Targeted complement inhibition and microvasculature in transplants: a therapeutic perspective

Abstract

SummaryActive 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.

Complement factor and T-cell interactions during alloimmune inflammation in transplantation

“…C3 is a central molecule in the complement cascade and a potent mediator of transplant injury during alloimmune reaction . After C3 splitting through C3 convertase, C3a mediates cellular interactions, while C3b molecule generates C4b2a3b/C3bBbC3b (C5 convertase) in the individual activation pathway, respectively . Both C5 convertase components later process the splitting of C5 into C5a and C5b molecules .…”

“…During complement cascade activation, complement C3 molecule cleaved into C3a and C3b through the proteolytic activity of C3 convertase (C4b2b or C3bBb). C3a is a potent anaphylatoxin involved in the interaction with T cells, B cells, mast cells, basophils, and macrophages on the site of infection or injury, whereas C3b, as a part of both C3 and C5 convertase, contributes to the opsonization and assembly of MAC during cell lysis . C3 has been reported to control the proliferation and differentiation of T cells, either by interacting with TCRs or by interacting with receptors on an APC, and molecular signaling between intracellular C3a and human T cells suggested a functional evidence of intracellular cleavage of C3 into C3a and C3b, which subdues TOR phosphorylation .…”

“…Tregs are crucial in maintaining immunotolerance and have been associated with improved long‐term transplant survival, as seen in various preclinical and clinical transplant studies . Complement and T‐cell interactions have been key to influence alloimmune state, which initiated through the activation of complement cascade, and their subsequent interactions with neighboring inflammatory cells have been critical to transplant‐associated injuries, which result in obliteration of graft microvasculature, and ultimately leads to the progression of airway fibrosis and chronic rejection . On the flip side, Tregs also display surface expression of various complement receptors, and binding of these receptors with corresponding activated complement fragments significantly affects the outcomes of the regulatory microenvironment of transplant.…”

“…The complement cascade is a vast collection of secreting plasma‐ and membrane‐bound proteins, which are produced by liver hepatocytes, and to some extent are produced by endothelial cells, mesangial cells, glomerular epithelial cells, and tubular epithelial cells . The complement cascade is unique in targeting actions and routinely defends foreign antigens by the activated peptides, and their terminal complexes, which result in a massive amplification of the alloimmune reaction . Molecular signaling between activated complement mediators and inflammatory cells is critical to further amplify an effective immune response to foreign bodies, which play a leading role in transplant‐associated injuries and chronic rejection .…”

“…Various approaches to inhibit the complement system have been tested in preclinical models, particularly in an ischemia‐reperfusion injury, and in transplantation . In addition, activated complement fragments regulate the release of alloantibodies and the generation of alloreactive T cells, which effectively modulate tissue inflammation, donor‐recipient microvascular injury, ischemia reperfusion injury, and pathological tissue remodeling during rejection, which play a critical role in the development of fibrosis during chronic rejection (Fig. , Table ).…”