4.5 Article

Phosphorylated S6 ribosomal protein expression by immunohistochemistry correlates with de novo donor-specific HLA antibodies in lung allograft recipients

Journal

JOURNAL OF HEART AND LUNG TRANSPLANTATION
Volume 40, Issue 10, Pages 1164-1171

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.healun.2021.06.021

Keywords

rejection; lung transplantation; pathology; immunohistochemistry; donor specific antibodies; mTOR; C4d

Funding

  1. NIAID [1R01AI135201]

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This study revealed a positive correlation between de novo DSA and p-S6RP expression in pneumocytes and macrophages using IHC. p-S6RP was found to be relatively sensitive, specific, and had superior inter-rater reliability compared to C4d.
BACKGROUND: Per the ISHLT 2016 definition, a C4d-positive lung biopsy is required to meet criteria for definite antibody-mediated rejection (AMR). Unfortunately, C4d has poor sensitivity and specificity, and low inter-rater reliability. Phosphorylated S6 ribosomal protein (p-S6RP) expressed via the mTOR pathway has been shown to be a biomarker of AMR and correlates with donor-specific antibodies (DSA) in heart allografts. However, p-S6RP immunohistochemistry (IHC) in the setting of pulmonary AMR has yet to be evaluated. We sought to determine whether p-S6RP IHC performed on lung biopsies correlates with de novo DSA. METHODS: IHC for p-S6RP performed on 26 biopsies from lung transplant recipients with de novo HLA DSA (DSA+) and 28 biopsies from patients with no DSA (DSA-) were evaluated by 3 pathologists who independently scored the degree of alveolar macrophage and pneumocyte staining. Staining in >= 50% of the biopsy as determined by at least 2 pathologists was considered positive. RESULTS: Twenty-one (81%) DSA+ biopsies stained positive for p-S6RP in pneumocytes and 21 (81%) in macrophages. Six DSA- biopsies (21%) stained positive for p-S6RP in pneumocytes, 6 (21%) were positive in macrophages. Pneumocyte p-S6RP staining was 81% sensitive and 79% specific for DSA. Macrophage staining showed the same sensitivity and specificity but with lower inter-rater agreement (K = 0.53 vs 0.68). CONCLUSIONS: This study demonstrates a positive relationship between de novo DSA and p-S6RP expression in pneumocytes and macrophages using IHC. p-S6RP is relatively sensitive and specific, and has superior inter-rater reliability compared to C4d. J Heart Lung Transplant 2021;40:1164-1171 (c) 2021 International Society for Heart and Lung Transplantation. All rights reserved.

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