CBER Research Projects

Project Title

Functional Characterization of Dendritic Cells That Induce Tolerance

Principal Investigator

Gary Kikuchi

Laboratory

Laboratory of Immunology; Division of Therapeutic Proteins; Office of Therapeutics Research and Review

Project Summary

We have isolated an immortalized antigen presenting cell line from the bone marrow of ts SV40 T Ag transgenic mice. Phenotypically, this cell line expresses myeloid markers CD11b, F4/80, and the dendritic cell marker CD11c, but no T cell markers and few B cell markers. The cell line is low in the expression of MHC class II and costimulatory molecules CD40, CD80, and CD86. Stimulation of this antigen presenting cell line with LPS induces the secretion of cytokines IL-6, IL-12 (p40) and TNF-alpha, but no upregulation of MHC class II or costimulatory molecules. Preliminary in vitro assays suggest that these cells induce hyporesponsiveness in allogeneic T cells, and in syngeneic T cells stimulated by anti-CD3 or antigen. Preliminary in vivo assays suggest that these cells can induce hyporesponsiveness in wild type mice primed with antigen into which CD8+ T cells transgenic for the TCR recognizing OVA 257-264 are adoptively transferred. Hyporesponsiveness in allogeneic T cells could be overcome by addition of exogenous high-dose IL-2 or blocking the interaction between Fas and Fas L. These cells may represent immortalized bone-marrow derived antigen presenting cells that induce functional tolerance.

Future experiments will be aimed at generating stable subclones of this original antigen presenting cell line and verifying that the subclones have the same phenotypic and functional characteristics of the original antigen presenting cell line. Next, in vitro characterization of the subclones will be performed with an eye toward elucidating the mechanism of tolerance, if any, observed. Finally in vivo experiments are planned either in a model of adoptive transfer of transgenic TCR or in a murine model of human autoimmune disease.

Last Updated: 4/1/2002

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Date created: September 25, 2003

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