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

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.

LPS-Stimulated Whole Blood Cytokine Production Is Not Related to Disease Behavior in Patients with Quiescent Crohn's Disease

“…Techniques of measuring cytokine production in peripheral blood have been well established. However, apart from studies comparing cytokine levels of healthy persons with patients with CD, the application of these techniques to explore a relation with disease characteristics in CD is limited to a few recent studies [ 20 , 21 , 44 ]. An alternative strategy to categorize patients as high- or low producers is to look at SNPs involved in cytokine regulation.…”

“…Recent studies with peripheral blood exploring cytokine production of stimulated white blood cells also showed an association with disease phenotype [ 20 , 21 ]. These data suggest that individual cytokine production from peripheral blood might be used as biomarker to stratify patients according to the disease course [ 1 ].…”

Amelioration of experimental colitis after short‐term therapy with glucocorticoid and its relationship to the induction of different regulatory markers

“…The effect of glucocorticoids (GC) on the immune system was first described in 1924 when a relationship between adrenalectomy and thymus hyperplasia was portrayed in rats . Since then, GC have become one of the most frequently prescribed drugs to treat patients with inflammatory disorders such as asthma, rheumatoid arthritis or inflammatory bowel disease (IBD) . Among these immune disturbances, those related to the gastrointestinal tract, such as Crohn's disease and ulcerative colitis, are of special interest because they affect millions of people around the world and are responsible for various physical, nutritional and immunological disabilities.…”

Combining Genetic and Nongenetic Biomarkers to Realize the Promise of Pharmacogenomics for Inflammatory Diseases

“…Multiple such studies have used phytohemagglutinin or direct T-cell receptor agonists to stimulate T-cell proliferation in the presence and absence of glucocorticoids. The relative inhibition of proliferation has been shown to be correlated with clinical response in patients with severe UC [46-48], Crohn’s disease [48], rheumatoid arthritis [49], asthma [50], and organ transplant rejection [51]. This approach is not limited to glucocorticoids.…”