The origins of autoimmune diseases are poorly understood and standard treatments still rely heavily on immune suppressants that block immunity to infections and tumors despite the recent introduction of novel immune modulatory reagents. Better treatments will likely emerge from improved understanding of the processes that induce and maintain immune tolerance to suppress autoimmunity, and the genetic and environmental factors that cause tolerance breakdown. Our long-term goals are to elucidate the role of the natural regulatory enzyme indoleamine 2,3 dioxygenase (IDO) in suppressing autoimmunity, and to harness this pathway as a novel approach to treat autoimmune syndromes. Chronic type I interferon (IFN??) production by plasmacytoid dendritic cells (pDCs) that sense microbial infections is a feature of several autoimmune syndromes, implying that sustained IFN?? release drives tolerance breakdown. However IFN?? induces some dendritic cell (DC) subsets to express IDO, and DCs expressing IDO suppress T cell responses, in part by stabilizing the default regulatory phenotypes of Foxp3-lineage CD4 T cells (Tregs). Thus reagents that induce IDO and activate Tregs may ameliorate autoimmune diseases. Recently, we reported that treating mice with DNA nanoparticles suppressed T cell responses to immunization and alleviated immune-mediated joint injury in a mouse model of arthritis. Tolerogenic responses to nanoparticle cargo DNA were mediated via IFN?? and IDO but were not dependent on TLR9 or IFN? signaling accordingly, removing TLR9 ligands (CpG motifs) from cargo DNA did not affect tolerogenic responses but lowered potentially toxic release of IFN?. In this revised application we identify the DNA sensing pathway in rare innate immune cells that drives tolerogenic responses to cargo DNA, and show that DNA nanoparticles inhibited autoimmune disease onset in mouse models of multiple sclerosis and type I diabetes. Our goals are to elucidate the tolerogenic pathway targeted by DNA nanoparticles and to engineer DNA nanoparticles as potential tolerogenic vaccines to treat and prevent autoimmune syndromes.

Public Health Relevance

We propose focused studies to identify key elements of a pathway targeted by DNA nanoparticles that mediates dominant tolerogenic effects on autoimmune syndromes, and to engineer these highly versatile reagents as vaccines designed to protect healthy tissues at risk of immune-mediated destruction in mouse models of clinical autoimmune syndromes. ! !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI103347-02
Application #
8678838
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Lapham, Cheryl K
Project Start
2013-06-15
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$375,000
Indirect Cost
$125,000
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Lemos, Henrique; Mohamed, Eslam; Huang, Lei et al. (2016) STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. Cancer Res 76:2076-81
Munn, David H; Mellor, Andrew L (2016) IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends Immunol 37:193-207
Lemos, Henrique; Huang, Lei; McGaha, Tracy et al. (2015) STING, nanoparticles, autoimmune disease and cancer: a novel paradigm for immunotherapy? Expert Rev Clin Immunol 11:155-65
Liu, Haiyun; Huang, Lei; Bradley, Jillian et al. (2014) GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology. Mol Cell Biol 34:428-38
Ding, Zhi-Chun; Lu, Xiaoyun; Yu, Miao et al. (2014) Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res 74:3441-53
Li, Minghui; Bolduc, Aaron R; Hoda, Md Nasrul et al. (2014) The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J Immunother Cancer 2:21
Lemos, Henrique; Huang, Lei; McGaha, Tracy L et al. (2014) Cytosolic DNA sensing via the stimulator of interferon genes adaptor: Yin and Yang of immune responses to DNA. Eur J Immunol 44:2847-53
Ravishankar, Buvana; Shinde, Rahul; Liu, Haiyun et al. (2014) Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proc Natl Acad Sci U S A 111:4215-20
Huang, Lei; Mellor, Andrew L (2014) Metabolic control of tumour progression and antitumour immunity. Curr Opin Oncol 26:92-9
Lemos, Henrique; Huang, Lei; Chandler, Phillip R et al. (2014) Activation of the STING adaptor attenuates experimental autoimmune encephalitis. J Immunol 192:5571-8

Showing the most recent 10 out of 15 publications