Enteropathy

In passive immunotherapy immune globulin (Ig) is an effective replacement in most forms of antibody deficiency (14). In the past, plasma was used instead of immune globulin, but plasma is rarely indicated in the 1990s because of the risk of disease, particularly AIDS, transmission. Because plasma contains many factors in addition to immunoglobulins (Igs), plasma is, however, of particular value in patients with protein-losing enteropathy, complement deficiencies, and refractory diarrhea. 

Functional bowel problems (e.g., Hirschsprung s disease, neuronal intestinal dysplasia, pseudo-obstruction, proteinlosing enteropathy, microvillous inclusion disease)... 

Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic gamma-delta T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/sezary syndrome... 

Garside, P., Grencis, R.K and Mcl Mowat, A.M. (1992) T lymphocyte dependent enteropathy in murine Trichinella spiralis infection. Parasite Immunology 14, 217-225. 

In those infections that are associated with enteropathy (exemplified by T. spiralis), no experimental manipulation has, until recently, been able to separate enteropathy and immune expulsion - if one is abrogated, so is the other. This chapter illustrates how the two processes can be separated, and discusses implications of this for understanding immune expulsion of gut nematodes and the prospects for anti-nematode vaccines that cause no ill effects at either the initial induction of immunity or the expression of protective responses. The definition of that which consitututes enteropathy may vary between authors, but we take as our primary definition the most destructive and quantifiable changes in intestinal tissue that are associated with expulsion, villus atrophy and crypt hyperplasia. 

Whilst the expulsion of intestinal nematodes is absolutely Th2-mediated (Chapter 17 and below), the associated enteropathy is indistinguishable from that previously attributed to Thl-like responses. The solution to this paradox, which is addressed below, may therefore reside in the recognition of common mediators of tissue destruction, remodelling and repair, induced by both Thl and Th2 cytokine-dependent processes. 

Immune expulsion of T. spiralis is clearly Th2- and, specifically, IL-4-dependent. However, contrary to expectations, enteropathy (as assessed by changes in villus/crypt ratios) is regulated by IL-4 and not IFN-y (Lawrence et al., 1998). Moreover, the usual severe pathology is not induced in p55 TNF receptor (TNF-R1) gene-deficient mice, which nevertheless expelled... 

In contrast with other enteropathies, there is no evidence that IFN-y plays an important role in either protection or pathology in T. spiralis infections. Infections in mice treated with anti-IFN-y antibody or in IFN-yR-deficient mice (Rose et al., 1994 Lawrence et al., 1998) were comparable in time course and pathology to those in controls. However, crypt hyperplasia was reduced following immunodepletion of IFN-y in SCID mice infected... 

Upon activation, mast cells release numerous mediators, including vasoactive amines, proteases, pro-inflammatory cytokines (e.g. IL-ip, IL-6, IL-18 and TNF-a) and also regulatory Th2 cytokines (e.g. IL-4, IL-10 and IL-13) (Burd et al., 1989 Gordon and Galli, 1990 Marietta el al., 1996 Toru et al., 1998 Aoki et al., 1999 Lorentz et al, 2000). Therefore, the mastocytosis in the infected mucosa represents an immunopathological rather than a protective response. Indeed, our studies have shown that expulsion of T. spiralis from TNF-Rl / or iNOS / mice was achieved in the absence of a substantial mastocytosis and subsequent amelioration of enteropathy (Lawrence etal., 1998, 2000). 

Whilst eosinophils appear unimportant in the induction of protective responses to GI helminths, they are present in large numbers in the inflamed gut and it has therefore been suggested that they play a part in the induction of enteropathy. Moreover, eosinophils have been implicated in the induction of intestinal inflammation eosinophilic gastroenteritis, ulcerative colitis and Crohn s disease. However, IL-5-deficient mice, or GM-CSF transgenic mice (which typically have a blood eosinophilia of approximately 25%) infected with T. spiralis did not show a significant exacerbation or amelioration of either protective or pathological responses (C.E. Lawrence, unpublished observation). 

Although it appears that severe IL-4-regulated enteropathy is not required for immune expulsion of T. spiralis, it is still possible that Th2 cytokines can act in a direct fashion to create an environment unfavourable for intestinal parasites. It remains to be shown directly whether these effects are sufficient to expel parasites. Indeed, there is considerable evidence to support a variety of pathophysiological effects of IL-4 and/or TNF on the gut. These effects may be mediated by factors including cytokines and mast-cell products (e.g. leukotrienes and 5-hydroxytryptamine). 7. spiralis infections result in increased fluid and mucus secretion into the lumen as well as increased intestinal propulsive activity and more rapid intestinal transit (Castro et al, 1979 Russell, 1986 Vermillion and Collins, 1988 Vermillion et al., 1991 Weisbrodt et al, 1994 Barbara et al, 1997). The increased contractility of radial and longitudinal muscle is greater in high-... 

IL-4 KO mice and wild-type controls were infected with 400 T. spiralis. One group of each was treated with 1 x 10s U rTNF-oc i.p. on days 4 and 7 p.i. Adult worm burdens and enteropathy were assessed at days 6 and 13. Muscle worm burdens were assessed at day 30 p.i. and expressed as mean + SEM. 

Garside, P., Bunce, C., Tomlinson, R.C., Nichols, B.L. and Mowat, A.M. (1993) Analysis of enteropathy induced by tumour necrosis factor alpha. Cytokine 5, 24-30. 

Guy-Grand, D., DiSanto,J.P., Henchoz, P., Malassis-Seris, M. and Vassalli, P. (1998) Small bowel enteropathy role of intraepithelial lymphocytes and of cytokines (IL-12, IFN-gamma, TNF) in the induction of epithelial cell death and renewal. European Journal of Immunology 28, 730-744. 

MacDonald, T.T. and Spencer, J. (1988) Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine./oMrrcaZ of Experimental Medicine 167, 1341-1349. 

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