Extracellular Matrix Injury of Kidney Allografts in Antibody-mediated Rejection

S. Clotet Freixas¹, C. McEvoy¹, I. Batruch², C. Pastrello³, M. Kotlyar³, J. Van¹, M. Arambewela¹, A. Boshart¹, S. Farkona¹, Y. Niu³, Y. Li¹, O. Famure¹, A. Bozovic⁴, V. Kulasingam⁴, P. Chen¹, J. S. Kim¹, E. Chan⁵, S. Moshkelgosha¹, S. A. Rahman⁶, J. Das⁶, T. Martinu¹, S. Juvet¹, I. Jurisica³, A. Chruscinski¹, R. John¹, A. Konvalinka¹

¹Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada, ²Department of Laboratory Medicine and Pathobiology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada, ³Krembil Research Institute, University Health Network, Toronto, ON, Canada, ⁴Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, ⁵Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON, Canada, ⁶Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Meeting: 2021 American Transplant Congress

Abstract number: 444

Keywords: Antibodies, Endothelial cells, Kidney transplantation, Tumor necrosis factor (TNF)

Topic: Basic Science » B-cell / Antibody /Autoimmunity

Session Information

Session Name: Basic 1

Session Type: Poster Video Chat

Date: Monday, June 7, 2021

Session Time: 7:30pm-8:30pm

Presentation Time: 7:50pm-8:00pm

Location: Virtual

*Purpose: Antibody-mediated rejection (AMR) accounts for >50% of kidney graft losses. AMR is caused by donor-specific antibodies (DSA) against HLA and non-HLA antigens in glomeruli and tubulointerstitium, which together with cytokines such as tumor necrosis factor alpha (TNFα), trigger graft injury. The mechanisms governing cell-specific injury in AMR remain unclear.

*Methods: We studied 30 for-cause kidney biopsies with early AMR, acute cellular rejection (ACR) or acute tubular necrosis (ATN). We laser-captured and microdissected glomeruli and tubulointerstitium and subjected them to unbiased proteome analysis.

*Results: Machine learning revealed that the intensities of all quantified proteins (>2000 per compartment) accurately discriminated AMR from ACR and from ATN (P<0.05). In each compartment, >200 proteins were significantly dysregulated in AMR, compared to ACR and/or ATN (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in AMR. We verified decreased glomerular and tubulointerstitial LAMC1 expression, and decreased glomerular NPHS1 and PTPRO expression in AMR. Cathepsin-V (CTSV) was predicted to cleave ECM-proteins in the AMR glomeruli. We identified galectin-1, an immunomodulatory protein upregulated in the AMR glomeruli and linked to the ECM. Anti-HLA class-I antibodies significantly increased CTSV expression, and galectin-1 expression and secretion, in human glomerular endothelial cells. Glutathione S-transferase omega-1, an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium, and in TNFα-treated proximal tubular epithelial cells.

*Conclusions: Basement membranes are often remodeled in chronic AMR. We demonstrated that this remodeling begins early in glomeruli tubulointerstitium. Targeting ECM-remodeling in AMR may represent a new therapeutic opportunity.

To cite this abstract in AMA style:

Freixas SClotet, McEvoy C, Batruch I, Pastrello C, Kotlyar M, Van J, Arambewela M, Boshart A, Farkona S, Niu Y, Li Y, Famure O, Bozovic A, Kulasingam V, Chen P, Kim JS, Chan E, Moshkelgosha S, Rahman SA, Das J, Martinu T, Juvet S, Jurisica I, Chruscinski A, John R, Konvalinka A. Extracellular Matrix Injury of Kidney Allografts in Antibody-mediated Rejection [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/extracellular-matrix-injury-of-kidney-allografts-in-antibody-mediated-rejection/. Accessed November 21, 2024.

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