DOI: 10.1097/TP.0b013e31818a69a9

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PMID: 19034002

Issn Print: 0041-1337

Publication Date: 2008/11/27


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Targeting of the Fifth Complement (C5) Component to Fight Graft Impairment After Ischemia-Reperfusion Injury

Stanislaw M. Stepkowski

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Excerpt

Recent review article in Transplantation has asked whether overcoming donor factors (including ischemia-reperfusion [I/R] injury) by therapeutic intervention should be called “mission impossible?” (1). Indeed, delayed kidney graft function (requiring at least one dialysis) and slow kidney graft function (without dialysis) have both negative impact on patient and graft survivals. Although even one posttransplant dialysis causes postoperative hyperkalemia or volume overload or both, an extended time of dialysis leads to high immunologic risks and eventually to dismal long-term outcomes. An average frequency with delayed graft function of 25% has dropped to single digits when performed from living donors but doubled when performed from marginal donors. Significant risk factors are increased even more with variables affecting donor tissue quality, namely brain or cardiac death, preservation and cold/warm ischemia times. All these factors elevate risks for acute rejection within 1 year from 28% in recipients with immediate kidney graft function to 44% in recipients with delayed graft function (1). Similarly, the 5-year graft survival rate of 89% for recipients with immediate graft function decreased to 67% for recipients with grafts requiring dialysis. Although I/R injury refers to the degree of graft damage during harvesting, preservation, cold/warm ischemia time, and revascularization, the severity of I/R injury is increased by risk factors in marginal donors (cerebrovascular incident, arterial hypertension, elevated serum creatinine, and most important age). The criteria for acceptable donors have been expanded to include donors older than 60 years. Thus, although graft quality is influenced by even mild dysfunction (donor history and graft I/R injury), the constant graft shortage motivates compromises and those have significant negative impact on the long-term outcomes.
Intensive research has revealed multiple and complex mechanisms involved in I/R injury. Overall, I/R induces activation of graft endothelial cells (ECs) initiating nonspecific inflammatory reactions (2). In particular, inflammation around ECs increases expression of adhesion molecules (ICAM-1, P- and E-selectins), costimulatory molecules (CD80 and CD86), and class II major histocompatibility complex antigens. This nonspecific phase also include a uniform activation of classical and alternative complement (C) pathways through neoepitopes that are exposed on injured ECs and recognized by such molecules as mannan-binding lectin directly or by natural immunoglobulin (Ig) M. This initiates the C cascade and graft tissue damage. The importance of C components in I/R injury has been documented by the fact that the damage may be prevented in C6-deficient mice or after blocking of C5a in rats. Further supporting evidence showed deposition of C components on EC of vessels (especially in capillaries and postcapillaries) in patients with signs of I/R injury. The presence of such deposits correlated with the episodes of acute rejection.
It seems logical that pharmacologic intervention that inhibits C activation should ameliorate I/R injury. The most recent approach described in the current issue by Ferraresso et al. is targeting C5 by constructing a neutralizing minibody composed of a single human variable chain linked to the CH2 and CH3 hinge region of the rat IgG1. Binding of this C5-specific minibody to C5 blocks the release of C5a, thereby halting the entire C5 to C9 terminal C complex (TCC). Administration of C5 minibody to recipients just 30 min prior transplantation prevented formation of TCC deposits, apoptosis, and necrosis within the heart grafts. In particular, the necrotic areas of 16.8% observed as soon as 3 hr after reperfusion in grafted control hearts have been reduced by ninefold to 1.93% after C5 minibody therapy. Similarly, necrotic damage of 47.2% within 24 hr of revascularization in controls has been reduced by fourfold to 12.2% by C5 minibody. TUNEL assay confirmed equally dramatic reduction in apoptosis of cardimyocytes after C5 minibody therapy.
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