Targeting complement component 5a promotes vascular integrity and limits airway remodeling

Abstract

Increased microvascular dilatation and permeability is observed during allograft rejection. Because vascular integrity is an important indicator of transplant health, we have sought to limit injury to blood vessels by blocking complement activation. Although complement component 3 (C3) inhibition is known to be vasculoprotective in transplantation studies, we recently demonstrated the paradoxical finding that, early in rejection, C3 −/− transplant recipients actually exhibit worse microvascular injury than controls. In the genetic absence of C3, thrombin-mediated complement component 5 (C5) convertase activity leads to the generation of C5a (anaphylatoxin), a promoter of vasodilatation and permeability. In the current study, we demonstrated that microvessel thrombin deposition is significantly increased in C3 −/− recipients during acute rejection. Thrombin colocalization with microvessels is closely associated with remarkably elevated plasma levels of C5a, vasodilatation, and increased vascular permeability. Administration of NOX-D19, a specific C5a inhibitor, to C3 −/− recipients of airway transplants significantly improved tissue oxygenation, limited microvascular leakiness, and prevented airway ischemia, even in the absence of conventional T-cell–directed immunosuppression. As C3 inhibitors enter the clinics, the simultaneous targeting of this thrombin-mediated complement activation pathway and/or C5a itself may confer significant clinical benefit.

Intravitreal inhibition of complement C5a reduces choroidal neovascularization in mice

“…The nonnatural chirality makes Spiegelmers resistant to nucleases that are prevalent in biological fluids [18]. NOX-D20 is a second-generation molecule with improved affinity compared to its parent molecule NOX-D19 that has been shown to reduce allograft rejection [42]. Improvement was attained by the exchange of six ribonucleotides by their corresponding deoxyribonulcotides, i.e., six oxygen atoms were removed.…”

Targeted complement inhibition and microvasculature in transplants: a therapeutic perspective

“…Alternatively, C5a could intervene in other pathways that lead to graft injury, and of particular interest is its potential to augment the alloimmune response [20,120,130]. Complement inhibitor of C5a, Spiegelmer NOX-D19 (NOXXON Pharma, Berlin, Germany) has been shown to reduce airway rejection in a mouse model of orthotopic tracheal transplantation [20] and another C5a inhibitor, Spiegelmer NOX-D20, has been reported to prolong survival and to reduce liver and kidney graft failure, inflammatory cytokines and vascular leakage [131] (Table 1).…”

“…CD8 1 T cells are required for allograft neovascularization following CD4 1 -mediated microvascular rejection. Similar to the role of CD4 1 T cells, antibodymediated complement activation is independently sufficient to induce allograft microvascular rejection [20,40]. Blocking complement, using the C3 inhibitor, complement receptor 2 complement-inhibitory protein (CR2-Crry), synergizes with CD4 1 -depletion to prevent transplant ischaemia and chronic allograft rejection [40].…”

“…The C3b molecule then combines with C3 convertase to form the C4bC2aC3b complex in classical and lectin pathways, and to the formation of the C3bBbC3b complex in the alternate pathway. Both C4bC2aC3b and C3bBbC3b complexes are C5 convertases, which cleave C5 into C5a and C5b [2,20,21]. The generated C5a can then function as a potent anaphylatoxin at the site of production, while C5b participates in the assembly of the membrane attack complex (C5b-9 or MAC) [22].…”

Complement Split Products C3a/C5a and Receptors: Are They Regulated by Circulating Angiotensin II Type 1 Receptor Autoantibody in Severe Preeclampsia?

“…In the current model, wherein unilateral uterine ischemia/reperfusion results in fetal growth restriction, mediated by a systemic mechanism, pathological process is completely dependent on intact C5 [34]. A recent study demonstrates how C5a lead to endothelial dysfunction that increased thrombin deposition on vascular endothelial cells in allografts of C3-deficient recipients, which is associated with increased systemic C5a levels [35]. It is not clear whether elevated products of complement activation are a cause or consequence of placental dysfunction.…”