28 Antigens
  • CD3 Complex
  • Glucocorticoids
  • Interleukin-1beta
  • Interleukin-6
  • Lipopolysaccharides
  • Phytohemagglutinins