TY - JOUR
T1 - Multiomic profiling of transplant glomerulopathy reveals a novel T-cell dominant subclass
AU - Cristoferi, Iacopo
AU - Varol, Hilal
AU - van Baardwijk, Myrthe
AU - Rahiem, Layla
AU - Lila, Karishma A.
AU - van den Bosch, Thierry P.P.
AU - Baan, Carla C.
AU - Hesselink, Dennis A.
AU - Kramann, Rafael
AU - Minnee, Robert C.
AU - Mustafa, Dana A.M.
AU - Reinders, Marlies E.J.
AU - Roelen, Dave L.
AU - Shahzad-Arshad, Shazia P.
AU - Smith, Rex N.
AU - Stubbs, Andrew P.
AU - Colvin, Robert B.
AU - Rosales, Ivy A.
AU - Clahsen-van Groningen, Marian C.
N1 - Publisher Copyright:
© 2023 International Society of Nephrology
PY - 2024/4
Y1 - 2024/4
N2 - Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody–mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher glomerular abundance and activity of T cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype.
AB - Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody–mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher glomerular abundance and activity of T cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype.
UR - http://www.scopus.com/inward/record.url?scp=85184058417&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2023.11.026
DO - 10.1016/j.kint.2023.11.026
M3 - Article
C2 - 38128610
AN - SCOPUS:85184058417
SN - 0085-2538
VL - 105
SP - 812
EP - 823
JO - Kidney International
JF - Kidney International
IS - 4
ER -