The role of complement in antibody mediated transplant rejection

Abstract

Antibody mediated transplant rejection (AMR) is a major cause of long-term allograft failure, and currently available treatments are of limited efficacy for treating the disease. AMR is caused by donor specific antibodies (DSA) that bind to antigens within the transplanted organ. DSA usually activate the classical pathway of complement within the allograft, and complement activation is believed to be an important cause of tissue injury in AMR. Several new clinical assays may improve our ability to identify patients at risk of AMR. Complement inhibitory drugs have also been tested in selected patients and in small series. Better understanding of the role of complement activation in the pathogenesis of AMR will likely improve our ability to diagnose the disease and to develop novel treatments.

Keywords: Antibody mediated rejection; Complement; Immunoglobulin; Transplant.

Figure 1.. Antibody mediated complement activation.

Multiple different elements influence complement activation on a target surface. 1) Antigen density will affect the clustering of bound IgG and IgM. Mobility of the antigen on the target surface may also affect clustering of the bound immunoglobulin. 2) IgG and IgM can activate the classical pathway. Some subclasses of IgG are better activators than others. In general IgG3 > IgG1 > IgG2 >> IgG4. C1q binds efficiently to six clustered IgG molecules or to a single IgM that is complexed to antigen. 3) Complement regulatory proteins on the target surface and in plasma control complement pathway activation by the immune complexes. Alternative pathway regulators, such as factor H, decrease amplification through the alternative pathway.

Figure 2.. Histologic findings in antibody mediated rejection.

A) By light microscopy the peritubular capillaries are congested with leukocytes (“capillaritis”, small arrows). The adjacent tubules are intact and there is little infiltration of the tubules by leukocytes. B) Immunohistochemistry for C4d. C4d staining (brown) can be seen throughout the peritubular capillaries (small arrows) and within the glomerular capillaries (arrowhead).