Immunological Mechanisms of Intestinal Graft-Versus-Host Reactions

Felstein, Michelle Victoria (1988) Immunological Mechanisms of Intestinal Graft-Versus-Host Reactions. PhD thesis, University of Glasgow.

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Abstract

The work in this thesis developed three separate models of acute graft-versus-host reaction in irradiated adult and one day old neonatal (CBA x BALB/c)F1 mice and (C57B1/10 x DBA/2)F1 mice given C57B1/10 cells. All these models were associated with weight loss and mortality as well as an enteropathy characterised by villus atrophy. Furthermore, these different hosts consistently developed a very similar biphasic pattern of systemic and intestinal Gvhr. An initial proliferative phase was characterised by the development of splenomegaly which coincided with an increase in intraepithelial lymphocytes and crypt cell production rate, in the small intestine, as well as a transient increase in splenic NK cell activity. These early changes were similar to those described previously in unirradiated, adult (CBA x BALB/c)F1 mice with Gvhr, but mice with acute Gvhr subsequently developed weight loss and villus atrophy, which were accompanied by specific CTL activity, features not observed in previous work on unirradiated (CBA x BALB/c)F1 hosts. The evolution of acute Gvhr was shown most clearly in irradiated (CBA x BALB/c)F1 hosts where the proliferative disease rapidly transformed into a lethal disorder with severe villus atrophy and ultimately mucosal necrosis. This was also accompanied by a reduction in the CCPR and the number of IEL. The systemic and intestinal consequences of a Gvhr in neonatal (CBA x BALB/c)F1 mice depended upon the age of the host, with one day old hosts developing an acute Gvhr, whereas seven day old animals merely showed a proliferative disorder with no weight loss, CTL activity or villus atrophy. Five day old mice were intermediate hosts, where some animals developed a lethal Gvhr while others developed a proliferative form of the disease. However even in those mice which developed villus atrophy, no evidence of specific CTL was found. These differences were not influenced by the number of donor cells used but it was found that spleen cells from one day old mice were defective at inducing allospecific delayed-type hypersensitivity and no anti-host DTH response developed during a Gvhr in one day old mice. Furthermore, one day old mice appeared to have a T-cell defect as shown by an inability of their lymphoid cells to induce a local Gvhr. In contrast to these findings spleen cells from 7 day old mice induced similar levels of allospecific DTH and developed an anti-host DTH response during Gvhr which was similar to that found in adult mice of the same strain. An acute destructive Gvhr also occurred in adult (C57B1/10 x DBA/2)F1 mice given B10 spleen cells, whereas BDF1 mice given DBA/2 cells had very little evidence of systemic or intestinal Gvhr, apart from some splenomegaly. In parallel, specific CTL were only found in hosts given B10 spleen cells and these mice also had evidence of active immunosuppression. The more potent ability of B10 donor cells to induce Gvhr was consistent with the observation that B10 cells responded better in vitro to both adult and neonatal BDF1 stimulators. Both B10 and DBA/2 donor cells could induce an acute Gvhr in one day old BDF1 mice, while 5 day old hosts showed a similar pattern to adult mice. These results suggest that DBA/2 cells are merely defective at inducing Gvhr and do not induce a qualitatively different disorder. Villus atrophy was also found in a fourth model of Gvhr which occurred in adult athymic (CBA x BALB/c)F1 mice given CBA donor cells. Compared with euthymic hosts of the same strain these mice developed more intense splenomegaly and crypt hyperplasia while only athymic hosts had villus atrophy, CTL activity and reduced NK activity. These findings suggested that one reason for the more severe Gvhr found in irradiated and neonatal (CBA x BALB/c)F1 mice was an absence of host T-cells which normally regulate the severity of the Gvhr in intact hosts. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Immunology
Date of Award: 1988
Depositing User: Enlighten Team
Unique ID: glathesis:1988-77659
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 11:53
Last Modified: 14 Jan 2020 11:53
URI: http://theses.gla.ac.uk/id/eprint/77659

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