The vertebrate immune system has the capacity to mount potent, destructive responses in the presence of threatening foreign antigens. A significant element of immune function relates to regulating antigen responses in order to prevent auto-destruction. This regulation, which can be broadly termed """"""""immune tolerance,"""""""" is now known to encompass a variety of active mechanisms. The goal of understanding these mechanisms holds great pathophysiologic and therapeutic significance for the study of allotransplant rejection, autoimmunity, neoplasia and chronic infection. A central event in the initiation of antigen-specific immune responses is the interaction between T cells and antigen presenting cells (APCs). It is now known that one subtype of APCs - the Dendritic Cell (DC) - can be both the most potent activator of T cells as well as a powerful negative regulator, depending on the level and nature and of accessory signals it presents along with antigen. The process by which DCs upregulate accessory ligands for T cell activation is termed """"""""maturation."""""""" Thus, the control of DC maturity is a central process in the regulation of T cell activation and tolerance. We have found that DC maturation is potently inhibited by physiological concentrations of Vitamin D3 and a related analog and that in vivo presentation of a specific alloantigen by vitamin D3-conditioned (immature) DCs results in hyporesponsiveness while unconditioned (mature) DCs mediate potent sensitization to the same antigen. This proposal will test the hypotheses that: (a) DCs conditioned by a Vitamin D3 analog mediate antigen-specific immune tolerance in vivo, (b) Vitamin D3 antagonizes DC maturation by modulating the NF-kB signaling pathway in DCs, and (c) Vitamin D3 contributes to immune homeostasis by maintaining DC immaturity in vivo. These hypotheses will be tested by: (i) the use of murine models of allograft rejection and adoptive transfer of TCR transgenic T cells in which specific T cell/DC interactions can be characterized, (ii) the strategy of blocking individual accessory pathways or administering pharmacological immunosuppressants at the time of DC inoculation, (iii) the in vitro characterization of the functional status of multiple elements of the NF-kB signaling pathway in the presence or absence of Vitamin D3 analog, (iv) the generation of in vivo models of the immune system in which the Vitamin D Receptor has been genetically deleted.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059505-02
Application #
6517898
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Eggers, Paul Wayne
Project Start
2001-07-15
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$222,233
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Griffin, Matthew D; Dong, Xiangyang; Kumar, Rajiv (2007) Vitamin D receptor-mediated suppression of RelB in antigen presenting cells: a paradigm for ligand-augmented negative transcriptional regulation. Arch Biochem Biophys 460:218-26
Griffin, Matthew D; Kumar, Rajiv (2005) Multiple potential clinical benefits for 1alpha,25-dihydroxyvitamin D3 analogs in kidney transplant recipients. J Steroid Biochem Mol Biol 97:213-8
Dong, Xiangyang; Lutz, Ward; Schroeder, Tania M et al. (2005) Regulation of relB in dendritic cells by means of modulated association of vitamin D receptor and histone deacetylase 3 with the promoter. Proc Natl Acad Sci U S A 102:16007-12
Griffin, Matthew D; Xing, Nianzeng; Kumar, Rajiv (2004) Gene expression profiles in dendritic cells conditioned by 1alpha,25-dihydroxyvitamin D3 analog. J Steroid Biochem Mol Biol 89-90:443-8
Schiavi, Susan C; Kumar, Rajiv (2004) The phosphatonin pathway: new insights in phosphate homeostasis. Kidney Int 65:1-14
Griffin, Matthew D; Kumar, Rajiv (2003) Effects of 1alpha,25(OH)2D3 and its analogs on dendritic cell function. J Cell Biochem 88:323-6
Kanaan, Nada; Bachman, Lori A; McGregor, Christopher G A et al. (2003) Porcine antigen presenting cells produce soluble adjuvants that stimulate B cells within and across the species. Am J Transplant 3:403-15
Griffin, Matthew D; Xing, Nianzeng; Kumar, Rajiv (2003) Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annu Rev Nutr 23:117-45
Lutz, Ward; Frank, Elena M; Craig, Theodore A et al. (2003) Calbindin D28K interacts with Ran-binding protein M: identification of interacting domains by NMR spectroscopy. Biochem Biophys Res Commun 303:1186-92
Dong, Xiangyang; Bachman, Lori A; Kumar, Rajiv et al. (2003) Generation of antigen-specific, interleukin-10-producing T-cells using dendritic cell stimulation and steroid hormone conditioning. Transpl Immunol 11:323-33

Showing the most recent 10 out of 19 publications