Targeted complement inhibition and microvasculature in transplants: a therapeutic perspective

Abstract

Active complement mediators play a key role in graft-versus-host diseases, but little attention has been given to the angiogenic balance and complement modulation during allograft acceptance. The complement cascade releases the powerful proinflammatory mediators C3a and C5a anaphylatoxins, C3b, C5b opsonins and terminal membrane attack complex into tissues, which are deleterious if unchecked. Blocking complement mediators has been considered to be a promising approach in the modern drug discovery plan, and a significant number of therapeutic alternatives have been developed to dampen complement activation and protect host cells. Numerous immune cells, especially macrophages, develop both anaphylatoxin and opsonin receptors on their cell surface and their binding affects the macrophage phenotype and their angiogenic properties. This review discusses the mechanism that complement contributes to angiogenic injury, and the development of future therapeutic targets by antagonizing activated complement mediators to preserve microvasculature in rejecting the transplanted organ.

Keywords: allograft rejection; angiogenesis; complement inhibition; complement-mediated injury.

Figure 1

Overview of complement system: highlights activation of classical, mannose‐binding lectin (MBL) and alternate pathway leading to tissue remodelling during the inflammatory condition.

Figure 2

Immune regulation of tissue repair: the model illustrates cross‐talk between regulatory T cells, complement activators and macrophages during tissue repair and angiogenesis in transplants. Binding of C3a and C5a to respective receptors on macrophages will polarize M1 macrophage and cause the T helper type 1 (Th1) response. Inhibition/blocking of both complements will shift in M2 macrophage and Th2 responses.

Figure 3

Inflammation and fibrosis: loss of pericyte during inflammation and/or local hypoxia in microvessel. Under normal conditions homeostatic repair occurs under the influence of vascular endothelial growth factor (VEGF). In contrast, during the chronic inflammatory condition, the pericyte loss facilitates epithelial–mesenchymal transition (EMT) and transforming growth factor (TGF)‐β, interleukin (IL)‐17 and connective tissue growth factor (CTGF) release, which in turn results in fibrosis and scarring of tissue.

Figure 4

Targeted complement blocking: model illustrates how targeted blocking will promote microvascular repair through vascular endothelial growth factor (VEGF) signalling and rescue allograft.