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Transplantation Research

, 1:15

Myeloid suppressor cell therapy

Abstract

Myeloid-derived suppressor cells MDSCs are natural immunosuppressive cells and endogenous inhibitors of the immune system. We describe a simple and clinically compatible method of generating large numbers of MDSCs using the cultures of peripheral blood-isolated monocytes supplemented with prostaglandin E2 PGE2. We observed that PGE2 induces endogenous cyclooxygenase COX2 expression in cultured monocytes, blocking their differentiation into CD1a dendritic cells DCs and inducing the expression of indoleamine 2,3-dioxygenase 1, IL-4Rα, nitric oxide synthase 2 and IL-10 - typical MDSC-associated suppressive factors. The establishment of a positive feedback loop between PGE2 and COX2, the key regulator of PGE2 synthesis, is both necessary and sufficient to promote the development of CD1a DCs to CD14CD33CD34 monocytic MDSCs in granulocyte macrophage colony stimulating factor-IL-4-supplemented monocyte cultures, their stability, production of multiple immunosuppressive mediators and cytotoxic T lymphocyte-suppressive function. In addition to PGE2, selective E-prostanoid receptor EP2- and EP4-agonists, but not EP3-1 agonists, also induce the MDSCs development, suggesting that other activators of the EP2-4- and EP2-4-driven signaling pathway adenylate cyclase-cAMP-PKA-CREB may be used to promote the development of suppressive cells. Our observations provide a simple method for generating large numbers of MDSCs for the immunotherapy of autoimmune diseases, chronic inflammatory disorders and transplant rejection.

KeywordsCancer COX2 Dendritic cells Human Immune dysfunction Immunotherapy Myeloid-derived suppressor cells PGE2 Transplantation AbbreviationsCOXCyclooxygenase

DCDendritic cell

EPE-prostanoid receptor

GM-CSFGranulocyte macrophage colony stimulating factor

GrBGranzyme B

HO-1Heme-oxygenase

IDOIndoleamine 2,3-dioxygenase

IFNInterferon

ILInterleukin

ILTInhibitory receptor Ig-like transcript

iMCImmature myeloid cells

iNOSInducible nitric oxide synthase

LinLineage

MDSCMyeloid-derived suppressor cell

NOSNitric oxide synthase

PBMCPeripheral blood mononuclear cell

PGE2Prostaglandin E2

ThT helper

TregRegulatory T cells.

Electronic supplementary materialThe online version of this article doi:10.1186-2047-1440-1-15 contains supplementary material, which is available to authorized users.

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Autor: Nataša Obermajer - Pawel Kalinski

Fuente: https://link.springer.com/







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