Preventing Alloimmune Rejection in Heart Transplantation by Tolerogenic Dendritic Cells Induced by GDF15 Through Up-Regulation of IDO and Inhibition of the NFκB Signalling Pathway.

Y. Zhang,^1,3 G. Zhang,¹ L. Moszczynski,¹ D. Zhao,^1,3 P. Abulizi,¹ D. Quan,² T. Mele,² K. Liu,³ X. Zheng.^1,2

¹Pathology, University of Western Ontario, London, ON, Canada
²Surgery, University of Western Ontario, London, ON, Canada
³Cardiovascular Surgery, Jilin University, Cahngchun, China

Meeting: 2017 American Transplant Congress

Abstract number: C284

Keywords: Antigen presentation, Heart/lung transplantation, Rejection, Tolerance

Session Information

Session Name: Poster Session C: Tolerance/Immune Regulation

Session Type: Poster Session

Date: Monday, May 1, 2017

Session Time: 6:00pm-7:00pm

Presentation Time: 6:00pm-7:00pm

Location: Hall D1

Rationale: Growth differentiation factor 15 (GDF15) can inhibit DC maturation, yet whether it can generate tolerogenic dendritic cells (Tol-DCs) to induce immune tolerance in heart transplantation and its signaling remains largely unknown.

Objectives: This study aims to investigate whether GDF15 mediated Tol-DCs can prevent alloimmune rejection in heart transplantation and to understand mechanisms by which GDF15 modulates DCs.

Methods and Results: Bone marrow derived DCs were cultured and treated to up- or down regulate GDF15 expression. Phenotype and immune function of DCs were detected. The signaling pathways of GDF15 activated were examined. The impact of GDF15 treated DCs on preventing allograft immune rejection was assessed in a MHC full mismatch mouse heart transplantation model. We found that BM-derived DCs themselves expressed GDF15. Overexpression of GDF15 increased immunosuppressive/inhibitory molecules indoleamine 2,3-dioxgenase (IDO), programmed cell death 1 ligand (PD-1L), T-cell immunoglobulin domain and mucin domain protein 3 (TIM-3) and galectin 9, and arrested DC immature status. GDF15 not only inhibited DC immune response, but also promoted DCs to generate Treg and to induce T cell exhaustion. GDF15 used tumor growth factor (TGF)β receptors I and II and activated nuclear factor kappa-light-chain-enhancer of activated B cells (NFқB) signaling pathway to regulate DCs. IDO is essential for GDF15 to induce tolerance. Administration of GDF15 treated DCs prevented allograft injection and induced immune tolerance in heart transplantation.

Conclusion: GDF15 induces tolerogenic dendritic cells through inhibition of the NFқB signaling pathway and up-regulation of IDO. GDF15-DCs can prevent alloimmune rejection in heart transplantation.

CITATION INFORMATION: Zhang Y, Zhang G, Moszczynski L, Zhao D, Abulizi P, Quan D, Mele T, Liu K, Zheng X. Preventing Alloimmune Rejection in Heart Transplantation by Tolerogenic Dendritic Cells Induced by GDF15 Through Up-Regulation of IDO and Inhibition of the NFκB Signalling Pathway. Am J Transplant. 2017;17 (suppl 3).

To cite this abstract in AMA style:

Zhang Y, Zhang G, Moszczynski L, Zhao D, Abulizi P, Quan D, Mele T, Liu K, Zheng X. Preventing Alloimmune Rejection in Heart Transplantation by Tolerogenic Dendritic Cells Induced by GDF15 Through Up-Regulation of IDO and Inhibition of the NFκB Signalling Pathway. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/preventing-alloimmune-rejection-in-heart-transplantation-by-tolerogenic-dendritic-cells-induced-by-gdf15-through-up-regulation-of-ido-and-inhibition-of-the-nfb-signalling-pathway/. Accessed November 21, 2024.

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