Background: Chronic exposure to immunosuppressive agents for organ transplant results in graft nephrotoxicity, infections and malignancies We have established durable immune tolerance in mismatched related and unrelated donor-recipient pairs for kidney transplantation, using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (SC) and tolerogenic CD8+/TCR− graft facilitating cells (FCRx) combined with nonmyeloablative conditioning. The present study aimed to characterize molecular pathways in allograft biopsies associated with induced tolerance by the FCRx protocol.

Patients and methods: Formalin-fixed paraffin-embedded (FFPE) graft biopsy samples were available from recipients with rejection (R; n =10), and without rejection under standard immunosuppression (SIS; n = 10) or FCRx induced tolerance (FCRx; n = 7) protocols, and at pre-transplant graft samples from FCRx-paired donors (n = 5). Gene expression was done using SensationPlus™ FFPE Amplification and WT Labeling Kit for Affymetrix^TM GeneChip^® HG-U133 2.0 microarray hybridization. A p-value ≤ 0.001 was considered significant and a controlled False Discovery Rate > 5%. Gene pathway analyses were performed using IPA tool.

Results: When we compared FCRx vs. R differential gene expression profile we found inhibition of molecular pathways involved in adaptive and cell-mediated immune response. Top molecular pathways significantly inhibited included antigen presentation, CD28 signaling in T helper cells, cytotoxic T cell-mediated apoptosis, GVHD signaling, allograft rejection signaling, and T helper cell differentiation.B-cell receptor signaling pathway was found to be up-regulated in FCRx together with activation of April-mediated signaling.

Conclusion: The FCRx protocol to induce tolerance in KT recipients is associated with a complete suppression of adaptive and cell-mediated immune responses. B-cell activation remains activated in FCRx protocol. The comparison of paired FCRx samples and pre-implantation donor samples suggests absence of an inflammatory or active immune response.

CITATION INFORMATION: Gallon L., Mathew J., Bontha S., Dumur C., Dalal P., Nadimpalli L., Maluf D., Shetty A., Ildstad S., Leventhal J., Mas V. Renal Allograft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation Am J Transplant. 2017;17 (suppl 3).

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