<p> Helminth parasite infection induces a strong immune response in the host aimed at destroying the parasite and reducing any associated inflammation. In humans and rodents, this response is dominated by the Th2 cytokines and involves the activation of mast cells, B cells and eosinophils, as well as increased production of lgE. There is evidence from both murine and human studies that the helminth-induced anti-inflammatory response is also capable of protecting the host from co-existing autoimmune disease, including asthma, allergies and colitis. My hypothesis is that infection with the parasitic helminth H. diminuta can treat and/or prevent the symptoms of Th1-dominated inflammation. This anti-colitic effect is dependent on IL-10 and involves the recruitment of the alternatively activated macrophages.</p> <p> Using the dinitrobenzene sulfonic acid (DNBS) model of colitis, I examined the ability of the rat tapeworm, Hymenolepis diminuta, to reduce inflammation in a non-permissive mouse host. H. diminuta was chosen as the ideal candidate for treating intestinal disease because it is non-invasive, does not have hooks or teeth which can damage the host, and can be easily maintained in the laboratory and controlled during experimental infection. Mice that received DNBS alone developed colitis within 72 hours. Mice that had been previously infected with five H. diminuta larvae were significantly protected from the colitis, as measured by reduced clinical disease and histological damage scores as well as reduced levels of myeloperoxidase (MPO) from colonic tissue samples. It was also determined that the anticolitic effect was dependent on a viable parasite infection. Infection with H. diminuta induced an increase in colonic IL-10 mRNA and IL-10 secretion by stimulated splenocytes - when IL-10 was blocked by administration of an anti-IL-10 antibody, the anticolitic effect of H. diminuta infection was reduced. H. diminuta infection also induced increased expression of the alternatively activated macrophage (AAM) markers arginase 1 and FIZZ1. Treatment with in vitro-derived AAMs reduced the symptoms of DNBS-colitis.</p> <p> The effect of H. diminuta infection on oxazolone colitis, a chemically induced colitis characterized by increases in IL-4 and IL-13, was also examined. Infection with H. diminuta induced a significant increase in inflammation and inhibited recovery from oxazolone-colitis. Increases in IL-5 and eosinophils were also observed. Further examination revealed that increased IL-5, induced by administration of an adenovirus carrying the IL-5 gene, had a deleterious impact on the oxazolone colitis, exacerbating inflammation and increasing eosinophilia.</p> <p> While the idea of helminth therapy may be unappealing, there is increasing interest in the use of helminth parasites for the treatment of inflammatory disease. There is some concern, however, that the Th2 response induced by H. diminuta infection could exacerbate some disorders involving increases in the Th2 cytokines. Thus, while this therapy may be beneficial for most, careful characterization of the immunological basis of any pre-existing disorders would be necessary in order to avoid any harmful side-effects.</p> / Thesis / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/17322 |
| Date | 06 1900 |
| Creators | Hunter, Meaghan M. |
| Contributors | McKay, Derek M., Medical Sciences |
| Source Sets | McMaster University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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