C4d in Liver Allografts: A Sign of Antibody-Mediated Rejection?
Year: 2006
Type: editorial
Abstract: Antibody-mediated rejection of organ allografts has received increased recognition in recent years due to the application of immunopathologic techniques to demonstrate a complement fragment, C4d, and solid phase detection of circulating donor reactive HLA antibody (1). In the kidney, C4d deposition in peritubular capillaries is strongly correlated with circulating anti-donor HLA or ABO antibodies and the existence of both acute and chronic forms of antibody-mediated rejection has been widely reported (2). Extension of the C4d test to the heart, lung and pancreas has revealed convincing evidence for antibody-mediated damage in these organs as well (2). The one organ that traditionally has been regarded as resistant to antibody-mediated rejection, even hyperacute rejection, is the liver. Postulated reasons for resistance include a large vascular bed, with a dual supply able to absorb antibody and complement, and secretion of soluble HLA molecules. The paper of Schmeding et al. in this issue of American Journal of Transplantation reports that C4d deposition in liver biopsies can help distinguish acute rejection from hepatitis C virus (HCV) recurrence, a difficult diagnostic differential for the pathologist (3). In this report, 68% of liver allograft biopsies with the histologic diagnosis of acute cellular rejection had C4d deposition, compared with 12% of patients with recurrent HCV and 7% of protocol biopsies from without rejection or HCV. This is the most recent of a series of studies from the group in Berlin that has sought evidence for antibody-mediated rejection in the liver. Their previous studies showed that B cells (CD20+) and plasma cells (CD138+) were demonstrable in the infiltrate in acute rejection along with C4d in portal capillaries (4). Overall, 50% of patients diagnosed with acute cellular rejection had C4d deposition along portal veins, arteries and capillaries, associated with portal infiltration by macrophages (5). Selective B cell V region repertoire in the infiltrate has been observed in two cases of acute rejection and deserves a further systemic analysis (6). These studies raise the possibility that antibodies might be produced locally in the graft. Japanese investigators also reported C4d deposition in 35 biopsies from living related liver transplants with acute rejection, but they described C4d in hepatic sinusoids or veins (7), in contrast to Schmeding (3). Further studies may reveal the reason for the difference and develop a consensus on the criteria for a positive C4d stain in the liver. The missing evidence from these studies is the demonstration of circulating anti-donor antibody. One might argue that C4d is a better indicator of antibody-mediated rejection than circulating antibody, because two sources of false negatives are eliminated: adsorption by the graft and non-HLA antibodies. However, C4d can be activated by non-antibody mechanisms, notably, C-reactive protein and the lectin pathway (mannan-binding lectin and ficolins) (2). Both bind to microorganisms and to damaged cells. When neither of these pathways has been shown to cause C4d deposition in capillaries, C-reactive protein is synthesized in the liver and may be particularly relevant in that organ. Thus, for publications, it is highly desirable to seek evidence for antibody activity in the donor, and if none found, pursue evidence for other mechanisms of C4d activation. The distinction of HCV recurrence and acute rejection in biopsies is at best difficult one. The pathologic criteria that favor acute rejection are endotheliitis, portal inflammation with eosinophils and neutrophils, and bile duct injury with overlapping nuclei (8). However, the agreement among experienced pathologists using histology to differentiate HCV from rejection is poor, and additional techniques are needed (9). Curiously, antibodies to detect HCV in tissue have been difficult to develop. A recent promising report describes a monoclonal antibody (IG222) to the E2 protein that has a low false positive rate and could demonstrate increased virus in liver transplant biopsies treated with steroids (10). The report by Schmeding argues that C4d staining may provide a useful addition to the pathologists' diagnostic armamentarium, and will stimulate further studies to determine the pathogenetic and therapeutic implications of C4d deposition in liver allografts.
Author: R.B. Colvin
Institutions: Harvard University, Massachusetts General Hospital
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,300
OpenAlex ID: W2131119427