Logo of gutGutView this articleSubmit a manuscriptReceive email alertsContact usBMJ
Gut. Sep 1999; 45(3): 382–388.
PMCID: PMC1727659

Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes

Abstract

BACKGROUND—Up to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown.
AIM—To investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes.
METHODS—Eighteen patients with severe UC were studied. After seven days' treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative effect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (Imax) was measured.
RESULTS—In vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an Imax of less than 60%; all CR patients had an Imax of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no difference between the groups.
CONCLUSIONS—Results suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity.


Keywords: glucocorticoids; lymphocytes; phytohaemagglutinin; predicting outcome; ulcerative colitis

Full Text

The Full Text of this article is available as a PDF (106K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Shanahan F. Pathogenesis of ulcerative colitis. Lancet. 1993 Aug 14;342(8868):407–411. [PubMed]
  • Elson CO. The basis of current and future therapy for inflammatory bowel disease. Am J Med. 1996 Jun;100(6):656–662. [PubMed]
  • Carpani de Kaski M, Hodgson HJ. Rolling review: inflammatory bowel disease. Aliment Pharmacol Ther. 1993 Oct;7(5):567–579. [PubMed]
  • Truelove SC, Willoughby CP, Lee EG, Kettlewell MG. Further experience in the treatment of severe attacks of ulcerative colitis. Lancet. 1978 Nov 18;2(8099):1086–1088. [PubMed]
  • Chakravarty BJ. Predictors and the rate of medical treatment failure in ulcerative colitis. Am J Gastroenterol. 1993 Jun;88(6):852–855. [PubMed]
  • Travis SP, Farrant JM, Ricketts C, Nolan DJ, Mortensen NM, Kettlewell MG, Jewell DP. Predicting outcome in severe ulcerative colitis. Gut. 1996 Jun;38(6):905–910. [PMC free article] [PubMed]
  • Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994 Jun 30;330(26):1841–1845. [PubMed]
  • Griffin MG, Miner PB. Review article: refractory distal colitis -- explanations and options. Aliment Pharmacol Ther. 1996 Feb;10(1):39–48. [PubMed]
  • Schreiber S, MacDermott RP, Raedler A, Pinnau R, Bertovich MJ, Nash GS. Increased activation of isolated intestinal lamina propria mononuclear cells in inflammatory bowel disease. Gastroenterology. 1991 Oct;101(4):1020–1030. [PubMed]
  • Walker KB, Potter JM, House AK. Interleukin 2 synthesis in the presence of steroids: a model of steroid resistance. Clin Exp Immunol. 1987 Apr;68(1):162–167. [PMC free article] [PubMed]
  • Carmichael J, Paterson IC, Diaz P, Crompton GK, Kay AB, Grant IW. Corticosteroid resistance in chronic asthma. Br Med J (Clin Res Ed) 1981 May 2;282(6274):1419–1422. [PMC free article] [PubMed]
  • Corrigan CJ, Brown PH, Barnes NC, Szefler SJ, Tsai JJ, Frew AJ, Kay AB. Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro. Am Rev Respir Dis. 1991 Nov;144(5):1016–1025. [PubMed]
  • Alvarez J, Surs W, Leung DY, Iklé D, Gelfand EW, Szefler SJ. Steroid-resistant asthma: immunologic and pharmacologic features. J Allergy Clin Immunol. 1992 Mar;89(3):714–721. [PubMed]
  • Kirkham BW, Corkill MM, Davison SC, Panayi GS. Response to glucocorticoid treatment in rheumatoid arthritis: in vitro cell mediated immune assay predicts in vivo responses. J Rheumatol. 1991 Jun;18(6):821–825. [PubMed]
  • Langhoff E, Ladefoged J, Jakobsen BK, Platz P, Ryder LP, Svejgaard A, Thaysen JH. Recipient lymphocyte sensitivity to methylprednisolone affects cadaver kidney graft survival. Lancet. 1986 Jun 7;1(8493):1296–1297. [PubMed]
  • TRUELOVE SC, WITTS LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J. 1955 Oct 29;2(4947):1041–1048. [PMC free article] [PubMed]
  • Forbes A. Frequency and significance of proximal extension of distal ulcerative colitis. Eur J Gastroenterol Hepatol. 1996 Jun;8(6):543–544. [PubMed]
  • Frey BM, Frey FJ. Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharmacokinet. 1990 Aug;19(2):126–146. [PubMed]
  • Beato M. Gene regulation by steroid hormones. Cell. 1989 Feb 10;56(3):335–344. [PubMed]
  • Schüle R, Rangarajan P, Kliewer S, Ransone LJ, Bolado J, Yang N, Verma IM, Evans RM. Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell. 1990 Sep 21;62(6):1217–1226. [PubMed]
  • Paliogianni F, Raptis A, Ahuja SS, Najjar SM, Boumpas DT. Negative transcriptional regulation of human interleukin 2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT. J Clin Invest. 1993 Apr;91(4):1481–1489. [PMC free article] [PubMed]
  • Iida S, Gomi M, Moriwaki K, Itoh Y, Hirobe K, Matsuzawa Y, Katagiri S, Yonezawa T, Tarui S. Primary cortisol resistance accompanied by a reduction in glucocorticoid receptors in two members of the same family. J Clin Endocrinol Metab. 1985 May;60(5):967–971. [PubMed]
  • Kam JC, Szefler SJ, Surs W, Sher ER, Leung DY. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol. 1993 Oct 1;151(7):3460–3466. [PubMed]
  • Adcock IM, Lane SJ, Brown CR, Lee TH, Barnes PJ. Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. J Exp Med. 1995 Dec 1;182(6):1951–1958. [PMC free article] [PubMed]

Figures and Tables

Figure 1
Inhibition of phytohaemagglutinin stimulated T lymphocyte proliferation by dexamethasone for the different clinical response groups; error bars represent SEM. Thymidine counts (mean (SD)): complete responders 54 611 (28 620) cpm; patients ...
Figure 2
In vitro T lymphocyte steroid sensitivity on admission compared with clinical outcome in severe ulcerative colitis.    
Figure 3
In vitro T lymphocyte steroid sensitivity at three months' follow up compared with initial clinical outcome in severe ulcerative colitis.    
Figure 4
Definition of Imax and IC50 in steroid sensitive and resistant subjects compared with previously used method of calculating IC50. In steroid sensitive individuals IC50 is similar using both methods; however, when the individual is steroid resistant there ...

Articles from Gut are provided here courtesy of BMJ Group

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...