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Although relatively little is known about the cellular and molecular immunopathology of ulcerative colitis, most would agree that it is an inflammatory disease. There is some support for the hypothesis that this inflammatory process is, at least in part, driven by T cells and their cytokine products. For example, anti-CD4 T cell monoclonal antibodies have been shown to abrogate disease in an animal “model” of colitis1. Anecdotally, monoclonal antibody against tumour necrosis factor α (derived in part from T cells) is effective therapy for ulcerative colitis.2 Finally, the fact that the powerful T cell suppressant cyclosporin A is effective in the treatment of acute severe colitis3 also suggests possible T cell involvement, although it should be borne in mind that cyclosporin A also has inhibitory effects on other inflammatory cells, including monocytes, basophils, and mast cells.
If this hypothesis were correct, one might expect that glucocorticoids, which are very potent inhibitors of T cell activation and cytokine secretion, would be an effective treatment for ulcerative colitis. Yet glucocorticoid therapy for acute exacerbations of ulcerative colitis frequently fails. A recent retrospective study4 of 97 patients with severe ulcerative colitis showed that, despite systemic glucocorticoid therapy, 34% required colectomy within 30 days of presentation. If, then, the “T cell hypothesis” of ulcerative colitis pathogenesis is not to be discarded completely, alternative explanations must be sought for this heterogeneity of clinical response.
One possibility is that severe ulcerative colitis is itself heterogeneous in terms of its pathology. The study cited above4 suggested that patients failing to respond to glucocorticoid therapy were more likely to have fever, persistent diarrhoea, rectal bleeding, and elevated serum concentrations of C-reactive protein at three days after admission than those who did respond. Another study5 has suggested that patients with ulcerative colitis refractory to glucocorticoid therapy have a higher incidence of perinuclear staining anti-neutrophil cytoplasmic antibody than glucocorticoid sensitive patients and normal controls. Although the significance, if any, of these clinical phenomena is presently unknown, they suggest the possibility of heterogeneity in the pathogenesis of severe ulcerative colitis, which might in turn influence the clinical response to glucocorticoid therapy.
A second possibility, tackled in this issue by Hearinget al (see page 382), is that glucocorticoid refractory acute severe ulcerative colitis arises in patients whose T cells are relatively resistant to glucocorticoid inhibition. In this study, the authors classified 18 patients with acute severe ulcerative colitis according to their clinical response (at seven days after admission) to a standardised course of intravenous glucocorticoid therapy at high dosage as complete responders (three or fewer stools daily with no visible blood), partial responders (four or more stools daily or visible blood with no indication for colectomy), or treatment failures (colectomy indicated). Concentration response curves were constructed for the antiproliferative effect of glucocorticoids on lectin stimulated peripheral blood T cells from these patients obtained within 48 hours of admission. Proliferation of peripheral blood T cells from five of the seven patients classified as partial responders or treatment failures was inhibited by less than 60% even at supra-physiological glucocorticoid concentrations. In contrast, proliferation of T cells from all 11 of the complete responders was inhibited by at least 60% at glucocorticoid concentrations that might be expected to be achieved in the peripheral blood in the course of intravenous glucocorticoid therapy at high dosage. When measured again three months later when the patients were in remission (some as a result of colectomy), these differences between the groups were no longer apparent, reflecting an increase in glucocorticoid sensitivity of T cells from the partial responder and treatment failure patients.
Similar correlations between T cell sensitivity to glucocorticoid inhibition and the clinical response to glucocorticoid therapy have been reported in other inflammatory diseases such as asthma (reviewed in6), rheumatoid arthritis and allograft rejection (cited by Hearing et al). These observations support a role for activated T cells in the pathogenesis of these diseases and also emphasise that, in a subset of patients with these diseases and likely others, glucocorticoid therapy is not viable because systemic glucocorticoid concentrations achieved even at high dosage are insufficient to inhibit T cell function significantly and, by inference, disease progression.
The mechanism of this phenomenon has been best studied in glucocorticoid resistant asthmatics, whose disease fails to respond to glucocorticoid therapy at high dosage despite the fact that their airways obstruction is clearly reversible in response to inhaled β2-agonists. These patients show no abnormalities of glucocorticoid absorption and clearance, and no innate abnormalities of the hypothalamus/pituitary/adrenal axis.6 Furthermore, they are not immune to developing the unwanted Cushingoid effects of glucocorticoid therapy. These observations suggest that the phenomenon of glucocorticoid resistance in these patients is not generalised, as in some rare cases of primary cortisol resistance, but somehow compartmentalised to T cells and possibly other inflammatory cells. It has been suggested that relative glucocorticoid resistance may be induced in T cells by the local inflammatory environment, as exposure of T cells to inflammatory cytokines in vitro reversibly increases their resistance to glucocorticoid inhibition, possibly at least partly by reducing the binding affinity of their intracellular glucocorticoid receptors for ligand.6 7 This is not, however, an entirely satisfactory explanation as most patients with severe asthma do respond to glucocorticoid therapy, despite the fact that, presumably, their T cells are in a similar inflammatory environment to those who do not. Similarly, in the present study on ulcerative colitis, although the numbers of patients were small, disease severity at presentation did not predict the subsequent response to glucocorticoid therapy. Another proposed mechanism for glucocorticoid resistance in T cells is inappropriate, elevated expression of other secondary messenger proteins such as the transcriptional activator protein AP-1 which can bind to, and inactivate the glucocorticoid receptor/ligand complex.8 Finally, these phenomena may be superimposed on a background of variable, innate T cell glucocorticoid responsiveness which is known to be highly variable even in normal people.9
The phenomenon of glucocorticoid resistance deserves further exploration in a wider variety of diseases, as its early recognition may save patients unnecessary and futile exposure to glucocorticoid therapy and its unwanted effects. Early assessment of possible glucocorticoid resistance may also facilitate management decisions in diseases such as acute, severe ulcerative colitis. Proliferation assays such as that described in the study by Hearing et al are relatively cheap and may be completed within 48 hours. Further studies are necessary better to define the repeatability and predictive value of these assays in larger groups of patients.
See article on page 382
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