| Summary: | Thirty years of research on the role of immune-mediated cytotoxic
activity in the tissue injury of inflammatory bowel disease (IBD) has yielded only
inconclusive data on the relevance of cytotoxic mechanisms. Two hypotheses
have been advanced. One is that the destruction of target cells is mediated by
direct recognition of target antigens by cytotoxic cells which in turn triggers lysis.
Another hypothesis is that lysis occurs via an indirect bystander mechanism in
which cells do not recognize a specific antigen on the target, but upon nonspecific
activation release cytokines which are capable of lysing the target. The authors
have investigated both hypotheses and studied the role of cytotoxic T cells and
cytotoxic rectors released from activated T cells in the destruction of epithelial
cells. Elevated levels of cytotoxic T cells were found in peripheral blood lymphocytes
of patients with IBD, particularly Crohn's disease. The cytotoxic T cells
were contained within the Leu 7+, CD8+ T cell subset and were detected using
anti-CD3-triggered lysis. Increased cytotoxic T cell activity was also present
within inflamed mucosa of patients with both Crohn's disease and ulcerative
colitis. The specific targets of this activity have yet to be determined. Activation
of mucosal T cells by antibodies to the T cell receptor (anti-CD3) in organ culture
of normal fetal jejunum induces an enteropathy characterized by villous atrophy
and crypt cell hyperplasia. This same change is seen near aphthous ulcers in
patients with Crohn's disease. Soluble cytokines produced by T cells might be
responsible for the mucosa! damage observed in these two models of mucosal
injury. The goal of this study was to establish in vitro if cytotoxic cytokines can
be released by triggering isolated colonic T cells, and what cytokine interactions
are required for killing of colonic epithelial cells. These results demonstrate that
human lamina propria lymphocyte T cells, triggered by addition of anti-CD3 and
target cells, produce tumour necrosis factor-alpha and interferon-gamma, both of
which are required for optimal killing of HT-29. Simultaneous release of these
cytokines in the vicinity of epithelial cells during immune responses could play
an important role in mucosal damage in IBD. The development of animal models
and long term cultures of epithelial cells will allow many advances in research of
the role of immune-mediated cytotoxicity in IBD.
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