A Clinicopathological Study of Human Liver Allograft Recipients Harboring Preformed Igg Lymphocytotoxic Antibodies

Abstract

Twenty-six adult patients with preformed IgG donor lymphocytotoxic antibodies received primary liver allografts under FK 506 immunosuppression. The effect of the crossmatch-positive state on early graft function and on the immunopathological and histo-pathological findings was compared with that of 52 crossmatch-negative control recipients. The presensitized (Crossmatch-positive) patients had prolongation of early graft dysfunction, underwent more clinically indicated biopsies and had a higher incidence of cellular rejection, both overall (p < 0.05) and within 10 days of transplantation (p < 0.01). They also had a higher incidence of graft failure in the first 180 days (p < 0.01). Hyperacute rejection with necrotizing or neutrophilic arteritis was not seen in the crossmatchpositive grafts. However, histological findings associated with presensitization included platelet margination in central veins and sinusoids in biopsy specimens 60 to 90 min after graft revascularization. Later biopsy specimens had neutrophilic portal venulitis followed by cholangiolar proliferation, acute cholangiolitis and centrilobular hepatocyte swelling that mimicked preservation injury, endothelial activation of arteries with medial changes and relapsing episodes of acute cellular rejection. These clinicopathological observations suggest that lymphocytotoxic antibodies can have a deleterious effect on liver allograft function and survival, even if they do not precipitate immediate or hyperacute rejection. (Hepatology 1992;16:671-681.) Although the liver is known to be more resistant than other solid organs to injury from preformed graft antibodies in the recipient (1-3), this privileged state is not absolute (4,5). Identification of the consequences of humoral antibody states on the liver has been hampered by the lack of distinctive pathological findings in many cases in which humoral rejection was suspected but was not proved. Consequently, in this study of liver recipients with preformed donor lymphocytotoxic antibodies, we have attempted to determine whether a unique, pathologically identifiable form of graft injury could be recognized and whether pathophysiological mechanisms of liver allograft injury could be deduced. A similar study on the pathological nature of ABO-mismatched livers in which the graft antibodies were isoagglutinins was published recently (6). MATERIALS AND METHODS Patient SelectionDuring the 11-mo period between November 31, 1989, and September 9, 1990, 243 adult patients ( > 16 yr) were given primary liver allografts under FK 506 and low-dose steroid therapy. The sera of 26 (11%) contained donor lymphocytotoxic antibodies. The crossmatchnegative control patients (n = 52) were those treated just before and after the crossmatchpositive cases. Most of these same cases were part of a recent clinical report (5). There were no statistically significant differences between the two cohorts with respect to age, United Network of Organ Sharing urgency of need status, original disease, donor demographic data or...

Increased bile duct complications and/or chronic rejection in crossmatch positive human liver allografts

“…Because of a dual blood supply, which may be one of the causes of resistance to antibody-mediated rejection, the biliary tree may injure because of its arterial-only-type circulation and more conventional arteriolar and capillary network. 11,17 The incidence of chronic rejection in the positive crossmatch group, which survived more than 3 months after OLTX, was significantly higher than those of negative cases in this series. However, recent reports do not support these observations.…”

“…The diagnosis of chronic rejection was based upon histological findings of disappearing interlobular bile ducts with scant mononuclear portal infiltrates, progressing later to bridging fibrosis with large, expanded portal tracts. 10,11 …”

“…However, the acute injury appears to be related to mechanical occulusion of microvasculature 17 and functional narrowing of the arterial tree because of immunologically mediated vasoconstriction has been reported. 11 This injury can manifest as focal intrahepatic infarcts and bile duct necrosis followed later by periductal fibrosis and stricturing. Because of a dual blood supply, which may be one of the causes of resistance to antibody-mediated rejection, the biliary tree may injure because of its arterial-only-type circulation and more conventional arteriolar and capillary network.…”

“…Immunoglobulin deposition on biliary epithelium and vascular endothelial cells has been reported in chronic rejection of liver transplants. 11,18,19 Ever since we recognized the increased immunology risk, we routinely include high-dose steroids (1 g methylpredonisolone) immediately after reperfusion and so-called steroid recycle starting postoperative day 1 and/or antileukocyte antibodies after this time period. 20 The etiology of transplant obstructive arteriopathy or chronic rejection is still unknown.…”

Preformed Lymphocytotoxic Antibodies: the Effects of Class, Titer and Specificity on Liver Vs. Heart Allografts

“…The dual hepatic vascu1ature' secretion of soluble major histocompatibility complex antigens and the protective activity of Kupffer cells, which clear immune complexes, platelet aggregates and activated coagulation proteins, may contribute to hepatic resistance (16)(17)(18)(19). However, our studies and earlier reports show that the liver's immunological privilege is only relative (4)(5)(6)(7)(8). In earlier reports of experimental liver transplantation in rats (6) and primates (5), no association was seen between the antibody titers and the outcome.…”