Local synthesis of complement component C3 regulates acute renal transplant rejection

155

135

Renal ischemia-reperfusion injury (IRI) is a feature of ischemic acute renal failure and it impacts both short- and long-term graft survival after kidney transplantation. Complement activation has been implicated in renal IRI, but its mechanism of action is uncertain and the determinants of complement activation during IRI remain poorly understood. We engineered mice deficient in two membrane complement regulatory proteins, CD55 and CD59, and used them to investigate the role of these endogenous complement inhibitors in renal IRI. CD55-deficient (CD55−/−), but not CD59-deficient (CD59−/−), mice exhibited increased renal IRI as indicated by significantly elevated blood urea nitrogen levels, histological scores, and neutrophil infiltration. Remarkably, although CD59 deficiency alone was inconsequential, CD55/CD59 double deficiency greatly exacerbated IRI. Severe IRI in CD55−/−CD59−/− mice was accompanied by endothelial deposition of C3 and the membrane attack complex (MAC) and medullary capillary thrombosis. Complement depletion in CD55−/−CD59−/− mice with cobra venom factor prevented these effects. Thus, CD55 and CD59 act synergistically to inhibit complement-mediated renal IRI, and abrogation of their function leads to MAC-induced microvascular injury and dysfunction that may exacerbate the initial ischemic assault. Our findings suggest a rationale for anti-complement therapies aimed at preventing microvascular injury during ischemia reperfusion, and the CD55−/−CD59−/− mouse provides a useful animal model in this regard.

Section: Resultsmentioning

confidence: 99%

Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

Yamada

Miwa

Liu

et al. 2004

155

135

“…This control can be overwhelmed by specific activators of this pathway, increased concentrations of alternative pathway components (due to local synthesis (20) or the release of these proteins by infiltrating neutrophils (21)), or insufficient function of the complement regulatory proteins (Fig. 2).…”

Section: Continous Active Control Of Alternative Pathway Activation Imentioning

confidence: 99%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

392

350

The complement system is increasingly recognized as important in the pathogenesis of tissue injury in vivo following immune, ischemic, or infectious insults. Within the complement system, three pathways are capable of initiating the processes that result in C3 activation: classical, alternative, and lectin. Although the roles that proinflammatory peptides and complexes generated during complement activation play in mediating disease processes have been studied extensively, the relative contributions of the three activating pathways is less well understood. Herein we examine recent evidence that the alternative complement pathway plays a key and, in most instances, obligate role in generating proinflammatory complement activation products in vivo. In addition, we discuss new concepts regarding the mechanisms by which the alternative pathway is activated in vivo, as recent clinical findings and experimental results have provided evidence that continuous active control of this pathway is necessary to prevent unintended targeting and injury to self tissues.

“…This may be particularly important to bronchial inflammation in acute and chronic rejection of lung allografts. In fact, local C3 production has been demonstrated to modulate the rejection of renal allografts (64).…”

Section: Figurementioning

confidence: 99%

Membrane Attack Complex Contributes to Destruction of Vascular Integrity in Acute Lung Allograft Rejection

Nakashima

Qian

Rahimi

et al. 2002

The lung is known to be particularly susceptible to complement-mediated injury. Both C5a and the membrane attack complex (MAC), which is formed by the terminal components of complement (C5b-C9), can cause acute pulmonary distress in nontransplanted lungs. We used C6-deficient rats to investigate whether MAC causes injury to lung allografts. PVG.R8 lungs were transplanted orthotopically to MHC class I-incompatible PVG.1U recipients. Allografts from C6-sufficient (C6+) donors to C6+ recipients were rejected with an intense vascular infiltration and diffuse alveolar hemorrhage 7 days after transplantation (n = 5). Ab and complement (C3d) deposition was accompanied by extensive vascular endothelial injury and intravascular release of von Willebrand factor. In contrast, lung allografts from C6-deficient (C6−) donors to C6− recipients survived 13–17 days (n = 5). In the absence of C6, perivascular mononuclear infiltrates of ED1+ macrophages and CD8+ T lymphocytes were present 7 days after transplantation, but vascular endothelial cells were quiescent, with minimal von Willebrand factor release and no evidence of alveolar hemorrhage or edema. Lung allografts were performed from C6− donors to C6+ recipients (n = 5) and from C6+ donors to C6− recipients (n = 5) to separate the effects of systemic and local C6 production. Lungs transplanted from C6+ donors to C6− recipients had increased alveolar macrophages and capillary injury. C6 production by lung allografts was demonstrated at the mRNA and protein levels. These results demonstrate that MAC causes vascular injury in lung allografts and that the location of injury is dependent on the source of C6.