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Abstract Number: 2170

Human Tolerogenic Dendritic Cells Generated with Protein Kinase C Inhibitor Are Optimal for Regulatory T Cell Induction-a Comparative Study

Endy Adnan1, Hitoshi Hasegawa2, Takuya Matsumoto1, Jun Ishizaki1, Sachiko Onishi1, Koichiro Suemori1 and Masaki Yasukawa1, 1Department of Hematology, Clinical Immunology, and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan, 2Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Dendritic cells, regulatory cells and tolerance

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Session Information

Session Title: Innate Immunity and Rheumatic Disease: Mediators, Cells and Receptors

Session Type: Abstract Submissions (ACR)

Background/Purpose

Tolerogenic dendritic cells (tDCs) are a promising tool for autoimmune diseases, transplantation and allergy. Actually, tDCs have been tried for the therapy of rheumatoid arthritis and type 1 diabetes. To date, immunomodulatory DCs are prepared from monocytes for in vitro experiments by using various agents. Previously, we generated stable tDCs with protein kinase C inhibitor (PKCI) in human and mouse and PKCI-tDCs prevented graft-versus-host disease in a murine model (J Immunol 191: 2247, 2013). The following functional characteristics are required for clinically applicable tDCs: efficient induction of functional regulatory T cells (Treg); CCR7-dependent migration; and stability under proinflammatory conditions. In this study, to select the optimal agent for clinically applicable tDCs, we compared the clinical-grade tDCs generated with various agents.

Methods

We compared tDCs generated with the following agents; vitamin D3 (Vit D3), dexamethasone (Dexa), bisindolylmaleimide I (PKCI), PPAR gamma plus retinoic acid (PPAR+RA), rapamicin (Rapa), IL-10, and TGF-beta. tDCs were prepared by adding these agents prior to the induction of maturation using TNF-alpha, IL-1beta and PGE2. We evaluated the effects of each agent on phenotype, CCR7-dependent migration, cytokine production, phagocytosis, stability, T-cell suppression, and induction of IL-10-producing T cells and functional Foxp3+ Treg cells.

Results

All tDCs except Rapa-tDCs showed an immature or semi-mature phenotype, whereas the phenotype of Rapa-tDCs resembled that of mature DCs. PKCI-tDCs, TGF-tDCs and Rapa-tDCs had moderate and high CCR7 expression, whereas tDCs generated with PPAR+RA, Vit D3, Dexa or IL-10 had very low CCR7 expression. IL-10 production by IL-10-tDCs and PKCI-tDCs was high. Immature DCs (iDCs) and PKCI-tDCs showed high production of TGF-beta. Functionally, iDCs, PKCI-tDCs, PPAR+RA-tDCs, Vit D3-tDCs and IL-10-tDCs strongly suppressed T-cell activation, whereas Dexa-tDCs, TGF-tDCs and Rapa-tDCs weakly suppressed. All tDCs showed phagocytic ability and stable tolerogenic properties under proinflammatory conditions. From these findings, PKCI-tDCs showed moderate expression of CCR7, leading to migrate toward CCR7 ligands, maintained stability, and strongly suppressed T-cell activation by generating IL-10-producing T cells and functional Foxp3+ Treg cells.

Conclusion

PKCI-tDCs appear to be optimal for clinically applicable tDCs. We expect that PKCI-tDCs are useful for tolerance-inducing therapies.


Disclosure:

E. Adnan,
None;

H. Hasegawa,
None;

T. Matsumoto,
None;

J. Ishizaki,
None;

S. Onishi,
None;

K. Suemori,
None;

M. Yasukawa,
None.

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