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. 2014 Nov-Dec;21(6):533-42.
doi: 10.1111/xen.12121. Epub 2014 Jul 9.

Pig to rat cell transplantation: reduced cellular and antibody responses to xenografts overexpressing PD-L1

Annegret Plege-Fleck  1 , Thorsten Lieke, Dorothee Römermann, Heike Düvel, Joachim Hundrieser, Anna Buermann, Lilli Kraus, Jürgen Klempnauer, Reinhard Schwinzer
Affiliations

Pig to rat cell transplantation: reduced cellular and antibody responses to xenografts overexpressing PD-L1

Annegret Plege-Fleck et al. Xenotransplantation. 2014 Nov-Dec.

Abstract

Background: Programmed death-1 (PD-1) costimulation acts as a negative regulator of T-cell responses to allografts. However, the role of the PD-1 pathway in xenotransplantation is not well defined yet. We have shown previously that human in vitro T-cell responses to porcine transfectants overexpressing PD-Ligand1 (L23-PD-L1 cells) are remarkably weak. In this report, we asked whether the PD-1/PD-L1 pathway has the potential to diminish xenogeneic immune responses also in vivo.

Methods: L23-PD-L1 or mock transfected control cells (L23-GFP) were transplanted under the kidney capsule of rats. The occurrence of kidney-infiltrating rat leukocytes and the induction of anti-pig antibodies were monitored in grafted animals.

Results: Assessment of cellular infiltrates revealed similar numbers of macrophages in kidneys grafted with L23-PD-L1 or L23-GFP control cells. However, the level of MHC class-II molecules was reduced on macrophages responding to L23-PD-L1 grafts, suggesting a lower state of activation. Furthermore, less T cells were found in kidneys receiving L23-PD-L1 cells. In addition, the titers of induced anti-pig antibodies were significantly lower in rats grafted with L23-PD-L1 cells.

Conclusions: These data suggest that signals triggered by PD-1-PD-L1 interaction interfere with activation pathways involved in the induction of cellular and antibody-mediated immune responses to xenografts in vivo. Targeting of PD-1 and/or PD-L1 may be a promising approach for immune modulation after xenotransplantation.

Keywords: PD-1/PD-Ligands; immune modulation; negative costimulation.

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