The role of cyclosporin A (CsA) as an immunomodulatory and antiparasitic drug was examined. The immune responses in various host:parasite relationships were examined giving an insight into the complicated nature of this relationship. In addition, analogues of CsA were screened to investigate the antiparasitic mode of action of cyclosporins. Expulsion of intestinal parasites has been proposed to involve the cellular immune response but its precise role is unknown. In CBA/ca mice infected with <I>Hymenolepsis diminuta</I>, peak intestinal mucosal mast cell (IMMC) numbers and release of mast cell protease (mMCP-I) correlated with parasite expulsion. Immunosuppression by cyclosporin A (CsA) treatment abrogated the response and allowed <I>H. diminuta</I> to survive to maturity. In contrast, <I>H. microstroma</I> survived long-term in MF1 mice, despite a significant and sustained IMMC response and mMCP-I release. It is proposed that the protease has different roles in these hymenolepid infections. Goblet cell proliferation did not occur in either infection. Adult <I>Schistosoma mansoni</I> are less susceptible to CsA than juveniles and reduced drug efficacy correlates with the onset of egg deposition and pathology in the liver of the host. This may alter metabolism of CsA and prevent the production of an active metabolite. CsA and metabolites were identified in mice tissues using reverse phase HPLC but problems with background peaks and low drug recovery prevented examination of the metabolite profile. CsA is antiparasitic against a range of protozoa and helminths but its mode of action is unknown. One possibility is that it involves the binding protein, cyclphilin (CyP). Three analogues of CsA, B-5-49, CsH and CsA-acetate (CsA-A) were screened against <I>H. microstroma in vitro</I>, which is susceptible to CsA. All analogues induced drug damage comparable to CsA. However, only B-5-49 bound to <I>H. microstroma </I>cytosolic CyP, suggesting that CyP is not necessary for the antiparasitic action of cyclosporins. Schistosomes suppress the activity of the internal defence system in their host in order to ensure their survival.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:593084 |
| Date | January 1998 |
| Creators | McLauchlan, P. E. |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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