C4d Deposition and Clearance in Cardiac Transplants Correlates With Alloantibody Levels and Rejection in Rats

Abstract

Antibody-mediated rejection of human cardiac transplants is correlated with C4d deposits and macrophage infiltrates in capillaries of endomyocardial biopsies. We produced an antibody to rat C4d to study C4d deposition and clearance in Lewis rats that were sensitized with a blood transfusion from DA rats 7, 14 or 21 days before cardiac transplantation. Cyclosporin A (CsA) immunosuppression was initiated after transplantation at a dose that inhibited graft rejection, antibody production and C4d deposition in unsensitized recipients. Blood transfusion elicited high levels of circulating IgG alloantibodies, predominantly of the complementactivating IgG2b subclass, that peaked 14 days after transplantation. At this time, macrophages accumulated in capillaries, and C4d deposits were diffuse and intense on arteries, capillaries and veins. Grafts that survived 90 days in sensitized recipients still had deposits of C4d that were associated with increased interstitial fibrosis and vasculopathy in arteries. Clearance of C4d was determined by retransplanting DA cardiac allografts from Lewis recipients back to DA recipients. C4d deposits were decreased to minimal levels within 5 days after retransplantation. Thus, C4d deposition is not limited to the capillaries, but extends throughout the arterial tree, and despite formation of a covalent bond, C4d is cleared within days.

Acute Antibody-Mediated Rejection Following Heart Transplantation

“…C4d deposition can occur as early as less than 3 months after heart transplantation to greater than 160 months and can be cleared fairly rapidly with appropriate therapy in patients with clinical AMR. This has been confirmed in animal studies using Lewis rats (28). C4d deposition in the nontransplanted heart has been described in less than 10% of patients with other forms of heart disease (22).…”

Banff ’09 Meeting Report: Antibody Mediated Graft Deterioration and Implementation of Banff Working Groups

“…In the early 1990s, clinicopathologic observations led to the recognition of histopathological features of acute ABMR in kidney (3,4), followed by discovery of C4d staining (5 (8,9) or noncomplement activating DSA (10)(11)(12) (27) (32). (38).…”

Platelets in Early Antibody-Mediated Rejection of Renal Transplants

“…5,6 Animal models have confirmed that donor-specific antibodies (DSAs) are associated with release of vWf in cardiac allografts. 7,8 When vWf is released, the end of the vWf multimer remains attached to endothelial cells, and strings of vWf interact with integrin GPIb-XI-V and GPIIb/IIIa on platelets. 9 In models of AMR, release of vWf is associated with adhesion of platelets to vascular endothelium of cardiac allografts.…”