Details
| Original language | English |
|---|---|
| Pages (from-to) | 2692-2704 |
| Number of pages | 13 |
| Journal | American Journal of Transplantation |
| Volume | 19 |
| Issue number | 10 |
| Early online date | 6 May 2019 |
| Publication status | Published - 26 Sept 2019 |
Abstract
The role of endothelial cells in the pathophysiology of antibody-mediated rejection after renal transplantation has been widely investigated. We expand this scenario to the impact of epithelial cells on the microenvironment during rejection. Primary proximal tubular epithelial cells were stimulated via HLA class I, CD155 and CD166 based on their potential signal-transducing capacity to mediate back signaling after encounter with either T/NK cells or donor-specific antibodies. Upon crosslinking of these ligands with mAbs, PTEC secreted IL-6, CXCL1,8,10, CCL2, and sICAM-1. These proteins were also released by PTEC as consequence of a direct interaction with T/NK cells. Downmodulation of the receptor CD226 on effector cells confirmed the involvement of this receptor/ligand pair in back signaling. In vivo, CD155 and CD166 expression was detectable in proximal and distal tubuli of renal transplant biopsies, respectively. The composition of the protein microenvironment in these biopsies showed a substantial overlap with the PTEC response. Cluster and principal component analyses of the microenvironment separated unsuspicious from rejection biopsies and, furthermore, ABMR, TCMR, and borderline rejection. In conclusion, our results provide evidence that epithelial cells may contribute to the rejection process and pave the way to a better understanding of the pathomechanisms of kidney allograft rejection.
Keywords
- basic (laboratory) research/science, biomarker, immune regulation, immunobiology, immunosuppression/immune modulation, kidney transplantation/nephrology, natural killer (NK) cells/NK receptors, rejection: antibody-mediated (ABMR), T cell biology
ASJC Scopus subject areas
- Medicine(all)
- Immunology and Allergy
- Medicine(all)
- Transplantation
- Medicine(all)
- Pharmacology (medical)
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In: American Journal of Transplantation, Vol. 19, No. 10, 26.09.2019, p. 2692-2704.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Back signaling of HLA class I molecules and T/NK cell receptor ligands in epithelial cells reflects the rejection-specific microenvironment in renal allograft biopsies
AU - Egelkamp, Johanna
AU - Chichelnitskiy, Evgeny
AU - Kühne, Jenny F.
AU - Wandrer, Franziska
AU - Daemen, Kerstin
AU - Keil, Jana
AU - Bräsen, Jan Hinrich
AU - Schmitz, Jessica
AU - Bellmàs-Sanz, Ramon
AU - Iordanidis, Susanne
AU - Katsirntaki, Katherina
AU - Hake, Kevin
AU - Akhdar, Ali
AU - Neudörfl, Christine
AU - Haller, Hermann
AU - Blume, Cornelia
AU - Falk, Christine S.
N1 - Funding information: This work was supported by the German Research Foundation DFG, SFB738, B3 (CSF), the German Ministry for Education and Research BMBF, IFB-Tx BMBF 01EO1302 (CSF), the German Center for Infection Research DZIF TTU-IICH (CSF), the Ministry of Lower Saxony for Research and Art (MWK), Project “gender sensible medicine in kidney transplantation” and the Jackstädt foundation (JHB, JS).
PY - 2019/9/26
Y1 - 2019/9/26
N2 - The role of endothelial cells in the pathophysiology of antibody-mediated rejection after renal transplantation has been widely investigated. We expand this scenario to the impact of epithelial cells on the microenvironment during rejection. Primary proximal tubular epithelial cells were stimulated via HLA class I, CD155 and CD166 based on their potential signal-transducing capacity to mediate back signaling after encounter with either T/NK cells or donor-specific antibodies. Upon crosslinking of these ligands with mAbs, PTEC secreted IL-6, CXCL1,8,10, CCL2, and sICAM-1. These proteins were also released by PTEC as consequence of a direct interaction with T/NK cells. Downmodulation of the receptor CD226 on effector cells confirmed the involvement of this receptor/ligand pair in back signaling. In vivo, CD155 and CD166 expression was detectable in proximal and distal tubuli of renal transplant biopsies, respectively. The composition of the protein microenvironment in these biopsies showed a substantial overlap with the PTEC response. Cluster and principal component analyses of the microenvironment separated unsuspicious from rejection biopsies and, furthermore, ABMR, TCMR, and borderline rejection. In conclusion, our results provide evidence that epithelial cells may contribute to the rejection process and pave the way to a better understanding of the pathomechanisms of kidney allograft rejection.
AB - The role of endothelial cells in the pathophysiology of antibody-mediated rejection after renal transplantation has been widely investigated. We expand this scenario to the impact of epithelial cells on the microenvironment during rejection. Primary proximal tubular epithelial cells were stimulated via HLA class I, CD155 and CD166 based on their potential signal-transducing capacity to mediate back signaling after encounter with either T/NK cells or donor-specific antibodies. Upon crosslinking of these ligands with mAbs, PTEC secreted IL-6, CXCL1,8,10, CCL2, and sICAM-1. These proteins were also released by PTEC as consequence of a direct interaction with T/NK cells. Downmodulation of the receptor CD226 on effector cells confirmed the involvement of this receptor/ligand pair in back signaling. In vivo, CD155 and CD166 expression was detectable in proximal and distal tubuli of renal transplant biopsies, respectively. The composition of the protein microenvironment in these biopsies showed a substantial overlap with the PTEC response. Cluster and principal component analyses of the microenvironment separated unsuspicious from rejection biopsies and, furthermore, ABMR, TCMR, and borderline rejection. In conclusion, our results provide evidence that epithelial cells may contribute to the rejection process and pave the way to a better understanding of the pathomechanisms of kidney allograft rejection.
KW - basic (laboratory) research/science
KW - biomarker
KW - immune regulation
KW - immunobiology
KW - immunosuppression/immune modulation
KW - kidney transplantation/nephrology
KW - natural killer (NK) cells/NK receptors
KW - rejection: antibody-mediated (ABMR)
KW - T cell biology
UR - http://www.scopus.com/inward/record.url?scp=85072717299&partnerID=8YFLogxK
U2 - 10.1111/ajt.15417
DO - 10.1111/ajt.15417
M3 - Article
C2 - 31062482
AN - SCOPUS:85072717299
VL - 19
SP - 2692
EP - 2704
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
IS - 10
ER -