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The therapeutic utility of Factor I in the treatment of complement dependent pathophysiological processes

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thesis
posted on 30.05.2017, 12:45 by Anna Buchberger
The complement system is an important defence system of our body. Of the three complement activation pathways, the alternative pathway is continuously activated at a low rate by a mechanism called tick-over. The alternative pathway is governed by the relative rate of two competing cycles, the C3b feedback and breakdown cycle. Correct regulation of the alternative pathway is essential to prevent damage and polymorphisms in alternative pathway regulation are increasingly associated with (particularly age-related) diseases. Factor I is unique in that it irreversible inactivates C3b. Raising the concentration of Factor I, slows down the rate of the C3b feedback cycle while the C3b breakdown cycle will be accelerated. Renal ischemia is an inevitable, injurious event during renal transplantation but can also occur as a consequence of impaired kidney perfusion and it is known that the alternative pathway exacerbates injury although recent data highlight the importance of a lectin pathway-mediated activation mechanism in the reperfusion period. To test the effect of increased Factor I plasma concentration, recombinant Factor I was generated and tested for functional activity. Administration of mouse Factor I reduced mortality and renal injury in a mouse model of renal ischemia reperfusion injury when compared to administration of a control protein. Factor I was also over-expressed in vivo as a gene therapy via an adeno-associated virus expression system. By titration of administrated virus particles, the levels of Factor I in mice could be raised up to 4x the normal concentration. In order to diagnose and test therapeutic progress of a future therapy for early age-related macular degeneration, a new, fast and reliable method is required. A ScFv mini antibody was generated that specifically recognises iC3b, a major opsonin and marker of inflammation, and C3dg. This biomarker is intended for fluorescent detection of complement activation products in the retina.

History

Supervisor(s)

Schwaeble, Wilhelm

Date of award

24/05/2016

Author affiliation

Department of Infection, Immunity and Inflammation

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

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