Abstract

The immune system is composed of multiple effectors, T, B, NK and NKT cells each of which has been classified into subsets according to their functions. Immune effectors are dependent on Dendritic Cells (DCs) for their activation and their differentiation. And, as the immune effectors, DCs are also composed of distinct subsets. When considering human DCs, two main pathways are currently recognized: 1) The myeloid DCs separated into Langerhans Cells, specific to epidermis, and Interstitial DCs, present in other tissues and probably representing a collection of as yet unidentified subsets; 2) The plasmacytoid DCs, unique for their ability to produce large amounts of IFN alpha/beta in response to viral encounter. Recent findings of Interferon (IFN) biology reactivated immunologists' interest in this family of molecules. This includes i) the ability of IFN alpha/beta to activate immature DCs and the ability of IFN to induce the differentiation of monocytes into DCs (IFN-DCs), the theme of this proposal; ii) the activity of IFN alpha/beta in the generation of memory CD8+T cells and the stimulation of antibody responses; iii) the central role of IFN alpha/beta in the pathogenesis of Systemic Lupus Erythematosus. It is our hypothesis that the stimulatory effect of IFNalpha/beta on monocytes/myeloid DCs explain most, if not all the immunoregulatory role of IFN alpha/beta. This represents the essence of our proposal for two main reasons: 1) IFN-DCs circulate in patients suffering from SLE, 2) IFN-DCs may explain the therapeutic effects of IFN alpha in patients suffering from i) cancer such as melanoma, myeloma and AML or ii) infectious diseases such as hepatitis B.
Four AIMS have been designed to provide an extensive characterization of IFN-DCs:
AIM 1 analyzes the DCs themselves including their phenotype and their migration pattern.
AIM 2 studies the functional effects of IFN-DCs on CD4+T cells.
AIM 3 characterizes the differentiation of CD8+ T cells in response to IFN-DCs, with or without T cell help.
AIM 4 identifies which IFN-DCs molecules skew the differentiation of T cells. This research, which focuses on the biology of human DC subsets has two important medical applications:1) better understanding of autoimmune diseases such as SLE; 2) the generation of more potent DC-based cancer vaccines. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078846-07
Application #
6896440
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Mccarthy, Susan A
Project Start
1999-04-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
7
Fiscal Year
2005
Total Cost
$308,813
Indirect Cost

  Institution

Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204

  Publications

Palucka, Karolina; Banchereau, Jacques (2013) Human dendritic cell subsets in vaccination. Curr Opin Immunol 25:396-402
Palucka, Karolina; Banchereau, Jacques (2013) Dendritic-cell-based therapeutic cancer vaccines. Immunity 39:38-48
Flamar, Anne-Laure; Zurawski, Sandra; Scholz, Felix et al. (2012) Noncovalent assembly of anti-dendritic cell antibodies and antigens for evoking immune responses in vitro and in vivo. J Immunol 189:2645-55
Banchereau, Jacques; Thompson-Snipes, LuAnn; Zurawski, Sandra et al. (2012) The differential production of cytokines by human Langerhans cells and dermal CD14(+) DCs controls CTL priming. Blood 119:5742-9
Banchereau, Jacques; Zurawski, Sandra; Thompson-Snipes, LuAnn et al. (2012) Immunoglobulin-like transcript receptors on human dermal CD14+ dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming. Proc Natl Acad Sci U S A 109:18885-90
Palucka, Karolina; Banchereau, Jacques (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12:265-77
Palucka, Karolina; Ueno, Hideki; Roberts, Lee et al. (2011) Dendritic cell subsets as vectors and targets for improved cancer therapy. Curr Top Microbiol Immunol 344:173-92
Palucka, K; Ueno, H; Fay, J et al. (2011) Dendritic cells and immunity against cancer. J Intern Med 269:64-73
Morita, Rimpei; Schmitt, Nathalie; Bentebibel, Salah-Eddine et al. (2011) Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34:108-21
Pedroza-Gonzalez, Alexander; Xu, Kangling; Wu, Te-Chia et al. (2011) Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation. J Exp Med 208:479-90

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