Immune-Mediated Cytotoxicity in Inflammatory Bowel Disease

Thirty years of research on the role of immune-mediated cytotoxicactivity in the tissue injury of inflammatory bowel disease (IBD) has yielded onlyinconclusive data on the relevance of cytotoxic mechanisms. Two hypotheseshave been advanced. One is that the destruction of target cells is mediated bydirect recognition of target antigens by cytotoxic cells which in turn triggers lysis.Another hypothesis is that lysis occurs via an indirect bystander mechanism inwhich cells do not recognize a specific antigen on the target, but upon nonspecificactivation release cytokines which are capable of lysing the target. The authorshave investigated both hypotheses and studied the role of cytotoxic T cells andcytotoxic rectors released from activated T cells in the destruction of epithelialcells. Elevated levels of cytotoxic T cells were found in peripheral blood lymphocytesof patients with IBD, particularly Crohn's disease. The cytotoxic T cellswere contained within the Leu 7+, CD8+ T cell subset and were detected usinganti-CD3-triggered lysis. Increased cytotoxic T cell activity was also presentwithin inflamed mucosa of patients with both Crohn's disease and ulcerativecolitis. The specific targets of this activity have yet to be determined. Activationof mucosal T cells by antibodies to the T cell receptor (anti-CD3) in organ cultureof normal fetal jejunum induces an enteropathy characterized by villous atrophyand crypt cell hyperplasia. This same change is seen near aphthous ulcers inpatients with Crohn's disease. Soluble cytokines produced by T cells might beresponsible for the mucosa! damage observed in these two models of mucosalinjury. The goal of this study was to establish in vitro if cytotoxic cytokines canbe released by triggering isolated colonic T cells, and what cytokine interactionsare required for killing of colonic epithelial cells. These results demonstrate thathuman lamina propria lymphocyte T cells, triggered by addition of anti-CD3 andtarget cells, produce tumour necrosis factor-alpha and interferon-gamma, both ofwhich are required for optimal killing of HT-29. Simultaneous release of thesecytokines in the vicinity of epithelial cells during immune responses could playan important role in mucosal damage in IBD. The development of animal modelsand long term cultures of epithelial cells will allow many advances in research ofthe role of immune-mediated cytotoxicity in IBD