Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease

Background and aims

Crohn''s disease is a life‐long form of inflammatory bowel disease (IBD) mediated by mucosal immune abnormalities. Understanding of the pathogenesis is limited because it is based on data from adults with chronic Crohn''s disease. We investigated mucosal T‐cell immunoregulatory events in children with early Crohn''s disease.

Methods

Mucosal biopsies and T‐cell clones were derived from children experiencing the first attack of Crohn''s disease, children with long‐standing Crohn''s disease, infectious colitis, and children without gut inflammation.

Results

As in acute infectious colitis, interleukin (IL) 12 induced T cells from early Crohn''s disease to acquire a strongly polarised T helper (Th) type 1 response characterised by high IFN‐γ production and IL12Rβ2 chain expression. Th1 polarisation was not induced in clones from late Crohn''s disease. Mucosal levels of IL12p40 and IL12Rβ2 messenger RNA were significantly higher in children with early than late Crohn''s disease. These results demonstrate that susceptibility to IL12‐mediated modulation is strongly dependent on the stage of Crohn''s disease.

Conclusions

At the onset of Crohn''s disease mucosal T cells appear to mount a typical Th1 response that resembles an acute infectious process, and is lost with progression to late Crohn''s disease. This suggests that mucosal T‐cell immunoregulation varies with the course of human IBD. Patients with the initial manifestations of IBD may represent an ideal population in which immunomodulation may have optimal therapeutic efficacy.Both forms of inflammatory bowel disease (IBD), Crohn''s disease and ulcerative colitis are life‐long conditions whose initial clinical manifestations appear in the first decades of life. The incidence of IBD is increasing worldwide, and recent epidemiological data show that the diagnosis of IBD is increasingly more frequent in children as the age of onset is decreasing,^1,2 with an equal incidence among all ethnic groups.³ Investigation of IBD has largely relied on studies of adult patients with established disease or animal models of acute IBD,⁴ making it difficult to reconcile data from humans with chronic disease with data from animals with acute disease. Pathogenic events may vary during the course of chronic gut inflammation,⁵ but claims that new‐onset and long‐standing IBD may be different, or that IBD in children is distinct from IBD in adults are so far unsubstantiated.⁶ The investigation of human IBD at the earliest possible time, as in children with the first clinical manifestations of Crohn''s disease, could obviate the many confounding variables associated with chronicity. In this population early mechanisms of gut inflammation could be examined before masking or modification by disease evolution or therapy. In addition, unique immunological reactivities associated with specific types of inflammation may be uncovered, as demonstrated in children with Crohn''s disease.⁷In addition to the type of triggering agents and the intrinsic properties of the affected tissue, the long‐term outcome of an inflammatory response is strongly influenced by the local cytokine milieu. This milieu changes with time, and different mediators are involved in the inductive versus the effector phase of an immune response, which eventually acquires distinctive T helper (Th) type 1, Th2, Th17 or alternative profiles.^8,9 On the basis of this paradigm, evidence indicates that Crohn''s disease is a Th1/Th17‐like condition,^10,11 whereas ulcerative colitis appears to represent an atypical Th2 condition.¹² These conclusions are largely based on T‐cell cytokine profiles from adults with long‐standing disease and numerous animal models of IBD.¹³ There is some evidence that cytokine levels may vary with the evolution of human IBD,⁵ but whether T cells produce quantitatively or qualitatively different cytokine profiles in the early compared with the late stages of IBD is unclear. More importantly, no information is available on cytokines produced by mucosal T cells at the time of disease onset. In addition to the type and quantity of antigen, and how antigen‐presenting cells handle the antigen(s), the outcome of an inflammatory process also depends on the cytokine make‐up at the beginning of such a process. Therefore, it seems essential to define as early as possible in the course of Crohn''s disease the response of mucosal T cells to the immunoregulatory cytokines that condition T helper cell differentiation.¹⁴ This could reveal whether the cytokine profiles found in late Crohn''s disease reflect a fixed response set in motion at the initiation of disease, or represent an evolutionary response to the progression of IBD. This fundamental question cannot be answered using T cells from resected tissues because children with early Crohn''s disease seldom undergo an operation. Therefore, with the caveat that the chosen approach may not be entirely representative of the intestinal immune response because other compartments such as the mesenteric lymph nodes are not sampled, we studied T cells derived from colonoscopic mucosal biopsies from a unique population of children with the very first attack of Crohn''s disease. The production of interleukin (IL) 2, IFN‐γ, IL4, and IL10, as well as IL12 receptor (IL12R) β1 and β2 chain expression were measured in T‐cell clones exposed to the immunomodulatory effects of IL12 and IL4. In addition, total levels of IL12 and IL12Rβ2 chain messenger RNA were measured in the biopsies. The results show that differences in cytokine production and susceptibility to immune modulation occur exclusively in early Crohn''s disease. IL12 conditioning of mucosal T cells from children with early Crohn''s disease induces high levels of IFN‐γ similar to those produced by IL12‐stimulated T cells from children with acute infectious colitis. In contrast, mucosal T cells of children with late Crohn''s disease fail to upregulate IFN‐γ production in response to IL12. In addition, the expression level of the IL12Rβ2 chain is significantly higher in T cells from children with early Crohn''s disease and infectious colitis than children with late IBD, and tissue IL12 and IL12Rβ2 chain mRNA were also higher in early than late Crohn''s disease. Therefore, at the beginning of IBD, mucosal T cells mount a Th1 response that resembles an acute infectious process, and is lost with progression to late disease.