Autoimmunity is reaching epidemic proportions with tens of millions of people suffering from diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes (T1D), systemic lupus erythematosus and others. In addition to its financial costs, the long term complications of these diseases can be devastating. A curative therapy is desperately needed. At present, efforts to prevent or reverse autoimmune diseases have been limited by the lack of safe and effective immunotherapies. With this challenge in mind, we believe the induction of immunological tolerance is a fundamental requirement for any effective therapy. Previous studies, including numerous published reports from our ACEs group and others, have focused on the use of regulatory T cells (Tregs) as one means of restoring tolerance in autoimmunity. This notion is based on the core "principle that treatment with Tregs will lead to the induction of long-term tolerance. Most significantly, there is strong evidence that self-antigen-specific Tregs are most effective to treat a variety of autoimmune diseases. However, the identification and application of these cells have been compromised by the lack of effective isolation and expansion protocols for these low frequency cells. Thus, novel approaches are necessary to address this need. Specifically, this application proposes to develop novel approaches to generate a sufficient quantity of antigen-specific Tregs capable of restoring tolerance and averting autoimmunity. These studies will be performed as a collaborative effort between the Abbas and Bluestone labs where multiple mouse models have been established and be used to rapidly test theoretical cell manipulations. These efforts will inform and enhance the bulk research efforts in his proposal develoted to human Treg studies and the development of engenerred Tregs that can be used both to study the biology of Tregs and potentially be developed for clinical application. To address these key issues, the following specific aims are proposed.
Aim 1. Develop engineered antigen-specific Tregs by introducing autoreactive T cell receptors (TCRs) and other therapeutic genes.
Aim 2. Assess the mechanisms and safety of cellular therapy with engineered Tregs.
Aim 3. To generate high numbers of autoreactive engineered Tregs capable of suppressing pathogenic autoreactive T cell responses.

Public Health Relevance

The ability to manipulate the immune system through re-establishing tolerance is a highly relevant goal to the treatment of autoimmune diseases. Cell-based therapies can provide a novel approach if we can develop a highly antigen-specific, stable autologous regulatory T cell population that can be administered in sufficient numbers. Success in the aims outlined in this project will move this field forward in clincally relevant ways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI056388-10
Application #
8454525
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$178,076
Indirect Cost
$36,746
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Sanchez Rodriguez, Robert; Pauli, Mariela L; Neuhaus, Isaac M et al. (2014) Memory regulatory T cells reside in human skin. J Clin Invest 124:1027-36
Stumpf, Melanie; Zhou, Xuyu; Chikuma, Shunsuke et al. (2014) Tyrosine 201 of the cytoplasmic tail of CTLA-4 critically affects T regulatory cell suppressive function. Eur J Immunol 44:1737-46
Gratz, Iris K; Truong, Hong-An; Yang, Sara Hsin-Yi et al. (2013) Cutting Edge: memory regulatory t cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J Immunol 190:4483-7
Herold, Kevan C; Vignali, Dario A A; Cooke, Anne et al. (2013) Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 13:243-56
Jeker, Lukas T; Bluestone, Jeffrey A (2013) MicroRNA regulation of T-cell differentiation and function. Immunol Rev 253:65-81
de Kouchkovsky, Dimitri; Esensten, Jonathan H; Rosenthal, Wendy L et al. (2013) microRNA-17-92 regulates IL-10 production by regulatory T cells and control of experimental autoimmune encephalomyelitis. J Immunol 191:1594-605
Stumpf, Melanie; Zhou, Xuyu; Bluestone, Jeffrey A (2013) The B7-independent isoform of CTLA-4 functions to regulate autoimmune diabetes. J Immunol 190:961-9
Jeker, Lukas T; Zhou, Xuyu; Blelloch, Robert et al. (2013) DGCR8-mediated production of canonical microRNAs is critical for regulatory T cell function and stability. PLoS One 8:e66282
Rosenblum, Michael D; Gratz, Iris K; Paw, Jonathan S et al. (2011) Response to self antigen imprints regulatory memory in tissues. Nature 480:538-42

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