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Dissertation Information for Geling Li

NAME:
- Geling Li

DEGREE:
- Ph.D.

DISCIPLINE:
- Microbiology and Immunology

SCHOOL:
- Indiana University (USA) (2005)

ADVISORS:
- Hal E Broxmeyer

COMMITTEE MEMBERS:
- Randy R. Brutkiewicz
- Maureen A. Harrington
- Kenneth G Cornetta

MPACT Status: Incomplete - Not_Inspected

Title: . Macrophage colony stimulating factor-induced differentiation of human cord blood monocytes into IL-10(high)IL-12(absent) dendritic cells with tolerogenic potential and into a rare population of CD16(+) monocytes

Abstract: Tolerogenic dendritic cells (DCs) play an extremely important role in establishing immune tolerance. However, it is not clear how they develop in vitro and in vivo . The aim of this study was to identify a differentiation pathway of DCs with tolerogenic potential in vitro and to characterize their migration capacity. Granulocyte-macrophage (GM)- colony stimulating factor (CSF), combined with interleukin (IL)-4 or IL-4/transforming growth factor (TGF)-β1 induces monocyte differentiation into DCs. Macrophage (M)-CSF is critical for the monocytic lineage, its level is dramatically elevated in immunosuppressive conditions, and M-CSF deficient mice are osteopetrotic. We hypothesized that M-CSF might be involved in generation of a novel subtype of suppressive DCs which may be capable of migrating into places where a non-efficient immune reaction occurs, such as tumour stroma, placenta and bone marrow. As SDF-1 is expressed in the above places, we hypothesized that M-CSF-induced suppressive DCs might respond chemotactically to SDF-1. Highly purified umbilical cord blood (CB) monocytes cultured in the presence of M-CSF and IL-4 differentiated, in a GM-CSF-independent fashion, into IL-10 high IL-12 absent cells with heterogeneous morphology and DC phenotype. The addition of TGF-β1 into M-DC cultures produced cells with a DC morphology. Single time stimulation with immature DCs derived from CB induced regulatory T cells. Mature M-DCs induced lower proliferation of naïve CD4 T cells in both primary and secondary mixed lymphocyte reaction (MLR) than mature DCs and showed tolerogenic potential. Furthermore, TGF-β-treated M-DCs expressed higher levels of surface CXCR4 than TGF-β-treated DC and demonstrated enhanced responsiveness to SDF-1-induced chemotaxis. Beyond its role in DC differentiation, M-CSF in combination with IL-4 and IL-10 induced monocyte differentiation into CD14 + CD16 ++ dendritic-like cells with a similar phenotype and function to that of the rare population of CD14 + CD16 ++ monocytes present in vivo . CB monocytes were more responsive than adult blood (AB) monocytes to the effect of IL-10 on the generation of CD14 + CD16 ++ cells. Together, our results demonstrate novel and multiple roles for M-CSF in the differentiation of suppressive DCs and CD14 + CD16 ++ dendritic-like cells. This information is of relevance to efforts to induce bone marrow chimerism and/or tolerance during bone marrow transplantation and/or autoimmune diseases.

MPACT Scores for Geling Li

A = 0
C = 0
A+C = 0
T = 0
G = 0
W = 0
TD = 0
TA = 0
calculated 2010-12-13 19:07:13

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