Complement inhibition in an ex vivo model of discordant hyperacute xenograft rejection.
dc.contributor.author | Gralinski, Michael Robert | en_US |
dc.contributor.advisor | Lucchesi, Benedict R. | en_US |
dc.date.accessioned | 2014-02-24T16:24:44Z | |
dc.date.available | 2014-02-24T16:24:44Z | |
dc.date.issued | 1996 | en_US |
dc.identifier.other | (UMI)AAI9624621 | en_US |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9624621 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/104947 | |
dc.description.abstract | This dissertation examined the role of complement inhibition in the reduction of ex vivo hyperacute xenograft rejection using the isolated rabbit heart perfused with human plasma. The normal human plasma that was added to the perfusate served as a source of complement in this experimental model. The observed myocardial damage and rejection in this model results from the interaction between rabbit heart tissue and human complement. This interaction initiates the activation of the complement in human plasma leading to the assembly of the membrane associated C5b-9 moiety known as the "membrane attack complex" (MAC). The assembly of the terminal MAC on the endothelial surface of the vascular bed of the rabbit heart is responsible for initiating the discordant rejection observed in this study. Through the use of the pathway-selective recombinant soluble complement inhibitors sCR1 and sCR1 (desLHR-A), it was determined that the alternative complement pathway is responsible for eliciting the severe myocellular injury characteristically observed in this setting. We also used whole body hyperthermia to confer immunological protection to the human plasma perfused rabbit heart. Hearts removed from animals that had been previously heat-stressed experienced a less fulminant rejection process compared to hearts removed from non-heat stressed animals. This novel observation demonstrates that whole-body hyperthermia has the capacity to alter the immunological characteristics of tissue with regard to xenocomplement activation. Results of studies demonstrating the anti-complement activity of various heparin derivatives commonly referred to as glycosaminoglycans are also presented. Perfusion of these ex vivo xenografts with glycosaminoglycan compounds prevented the alterations in hemodynamics and the release of biochemical indicators associated with rejection in this model. These studies are the first demonstrations of the ability of pathway-specific recombinant human complement inhibitors, whole body hyperthermia, and structurally altered glycosaminoglycans to modulate complement activation in a model of inflammatary xenograft rejection; the results of these experiments may provide future approaches toward the control of many pathological states associated with human complement activation. | en_US |
dc.format.extent | 117 p. | en_US |
dc.subject | Health Sciences, Pharmacology | en_US |
dc.subject | Health Sciences, Immunology | en_US |
dc.title | Complement inhibition in an ex vivo model of discordant hyperacute xenograft rejection. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Pharmacology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/104947/1/9624621.pdf | |
dc.description.filedescription | Description of 9624621.pdf : Restricted to UM users only. | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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