Gut immunity and inflammatory bowel disease

As discussed in other chapters of this book dealing with treatment of pediatric IBD, it is obvious that all recent advances in the field of novel therapeutic approaches, notably biological therapies, are directly derived from knowledge harnessed by studies of mucosal immunity in the normal and inflamed intestine [82]. In spite of these striking advances, some aspects of gut immunity remain unclear. Perhaps the most critical one is how the mucosal immune system interacts with the endogenous commensal flora under physiological and pathological conditions, a fundamental issue considering the widely accepted notion that IBD is an abnormal immune response to the autologous enteric bacteria in genetically susceptible individuals [83]. The problem in understanding the mutual relationship between the gut and its luminal flora resides more in the latter than the former. In fact, the immune cells and the molecular tools the gut uses to communicate with intestinal microorganisms are reasonably understood, but far less knowledge exists on the composition and the function of the commensal flora. This is due in part to the limited attention paid to classical enteric microbiology for several decades, but in even greater part to the unrecognized complexity of the gut flora and the practical observation that most of it cannot be identified by traditional culture techniques. New perceptions of the gut microbiota are needed as well as new tools to dissect and classify it, and some of these are being now implemented, such as fluorescence in situ hybridization (FISH), terminal restriction length polymorphism (T-RFLP), polymerase chain reaction combined with denaturing gradient or temperature gradient gel electrophoresis (PCR/DGGE and PCR/TGEE), and 16S rRNA gene libraries [84]. These new methodologies do not necessarily allow the isolation of the actual microbes, but provide a far more detailed molecular classification of the hundreds of bacterial strains that populate the gut, and permit to get closer to the identification of bacteria against which the gut mucosal immune system reacts and induces inflammation. Another critical aspect of gut immunity is the nature of the mucosal immune response mediating inflammation during the course of a chronic disease, as typically found in IBD. It is plausible, if not probable, that long lasting intestinal inflammatory processes like Crohn disease and ulcerative colitis undergo substantial changes of the underlying biological response regardless of the initial triggering events. This point is fundamentally important for pediatric IBD, when the disease is at its earliest possible stages of detection and there is perhaps an opportunity to change the natural history of the disease, a far more difficult goal to attain in adult IBD patients with a long clinical history. Studying early events of IBD pathogenesis and follow them up during disease evolution into chronicity is obviously difficult in humans and more so in children, but this can be accomplished in animal models, which are starting to generate concrete evidence of substantial changes in the gut immune response from the early to the chronic stages of inflammation. Switches from a Th1 to a Th2 pattern occur in at least two models of experimental IBD. In the colitis of IL-10-deficient mice and the ileitis of SAMP1/YitFc mice, both of which are Th1-mediated initially, there is a marked increase in disease-mediating Th2 cytokines in late disease, e.g., IL-4 and IL-13 in the colitis model, and IL-5 and IL-13 in the ileitis model [85, 86]. The lesson here is that, even though the clinical manifestations of IBD remain constant, the underlying pathogenic immunopathology changes rather dramatically over time. Therefore, immunomodulators that are effective in early disease may no longer be effective in chronic disease, as again exemplified by the above animal models where blockade of Th1 cytokines is therapeutically effective in early but not late inflammation, a period when blockade of Th2 cytokines ameliorates disease. When these observations and concepts are translated into the human situation it is reasonable to assume that different immunomodulatory approaches should be used at different stages of IBD. Preliminary evidence for the existence of a differential susceptibility to immune modulation in children with IBD comes from both clinical and in vitro studies. Children with early onset Crohn disease have a significantly longer remission in response to TNF-blockade than children with late disease [87], and the cytokine secretory pattern of mucosal T cell clones derived from children with IBD can be modulated only in patients with early but not late disease (Kugathasan et al., submitted). In summary, investigation of gut immunity in IBD has been and still is extremely rewarding, as it has provided not only new information on the biology of its components and overall function, but also practical new ways to exploit this new information for current and future therapeutic applications.