Abstract
Inappropriate activation of complement on the vascular endothelium of specific organs, or systemically, underlies the etiology of a number of diseases. These disorders include atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, atherosclerosis, age-related macular degeneration, diabetic retinopathy, and transplant rejection. Inhibition of the terminal step of complement activation, i.e. formation of the membrane attack complex, using CD59 has the advantage of retaining the upstream processes of the complement cascade necessary for fighting pathogens and retaining complement's crucial role in tissue homeostasis. Previous studies have shown the necessity of membrane targeting of soluble CD59 in order for it to prove an effective inhibitor of complement deposition both in vitro and in vivo. In this study we have generated an in vivo model of human complement activation on murine liver vascular endothelium. This model should prove useful for the development of anti-complement therapies for complement-induced pathologies of vascular endothelium. Using this model, we have demonstrated the viability of a non membrane-targeted soluble CD59 to significantly inhibit complement deposition on the endothelium of murine liver vasculature when expressed in vivo from an adenovirus. This result, unanticipated based on prior studies, suggests that the use of non membrane-targeted sCD59 as an anti-complement therapy be re-visited.
Highlights
Complement is a key component of innate immunity [1]
Deposition of human membrane attack complex on murine endothelial cells ex vivo To determine whether human complement is activated by murine endothelial cells, an explant of murine aorta was incubated with either an antibody against murine platelet/endothelial cell adhesion molecule or a generic anti-mouse (GAM) antibody and subsequently incubated with either normal human serum (NHS) or heat inactivated NHS (HI-NHS)
The only FDA approved therapeutics targeting complement include an antibody against complement component 5 and C1 inhibitor, but there are a number of ongoing trials investigating the safety and potency of complement regulators
Summary
Complement is a key component of innate immunity [1]. Activation of complement results in the generation of anaphylatoxins - pleiotropic effector molecules that mediate both inflammatory processes, such as chemoattraction, vasodilation and vasopermeability. Damage and detachment of the endothelium due to abnormal complement activity has been documented in atypical hemolytic uremic syndrome (aHUS) [3]. Both types of membranoproliferative glomerulonephritis (MPGN), type I and dense deposit disease (MPGN type II), are characterized by the presence of complement proteins within the subendothelial dense-deposit along the glomerular basement membrane [4]. Complement proteins have been documented to be deposited on the choriocapillaris of patients with diabetic retinopathy, as well as in the retinal vessels of diabetic subjects [9]. Ischemia/ reperfusion (I/R) injury, a complication of a number of pathologies including organ transplantation, stroke, myocardial infarction, sepsis and shock, has been shown to be mediated by complement-induced damage of endothelial cells of the vasculature and a number of studies have shown the effectiveness of complement inhibitors to reduce I/R injury (reviewed in [12])
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