The long term objectives of the research project to which these studies relate is to identify natural mechanisms that suppress T cell immunity and promote immune tolerance. The specific focus of studies proposed is to examine molecular and cellular mechanisms that explain how some dendritic cells capable of expressing the enzyme indoleamine 2,3 dioxygenase (IDO-competent DCs) inhibit T cell proliferation, suppress allogeneic T cell responses in vivo, and promote tolerance to skin allografts in mice. Cells expressing IDO protect fetal tissues from attack during pregnancy and suppress T cell immunity to tumors. The significance of studies proposed is that they will provide key new insights into a natural immunoregulatory mechanism that may be manipulated to provide new therapeutic approaches to enhance anti-tumor and anti-pathogen immunity, and to promote tolerance in patients with autoimmune diseases, or who have received organ or tissue allografts, in published and preliminary studies we show that IDO-transgenic mice exhibited enhanced tolerance to skin allografts, while IDO deficient mice exhibited defects in acquired tolerance and CTLA4-Ig-mediated suppression of allogeneic T cell responses. Studies conducted in vitro revealed that minor subsets of murine splenic DCs expressed IDO and blocked T cell proliferation in response to CTLA4-Ig treatment, or when cultured with regulatory T cells (Tregs) expressing surface CTLA4. Hence, the hypothesis that guides this proposal is that CTLA4+ Tregs and IDO-competent DCs collaborate to form a regulatory network that suppresses effector T cell responses and promotes tolerance. Studies proposed in Aim 1 examine the mechanisms that induce IDO gene expression following B7 ligation. Studies in Aim 2 examine how minor subsets of IDO-competent DCs promote dominant T cell suppression and studies in Aim 3 examine the relationship between IDO expression and Treg development and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063402-03
Application #
7149138
Study Section
Special Emphasis Panel (ZRG1-IMM-A (03))
Program Officer
Kehn, Patricia J
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
3
Fiscal Year
2007
Total Cost
$271,179
Indirect Cost
Name
Georgia Regents University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Sharma, Madhav D; Huang, Lei; Choi, Jeong-Hyeon et al. (2013) An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38:998-1012
Munn, David H; Mellor, Andrew L (2013) Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 34:137-43
Ravishankar, Buvana; Liu, Haiyun; Shinde, Rahul et al. (2012) Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A 109:3909-14
Divanovic, Senad; Sawtell, Nancy M; Trompette, Aurelien et al. (2012) Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. J Infect Dis 205:152-61
Huang, Lei; Lemos, Henrique P; Li, Lingqian et al. (2012) Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells. J Immunol 188:4913-20
Li, Lingqian; Huang, Lei; Lemos, Henrique P et al. (2012) Altered tryptophan metabolism as a paradigm for good and bad aspects of immune privilege in chronic inflammatory diseases. Front Immunol 3:109
Mellor, Andrew L; Munn, David H (2011) Physiologic control of the functional status of Foxp3+ regulatory T cells. J Immunol 186:4535-40
Medzhitov, Ruslan; Shevach, Ethan M; Trinchieri, Giorgio et al. (2011) Highlights of 10 years of immunology in Nature Reviews Immunology. Nat Rev Immunol 11:693-702
Makala, Levi H C; Baban, Babak; Lemos, Henrique et al. (2011) Leishmania major attenuates host immunity by stimulating local indoleamine 2,3-dioxygenase expression. J Infect Dis 203:715-25
Baban, Babak; Chandler, Phillip R; Johnson 3rd, Burles A et al. (2011) Physiologic control of IDO competence in splenic dendritic cells. J Immunol 187:2329-35

Showing the most recent 10 out of 27 publications