Activation of the complement system results in the production of the anaphylatoxins C3a, C4a, C5a, and the terminal membrane attack complex. These inflammatory mediators act as an initial defence mechanism, a vital component of the passive immune response. Of the anaphylatoxins, C5a is the most potent and therefore most extensively investigated. Due to the potent inflammatory activity of C5a, over-activation or insufficient regulation of the complement system, leading to excessive C5a production, may result in disease pathology. This process has been implicated in numerous immunoinflammatory disease states.
A small molecule, cyclic peptide C5a receptor antagonist, AcF-[OPdChaWR], has been recently developed in the laboratories of A/Prof. Steve Taylor and Prof. David Fairlie. This compound binds with high affinity to human polymorphonuclear leukocytes and is orally active against several models of disease in rats. The focus of
this thesis was to expand on the known pharmacology of this antagonist, and in particular, to examine the protective effects of this compound in a broader range of inflammatory disease states.
The C5a receptor affinity of AcF-[OPdChaWR] on various immunoinflammatory cells was examined first. It was found that AcF-[OPdChaWR] bound with equal affinity to C5a receptors located on either human PMNs, lymphocytes, monocytes or monocyte-derived macrophages. These results confirmed that the antagonist would likely block the activation of immunoinflammatory cells by C5a, a process that occurs in inflammatory disease states.
The therapeutic activity of the C5a antagonist was then examined in a model of experimental mesangioproliferative glomerulonephritis. It was found that oral pre-treatment of rats with the antagonist, displayed improved renal fimction as measured by various disease markers and mesangioproliferative scores of diseased
The second disease modeled was rheumatoid arthritis using a model of antigeninduced monoarticular arthritis. This study allowed for the examination of the efficacy of the antagonist in a chronic setting. It was found that AcF-[OPdChaWR] demonstrated superior disease modifying activity, compared to ibuprofen, when orally dosed either prior to, or following the induction of arthritis.
The efficacy of the C5a antagonist was further characterised in a model of tourniquet-induced limb ischemia-reperfusion. In this acute shock model the C5a antagonist was once again found to provide significant protective effects in rats when administered either intravenously or orally. A final disease model of inflammatory bowel disease was explored. In this model, the C5a antagonist was found to prevent mortality and markers of disease pathology, to a greater extent than either prednisolone or the TNF-α inhibitor, infliximab.
Therapeutic inhibition was observed in rats treated either orally or subcutaneously, pre- or post disease induction.
The results from these experiments demonstrate that the inhibition of C5a improves disease pathology in rat models of disease. In these studies the C5a receptor antagonist, AcF-[OPdChaWR], when administered either intravenously, subcutaneously or orally to rats, provided therapeutic efficacy as either a prophylactic agent, or even when reversing established disease. The successfial modulation of disease pathology by AcF-[OPdChaWR], in these in vivo models, also provides evidence for the future therapeutic use of this compound, or other C5a inhibitors, against these disease states in the human or veterinary clinical situation.