A novel mouse model of acute antibody-mediated transplant rejection shows simultaneous complement activating and anti-inflammatory effects of donor specific IgG antibodies
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Abstract
We developed a small animal model of pure antibody-mediated rejection (ABMR) by utilizing fully major histocompatibility complex (MHC) mismatched kidney allografts in mice. By examining resultant ABMR pathology, we show that terminal complement products C5a and C5b-9 are crucial in establishing antibody-mediated allograft microvascular and tubular injury, and the presence of proximal complement product C4d alone is not indicative of ABMR. We demonstrate allorecognition capabilities in NK cells to induce micro-inflammation and apoptosis in MHC mismatched transplants. By gene expression profiling, we found that binding of donor specific antibodies (DSA) into kidney allograft tissues induces a ‘self-protective’ anti-inflammatory response in kidney parenchyma. The data suggests that the anti-inflammatory response associated with DSA may be regulated via inhibitory Fc receptors for immunoglobulin G. In summary, we established a mouse model demonstrating pure acute ABMR of kidney allografts mimicking some aspects of human ABMR pathology in the absence of T cell-mediated rejection.