Experimental studies of immunologically mediated enteropathy. Development of cell mediated immunity and intestinal pathology during a graft-versus-host reaction in irradiated mice.

Abstract

SUMMARYThe intestinal component of a graft-versus-host reaction (GvHR) provides a useful experimental model to elucidate the pathogenesis of clinical enteropathies which cause villus atrophy and crypt hyperplasia and which are associated with a local immune response. One to three days after induction of GvHR in heavily irradiated (CBAxBALB/c)F, mice, a proliferative form of enteropathy developed. Compared with controls, these mice had increased counts of jejunal intraepithelial lymphocytes and had a four-fold increase in crypt cell production rate as well as an increase in crypt length. These changes were accompanied by a marked enhancement of splenic natural killer cell activity. After day three, the crypt cell production rate fell to zero and cytotoxic T lymphocytes (CTL) which could lyse targets of host origin appeared. In parallel, mice with GvHR developed significant villus shortening and their clinical condition deteriorated. Further experiments showed that increased counts of intraepithelial lymphocytes, villus atrophy and crypt hyperplasia also occurred in grafts of fetal CBA intestine implanted under the kidney capsule of (CBAxBALB/c)Fl mice with GvHR. As these grafts are syngeneic to the injected CBA spleen cells, they should not be attacked by anti-host cytotoxic T lymphocytes. We suggest that the proliferative and destructive components of enteropathy in GvHR are caused by lymphokines released by an antihost delayed type hypersensitivity reaction.

Host intestinal intraepithelial γδ T lymphocytes present during acute graft‐versus‐host disease in mice may contribute to the development of enteropathy

“…Therefore, to compare the numbers of i-IEL between mice given anti-TcR y6 mAb or control mAb during acute GVHD, the number of 1-IEL per 100 epithelial cells was counted under the light microscope. Consistent with our previous report, the 1-IEL counts temporarily increased on day 9, and thereafter declined remarkably on day 12 following acute GVHD induction in control mice. On the other hand, a significant increase of 1-IEL was not evident on day 9 and only a marginal decrease was detected in the mice given anti-TcR y6 mAb (Fig.…”

“…Unusual target organs such as the skin and intestine are first affected during acute graft-versus-host disease (GVHD), which is initiated by donor-derived mature T cells recognizing alloantigens on host cells [9] .The fact that TcR y6 T cells are relatively abundant in the epithelia of the epidermis and the intestine raises the possibility that unique IEL partici-pate in the pathogenesis of epithelial lesions during acute GVHD. To verify this, we examined the kinetics of TcR y6 i-IEL during the course of acute GVHD caused in inbred F1 mice by injecting them with T cells of parental origin.…”

Specific Circulating Anti-Gliadin IgG-Class Antibody Does Not Mediate Intestinal Enteropathy in Gliadin-Fed Mice

“…This could be a reflection of sparse immune complex deposition in the intestinal mucosa, as suggested by our radiotracer experiments. In other ex perimental animal models, enteropathies similar to those seen in coeliac disease have been observed after the in duction of graft-versus-host disease [25]. It is therefore possible that an immune-mediated enteropathy also re quires a cell-mediated component and cannot be induced by circulating antibody alone.…”

“…Taken together, the available data suggest that im mune-mediated intestinal damage involves an autoim mune element, either due to circulating antibodies to tis sue components [21][22][23][24], or due to cell-mediated immunity against self-antigens [25], or possibly both. This would imply that elevated anti-gliadin antibody titres in patients with coeliac disease may be a contributory factor, but alone arc unlikely to mediate the intestinal lesion.…”

The Immune System and Mucosal Transformation – Historical Perspective

“…In immu nocompetent animals not previously irra diated this has been generally the most severe enteropathy produced by GvHR. However, in allograft rejection and in some immunodeficient animals, a destructive lesion with vil lus flattening in addition to crypt hyperplasia and IEL infiltrate occurs and Mowat et al [1988] report crypt hypoplasia early in the course of GvHR in irradiated mice. In a recent experiment we have found that a com plete spectrum of histopathological changes develop in adult BDFi mice studied at inter vals up to five weeks after induction of GvHR [Watret and Ferguson, unpublished].…”