*Purpose: In 2013, the ISHLT (International Society of Heart and Lung Transplant) introduced the working classification for pathological changes associated with antibody-mediated rejection of the heart allograft, known as p-AMR (pathology-Antibody Mediated Rejection). With two components H (histologic changes) and I (immunolabeled markers) associated with AMR, the proposed classification also suggests the use of Class II HLA as a marker of endothelial integrity. It is known that during allograft rejection, endothelial Class II HLA are activated, therefore, we hypothesized that Class II HLA rather than a marker of mere endothelial presence, is a marker of endothelial activation, and becomes upregulated in AMR.

*Methods: 838 heart allograft biopsies, collected from January 2016 to September 2018 at a single institution from patients who had at least one biopsy as “H” or “I” component for AMR were evaluated for both “H” and “I” changes of AMR. Biopsies were immunolabeled with immunofluorescence with antibodies against C4d, and for immunohistochemistry with antibodies against C3d, CD68 and Class II HLA. ISHLT criteria was used to classify the biopsies, and for Class II HLA, both the percentage and the stain intensity were recorded.

*Results: 74.8% of biopsies from our cohort showed either a H, I or a combined H+I evidence of AMR. Endothelial HLA Class II was significantly correlated with the diagnosis of AMR by percentage (r=0.32) and intensity of staining (r-0.34). HLA Class II showed a spectrum of intensity, quantified as negative (0) to strongly positive (+3). The diagnosis of AMR significantly correlated with moderate (+2) and strong (+3) staining intensity for Class II HLA, as follow: H+I (OR 28.3, p<0.0001); H alone (OR 22.73, p<0.0001) and I alone (32.63, p<0.0001). Our study also confirmed the value of the other AMR markers proposed by the ISHLT, such as C4d, C3d and CD68 (all p<0.0001), but importantly, and in contrast to prior observations, we showed in our cohort that the C4d focally positive category (10-50%) is also significantly correlated to the diagnosis of AMR (OR 12.256, p<0.0005).

*Conclusions: We confirmed our hypothesis that in heart allograft biopsies there is a spectrum of both percentage and intensity of HLA Class II in endothelial cells, and that Class II HLA by IHC is a marker significantly correlated with the diagnosis of AMR. In addition, the group of focally positive C4d biopsies (10-50%) should be considered positive for the I component of the 2013 ISHLT classification, as this group of biopsies also correlated with the diagnosis of AMR.

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