Complement split product C4d deposition in human organ transplants is a biomarker of classical complement activation triggered by antibody binding to donor antigens, but this process does not always result in allograft rejection. The basis for C4d deposition without allograft injury is unknown. We tested the hypothesis that antibody-induced complement activation fails to produce allograft injury if distal complement effector products are not generated. We transplanted wild-type H-2^k donor kidneys into T-cell/B-cell-null Rag1^–/^– H-2^b recipients. Low or high doses of donor specific anti-class-I monoclonal antibodies with rabbit complement were transferred into transplant recipients: intraperitoneal injection of 100ug anti-H-2K^k IgG2a on day 6 post-transplant and harvesting kidneys 24 hours later (n=9), three injections of 1000ug anti-H-2K^k IgG2a plus 1000ug anti-H-2K^kD^k IgG2b plus 1000ug anti-H-2K^k IgG1 on days 3,5,7 post-transplant and harvesting kidneys 45 minutes after the last injection (in each group n≥5). Adoptive transfer of low dose donor specific anti-class-I antibodies into allograft recipients induced intragraft antibody deposition and diffuse C4d staining in peritubular capillaries, which were absent in control allograft and normal kidneys. C4d positive allografts following low dose antibody transfer showed normal histology and no molecular signs of injury, inflammation, and endothelial activation by expression microarrays. Also, there was no molecular evidence for acquired graft resistance to alloantibody (accommodation): no gene expression changes were present in C4d positive allografts following low dose antibody transfer. In contrast, C4d positive allografts following high dose antibody transfer showed acute microvascular endothelial and tubular injury and weak inflammation. Surprisingly, serum levels of distal complement effector products C5a and C5b-9 were significantly increased in mice with C4d positive allografts following high dose antibody transfer, but not in mice with C4d positive allografts following low dose antibody transfer, control allograft recipient mice, and naÏve mice. These data indicate that alloantibody-induced complement activation with C4d deposition does not produce allograft injury when distal complement effector products are not generated.

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