C4d: A Marker for Hepatic Transplant Rejection

Lorho, R.; Turlin, Bruno; Aqodad, Nourdin; Triki, N.; Lajarte-Thirouard, A.S. de; Camus, Christophe; Lakéhal, M.; Compagnon, Philippe; Dupont-Bierre, Eric; Meunier, Brigitte; Boudjéma, Karim; Messner, M.

doi:10.1016/j.transproceed.2006.06.120

Cited by 36 publications

(31 citation statements)

References 5 publications

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“…Thus, in addition to defective synthesis (28), complement consumption may contribute to the dramatic reduction of serum complement levels seen in ALF. In particular, C4d is considered a specific marker of humoral immune response in renal allografts (29), and more recently it has been detected in acute liver allograft humoral rejection (30). Our data are consistent with the hypothesis that anti-HBc antibodies massively produced in the liver may combine with HBcAg, leading to the extensive formation of antigen-antibody complexes on the surface of hepatocytes and Kupffer cells, resulting in the activation of the classical complement pathway and massive liver necrosis.…”

Section: Discussionsupporting

confidence: 87%

B cell gene signature with massive intrahepatic production of antibodies to hepatitis B core antigen in hepatitis B virus–associated acute liver failure

Farci

Diaz

Chen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

109

112

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Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome due to a sudden loss of hepatic cells leading to multiorgan failure. The mechanisms whereby HBV induces ALF are unknown. Here, we show that liver tissue collected at the time of liver transplantation in two patients with HBVassociated ALF is characterized by an overwhelming B cell response apparently centered in the liver with massive accumulation of plasma cells secreting IgG and IgM, accompanied by complement deposition. We demonstrate that the molecular target of these antibodies is the hepatitis B core antigen (HBcAg); that these antibodies display a restricted variable heavy chain (V H ) repertoire and lack somatic mutations; and that these two unrelated individuals with ALF use an identical predominant V H gene with unmutated variable domain (IGHV1-3) for both IgG and IgM anti-HBc antibodies, indicating that HBcAg is the target of a germline human V H gene. These data suggest that humoral immunity may exert a primary role in the pathogenesis of HBV-associated ALF.

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Section: Discussionsupporting

confidence: 87%

B cell gene signature with massive intrahepatic production of antibodies to hepatitis B core antigen in hepatitis B virus–associated acute liver failure

Farci

Diaz

Chen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

109

112

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“…These include staining for C4d as a marker of rejection [75][76][77], for HCV antigens as a marker of HCV infection [78][79][80] and for the cell-cycle protein mcm-2 to identify the rate of proliferation in portal lymphocytes, which is higher in rejection than HCV [81]. Some of these approaches have helped to identify the main cause of graft damage when histological findings were otherwise inconclusive [78,79,81].…”

Section: Recurrent Hepatitis Cmentioning

confidence: 99%

Current views on rejection pathology in liver transplantation

Neil¹,

Hübscher²

2010

Transplant International

133

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“…As in other reports, late-phase chronic rejection tended to show a high percentage of C4d positivity and chronic hepatitis C showed low C4d positivity. 15,18 However, less than half of the acute rejection cases showed C4d positivity, and a similar frequency of C4d staining was observed in lobular hepatitis C, which makes it difficult to use C4d as a marker of acute rejection in patients with hepatitis C infection. In this series, C4d staining for crossmatch-negative and ABOcompatible/identical liver transplantation does not seem to be a useful marker for histological diagnosis.…”

Section: C4d In Liver Transplantationmentioning

confidence: 99%

“…The Berlin group reported that half or more of patients diagnosed with acute rejection showed C4d deposits along portal vessels, mainly portal veins, and C4d may be a useful marker to distinguish acute rejection from recurrent hepatitis C. 11,14,15 Other groups emphasized that hepatic lobules or sinusoidal deposition was more specific in hepatic rejection and may be useful to differentiate rejection from recurrent viral hepatitis. 12,[16][17][18] Complement activation in the sinusoids may be seen in conditions other than rejection, and clinicopathological correlation is always necessary in the evaluation of C4d deposition. 27,28 Nonspecific staining should also be excluded using proper positive and negative controls.…”

Section: C4d In Liver Transplantationmentioning

confidence: 99%

“…8 Recent papers reported the demonstration of C4d in liver allografts, especially in allografts showing cellular or apparent humoral rejection, but the status of anti-donor antibodies was not described in most cases. [11][12][13][14][15][16][17][18][19] In ABO-incompatible transplantation, our group reported that portal stromal C4d immunostaining was associated with a high postoperative titer of anti-A/B antibody and reduced graft survival, suggesting the association of C4d deposition and ABO-incompatible humoral rejection. 20 In this study, we focused on the role of C4d immunohistochemistry in ABO-identical/compatible liver allografts with reference to preformed alloantibodies evaluated by lymphocyte crossmatch tests.…”

mentioning

confidence: 99%

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Significance of C4d staining in ABO-identical/compatible liver transplantation

et al. 2007

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Complement degradation product C4d has become an important marker of humoral or antibody-mediated rejection in renal and heart allograft biopsies. Although there have been several reports on the detection of C4d in liver allografts, the significance of C4d in liver transplantation and its relationship with humoral rejection are still not clear. We investigated the frequency and pattern of C4d staining in liver allograft biopsies with reference to preoperative lymphocyte crossmatch tests, which detect donor-reactive lymphocyte antibody. Survival rates at 5 years were 77% for crossmatch-negative patients and 53% for crossmatch-positive patients (P ¼ 0.009). In crossmatch-negative patients, reproducible positive staining was obtained in 28 of 86 (33%) biopsies taken within 90 days after transplantation and 33 of 96 (34%) biopsies 90 days or after transplantation. Most C4d staining was observed in the portal areas, and no clear correlation was observed between C4d positivity and histological diagnosis. In crossmatch-positive patients, 9 of 11 (82%) biopsies showed positivity for C4d. C4d stained perivenular areas as well as portal areas. Histology of crossmatch-positive patients included acute rejection and cholangitis, but did not include periportal changes that were seen in humoral rejection in ABO-incompatible liver transplantation. In summary, focal C4d deposition was seen in various types of liver allograft injury and had little clinical impact on crossmatch-negative patients, but extensive C4d staining in crossmatch-positive patients may be associated with humoral rejection and poor graft survival.

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C4d: A Marker for Hepatic Transplant Rejection

Cited by 36 publications

References 5 publications

B cell gene signature with massive intrahepatic production of antibodies to hepatitis B core antigen in hepatitis B virus–associated acute liver failure

B cell gene signature with massive intrahepatic production of antibodies to hepatitis B core antigen in hepatitis B virus–associated acute liver failure

Current views on rejection pathology in liver transplantation

Significance of C4d staining in ABO-identical/compatible liver transplantation

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