Complement as a multifaceted modulator of kidney transplant injury

Abstract

Improvements in clinical care and immunosuppressive medications have positively affected outcomes following kidney transplantation, but graft survival remains suboptimal, with half-lives of approximately 11 years. Late graft loss results from a confluence of processes initiated by ischemia-reperfusion injury and compounded by effector mechanisms of uncontrolled alloreactive T cells and anti-HLA antibodies. When combined with immunosuppressant toxicity, post-transplant diabetes and hypertension, and recurrent disease, among other factors, the result is interstitial fibrosis, tubular atrophy, and graft failure. Emerging evidence over the last decade unexpectedly identified the complement cascade as a common thread in this process. Complement activation and function affects allograft injury at essentially every step. These fundamental new insights, summarized herein, provide the foundation for testing the efficacy of various complement antagonists to improve kidney transplant function and long-term graft survival.

Figure 1. Schematic representation of the complement cascade.

C1q,r,s cross-linking of antibodies activates the classical pathway. Mannose-associated serine proteases (MASPs) bind to mannose motifs expressed on bacteria to activate complement via the MBL pathway. Subsequent cleavage and assembly of C4 and then C2 form the C4bC2b C3 convertase. C3 spontaneously binds to H₂O, forming C3(H₂O), which binds to cell surfaces and initiates factor B–dependent (fB-dependent) and fD-dependent assembly of the alternative pathway C3 convertase (C3bBb). The latter cleaves C3 into C3a and C3b, amplifying complement activation. Addition of a second C3b molecule to either C3 convertase forms the C5 convertase, which cleaves C5 into C5a and C5b. C5b, in conjunction with C6 to C9, comprises the MAC. C3b functions as an opsonin, whereas C3a and C5a have inflammatory and chemotactic properties. DAF (CD55) and MCP (CD46) are cell surface–expressed complement regulators that accelerate the decay of all surface-assembled C3 convertases, thereby limiting amplification of the downstream cascade. MCP and fH also have cofactor activity: in conjunction with soluble fI, they irreversibly cleave C3b to iC3b, thereby preventing re-formation of the C3 convertase. CD59 inhibits formation of the MAC.

Figure 2. Overview of pathogenic mechanisms linking complement to kidney transplant injury.

(A) During cognate interactions between alloreactive T cells and APCs, alternative pathway complement components are released and undergo activation, yielding C3a and C5a. Upon binding to their respective G protein–coupled receptors, these anaphylatoxins stimulate PKA and induce PI3Kγ-dependent pAKT, together amplifying alloreactive Th1 T cell expansion and inhibiting Treg induction, function, and stability, thus facilitating acute and chronic graft rejection. (B) The antigen-bound complement degradation product C3dg binds to B cell–expressed CR2, lowering the threshold for B cell activation and antibody production. Complement may indirectly enhance antibody production by augmenting T cell help (not shown). Classical pathway–dependent, complement-mediated effector mechanisms initiated by cross-linking tissue-bound, donor-reactive (IgG) antibodies also contribute to allograft injury. Insertion of the MAC into the EC results in EC activation. C3a and C5a mediate chemoattraction and activation of polymorphonuclear (PMN) cells, which, through Fc receptors, ligate Fc portions of antibodies bound to endothelium, contributing to injury. (C) IR leads to the production of ROS, which in turn promote release of DAMPs, including HMGB1, chemokines, cytokines, and complement components, by ECs and tubular and infiltrating cells. Through alternative complement pathway activation, locally generated C3a and C5a contribute to EC and tubular cell activation and injury, enhancing inflammation and graft immunogenicity. (D) Locally produced (intragraft) and activated complement contributes to progressive injury and fibrosis, in part through stimulating the renin angiotensin system and drivingΠepithelial-mesenchymal transition.