Tissue talks: immunophenotype of cells infiltrating the graft explains histological findings and the benefits of belatacept at 10 years

Author:

Furuzawa-Carballeda J1ORCID,Uribe-Uribe N O2,Arreola-Guerra J M3ORCID,Reyes-Acevedo R3,Vilatobá M4,López-Toledo A5,Mondragón-Salgado G5,Chávez-Fernández R1,López-Verdugo F1,Mondragón-Ramírez G5,Alberú J4ORCID

Affiliation:

1. Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

2. Department of Pathology and Anatomic Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

3. Department of Transplantation, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico

4. Department of Transplantation, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

5. Instituto Mexicano de Trasplantes, Cuernavaca, Morelos, Mexico

Abstract

Summary Previously, we found a substantial number of regulatory T cells (Tregs) and fewer senescent and T helper type 17 (Th17) and a decrease in interstitial fibrosis (IF) in 12-month graft biopsies in belatacept versus cyclosporin (CNI)-treated patients [Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) study]. Seven years after kidney transplantation (KT), mean estimated glomerular filtration rate (eGFR), patient and graft survival were significantly higher with belatacept versus CNI treatment. The aim of this study was to determine whether the immunophenotypes of inflammatory and regulatory cell subsets infiltrating the grafts contribute to the BENEFIT’s clinical findings a decade after KT. Twenty-three adult patients with functionally stable KT treated with belatacept and 10 treated with CNI were enrolled. Biopsies were analyzed by histomorphometry and immunohistochemistry for proliferation, senescence, apoptosis, inflammatory and regulatory cell markers in a blinded manner. Significantly lower percentages of inflammatory/fibrogenic cells [interleukin (IL)-22+/Th17/Th2/M1 macrophages] were observed in patients treated with belatacept than in patients treated with CNI. By contrast, remarkably higher percentages of regulatory cells [Tregs/Bregs/ plasmacytoid dendritic regulatory cells (pDCregs)/M2] were found in belatacept-treated patients than in CNI-treated patients. Conspicuously lower percentages of apoptosis and senescence and higher proliferation markers were found in belatacept-treated patients than in CNI-treated patients. Consequently, there was significantly more inflammation in the microvascular compartments as well as increased tubular atrophy and IF in CNI-treated patients. These findings strongly suggest that regulatory mechanisms, along with the absence of deleterious effects of CNI, contribute to the long-term graft histology and function stability in patients treated with belatacept.

Funder

Bristol-Myers Squibb

Publisher

Oxford University Press (OUP)

Subject

Immunology,Immunology and Allergy

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