Qualitatively similar, but more histopathologically subtle, injury characterizes indolent or chronic AMR, which was not addressed in this study

Qualitatively similar, but more histopathologically subtle, injury characterizes indolent or chronic AMR, which was not addressed in this study. We attempted to mitigate most of these shortcoming by selecting cases from 3 different institutions, evaluating all material without knowledge of C4d or DSA test results, including 4 different pathologists, creating training Griseofulvin and validation cohorts (the latter having solid phase DSA testing for most cases) and, relying on stringent criteria, including: 1) histopathological evidence of diffuse microvascular activation, injury, and microvasculitis; 2) diffuse microvascular C4d staining; 3) serum DSA (usually high c-ABL MFI); and 4) reasonable exclusion of other causes of a similar type of injury (23). that optimized specificity at a score >1.75 (sensitivity = 34%, specificity = 87%) and a second that optimized sensitivity at a score >1.0 (sensitivity = 81%, specificity = 71%). In Griseofulvin conclusion, routine histopathological features of the aAMR score can be used to screen for acute AMR on routine H&E in liver transplant biopsies, a diagnosis that requires substantiation by donor-specific HLA alloantibody testing, C4d staining, and exclusion of other insults. Keywords: Acute-AMR, Microvasculitis, Antibody-Mediated Rejection, liver transplantation, donor-specific antibodies Griseofulvin Introduction The first evidence that antibodies can cause acute injury/rejection (antibody-mediated rejection; AMR) in human liver allografts was observed in ABO-incompatible cadaveric, brain-dead whole organ donors (1, 2). Antibody and complement deposition, platelet-fibrin thrombi, micro-vasculitis, and arteritis were typical and expected histopathological findings (1), based on previous observations in ABO-incompatible renal allografts (3) and in ABO-compatible renal allografts harboring allo-antibodies (4, 5). It was recognized early on, however, that human liver allografts were highly resistant to acute AMR from preformed HLA alloantibodies compared to kidney allografts (6). This relative resistance was attributed to: the liver’s inherent tolerogenic properties, the difficultly detecting antibody and complement tissue deposits, the paucity of typical histopathological findings (6) and, even when damage was present, the noticeably diminished severity of injury compared to ABO-incompatible liver transplants (7, 8). Relative hepatic resistance to AMR has been attributed to: a) secretion of soluble HLA class I molecules that form immune complexes with alloantibodies, which are then cleared by Kupffer cells; b) Kupffer cell phagocytosis of platelet aggregates, immune complexes, and activated complement components (9); c) limited distribution of HLA class II expression in the microvasculature; d) large liver size and dual hepatic vasculature; and e) marked hepatocyte regenerative capacity after injury [reviewed in (7, 8)]. In addition, the imperfect sensitivity and specificity of cytotoxic cell-based antibody detection methods impaired prior investigators abilities to find associations between HLA antibodies and adverse patient and graft outcomes (1, 7, 8). Nevertheless, in the late 1980’s and early to mid-1990’s HLA class I and II antibodies, as measured in cytotoxic cell-based assays, were suspected to cause or substantially contribute to Griseofulvin acute and chronic liver allograft rejection (7, 10-13). In addition, experimental rat studies clearly showed that extreme sensitization (14, 15) could override the liver’s natural resistance and defense mechanisms. Similar observations were made in humans and risk factors for acute liver allograft AMR included high-titer pretransplant sensitization with persistence of serum alloantibodies after transplantation. When acute liver allograft AMR ensued refractory thrombocytopenia, circulating immune complexes, and severe liver injury were then seen (7, 11). Recent studies using more sophisticated and sensitive (16) solid phase donor-specific HLA alloantibody (DSA) detection methods have confirmed and extended earlier studies with cytotoxic cell-based assays, even though the two tests have been documented to sometimes produce substantially different results on the same serum samples (17, 18). These confirmed findings include: 1) the liver allograft’s relative resistance to AMR (18) associated with the rapid disappearance of the vast majority of low to moderate MFI class I and II alloantibodies (11, 17, 18); and 2) an association of acute AMR with high-titer alloantibodies that most-often persist after transplantation and result in refractory thrombocytopenia and acute liver injury that can evolve into combined acute antibody-mediated and T-cell-mediated rejection. Inadequately treated, the end result can be chronic or ductopenic rejection (17, 19-23). Solid phase DSA analyses have also shown an association between multiple IgG subclasses, especially when alloantibodies of the IgG3 subclass are present, and chronic rejection and diminished allograft survival (24). These newer serum assays have also facilitated a closer correlation between histopathological findings and serum DSA characteristics (18, 22, 23, 25). Similar to AMR in other solid organ allografts, histopathological patterns of injury associated with liver allograft AMR.