The basic studies described in project one are focused on mechanistic studies of autoimmunity, self-tolerance, and immune modulation in human CD4 T cells. Recent studies have identified a gene product GRAIL, required for maintenance of unresponsiveness in murine and human CD4 T cells. When GRAIL is present, both murine and human CD4 T cells have a markedly decreased ability to proliferate in response to activation signals. Mechanism of action studies for three therapeutic agents developed for clinical intervention in autoimmunity and transplantation (Rapamycin, anti-IL-2, and CTLA-4Ig). have linked molecular regulators of CD4 T-cell anergy including GRAIL and its epistatic regulators, to therapeutic effect These studies demonstrated that activation of naive, but not memory CD4 T cells, could be blocked by treatment with all three drugs and that the therapeutic effect was linked to the selective inhibition of the translation of an epistatic regulator of GRAIL, called Otubain-1 (Otub-1), that maintained nai've CD4 T cell unresponsiveness (anergy). Preliminary studies suggest that these findings translate in human CD4 T cells as well. A second set of preliminary data were generated in the study of murine regulatory T cells (Tregs), where obligate cellxell interaction requirements between Tregs (surface CTLA4) and T effectors (Teffs) (TCR induced B7 molecules) were characterized, that can be translated in human CD4 Tregs and Teffs as described below.
Four Specific Aims have been developed to address the following hypotheses: (1) naive and memory human CD4 T cells are held in check by GRAIL expression and overcoming GRAIL mediated inhibition of activation is differentially regulated in naive versus memory human CD4 T cells, thus requiring selective agents for therapeutic effect;and (2) CD4 Tregs regulate CD4 Teffs through Treg CTLA4 engagement of activation induced B7 products on Teffs, (3) expression of GRAIL and its epistatic regulators (in Tregs or Teffs) may be important in certain autoimmune diseases, and, (4) there may be a defect in Teffs, not Tregs, in autoimmune disease. The significance of these studies in human T cells is the potential for characterization of mechnism of action of immune inteventions to allow appropriate CD4 T cell targeted therapy.

Public Health Relevance

The Stanford ACE will support an integrated basic and clinical research program focused on tolerance induction and immune modulation to prevent or treat autoimmune (Al) disease. The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082719-05
Application #
8461900
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$247,565
Indirect Cost
$91,913
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Lee, Jung-Rok; Haddon, D James; Wand, Hannah E et al. (2016) Multiplex giant magnetoresistive biosensor microarrays identify interferon-associated autoantibodies in systemic lupus erythematosus. Sci Rep 6:27623
Slight-Webb, Samantha; Lu, Rufei; Ritterhouse, Lauren L et al. (2016) Autoantibody-Positive Healthy Individuals Display Unique Immune Profiles That May Regulate Autoimmunity. Arthritis Rheumatol :
Haddon, D James; Diep, Vivian K; Price, Jordan V et al. (2015) Autoantigen microarrays reveal autoantibodies associated with proliferative nephritis and active disease in pediatric systemic lupus erythematosus. Arthritis Res Ther 17:162
Haddon, David James; Jarrell, Justin Ansel; Diep, Vivian K et al. (2015) Mapping epitopes of U1-70K autoantibodies at single-amino acid resolution. Autoimmunity 48:513-23
Haddon, D James; Jarrell, Justin A; Hughes, Michael R et al. (2015) Measurement of mast cell surface molecules by high-throughput immunophenotyping using transcription (HIT). Methods Mol Biol 1220:381-400
Price, Jordan V; Haddon, David J; Kemmer, Dodge et al. (2013) Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus. J Clin Invest 123:5135-45
Balboni, Imelda; Niewold, Timothy B; Morgan, Gabrielle et al. (2013) Interferon-α induction and detection of anti-ro, anti-la, anti-sm, and anti-rnp autoantibodies by autoantigen microarray analysis in juvenile dermatomyositis. Arthritis Rheum 65:2424-9
Zhang, Bo; Jarrell, Justin A; Price, Jordan V et al. (2013) An integrated peptide-antigen microarray on plasmonic gold films for sensitive human antibody profiling. PLoS One 8:e71043
Chruscinski, Andrzej J; Singh, Harvir; Chan, Steven M et al. (2013) Broad-scale phosphoprotein profiling of beta adrenergic receptor (β-AR) signaling reveals novel phosphorylation and dephosphorylation events. PLoS One 8:e82164
Price, Jordan V; Jarrell, Justin A; Furman, David et al. (2013) Characterization of influenza vaccine immunogenicity using influenza antigen microarrays. PLoS One 8:e64555

Showing the most recent 10 out of 21 publications