The studies presented in this thesis investigated the mechanism responsible for glucococorticoid secretion during graft-versus-host disease (GVHD), and the role of endogenous glucocorticoids on the outcome of the disease. GVHD was induced in unirradiated F1 hybrid mice by an intravenous injection of parental lymphoid cells. Our results demonstrated that the secretion of glucocorticoids during GVHD was independent of pituitary adrenocorticotropin hormone (ACTH). However, adrenal hyperactivity was associated with increased expression of proopiomelanocortin (POMC) mRNA in the adrenal glands of GVHD mice. Expression of adrenal POMC transcripts was not due to mononuclear infiltrates. The transcripts for interleukin-12, a cytokine produced by activated macrophages, were also upregulated in GVHD adrenals. Since macrophages have been shown to reside in the adrenal glands and produce ACTH, it appeared that resident adrenal macrophages were activated during GVHD to produce local ACTH that stimulated the secretion of glucocorticoids, independent of pituitary ACTH. / We next investigated the role of endogenous glucocorticoids on the outcome of GVHD by adrenalectomizing the F1 recipient mice before GVHD induction in order to deplete the source of glucocorticoids. Our results showed that adrenalectomized (ADX), but not non-ADX, F1 recipients injected with parental lymphoid cells recovered rapidly from symptoms characteristic of GVHD, after a two week manifestation of the disease. Recovery from GVHD was attributed to the induction of a glucocorticoid sensitive, asialoGM1$ sp+$ and/or CD8$ sp+$, but not NK1.1$ sp+$, F1-anti-parental effector cell that rejected or eliminated the parental graft, after an initial period of engraftment. In addition, the effector was not dependent on a mature thymus and was not renewed after anti-asialoGM1 treatment, but was renewed after glucocorticoid treatment. / We further demonstrated that high levels of glucocorticoids during GVHD caused severe deficiency of host T cell populations in the lymph nodes and contributed to the suppression of lymph nodes T cells. Taken together these studies suggest that endogenous glucocorticoids play a central role in the pathogenesis of GVHD.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.40291 |
| Date | January 1995 |
| Creators | You-ten, Fung Voon Kong Eric |
| Contributors | Lapp, Wayne S. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Physiology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001480836, proquestno: NN12516, Theses scanned by UMI/ProQuest. |
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