Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation

Lorenzo Gallon, James M. Mathew, Sai Vineela Bontha, Catherine I. Dumur, Pranav Dalal, Lakshmi Nadimpalli, Daniel Maluf, Aneesha A. Shetty, Suzanne T. Ildstad, Joseph R. Leventhal, Valeria Mas

Research output: Contribution to journalArticle

Abstract

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways.

Original languageEnglish (US)
Pages (from-to)423-433
Number of pages11
JournalJournal of the American Society of Nephrology
Volume29
Issue number2
DOIs
StatePublished - Feb 1 2018

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Kidney Transplantation
Immunosuppression
Allografts
Tissue Donors
MicroRNAs
B-Lymphocytes
Up-Regulation
Transplantation Tolerance
Biopsy
Gene Expression
Chimerism
Critical Pathways
Gene Regulatory Networks
Gene Expression Profiling
Graft Survival
Homeostasis
Anti-Inflammatory Agents
Stem Cells
Down-Regulation
Maintenance

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation. / Gallon, Lorenzo; Mathew, James M.; Bontha, Sai Vineela; Dumur, Catherine I.; Dalal, Pranav; Nadimpalli, Lakshmi; Maluf, Daniel; Shetty, Aneesha A.; Ildstad, Suzanne T.; Leventhal, Joseph R.; Mas, Valeria.

In: Journal of the American Society of Nephrology, Vol. 29, No. 2, 01.02.2018, p. 423-433.

Research output: Contribution to journalArticle

Gallon, L, Mathew, JM, Bontha, SV, Dumur, CI, Dalal, P, Nadimpalli, L, Maluf, D, Shetty, AA, Ildstad, ST, Leventhal, JR & Mas, V 2018, 'Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation', Journal of the American Society of Nephrology, vol. 29, no. 2, pp. 423-433. https://doi.org/10.1681/ASN.2017030348
Gallon, Lorenzo ; Mathew, James M. ; Bontha, Sai Vineela ; Dumur, Catherine I. ; Dalal, Pranav ; Nadimpalli, Lakshmi ; Maluf, Daniel ; Shetty, Aneesha A. ; Ildstad, Suzanne T. ; Leventhal, Joseph R. ; Mas, Valeria. / Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 2. pp. 423-433.
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