This application focuses on the potential for using ex vivo expanded autologous regulatory T cells (Tregs) in the treatment of autoimmune diseases. The central theme is that Tregs provide important protection against autoimmunity. Based on this theme, the central hypothesis is that Treg therapy may be a safe and effective approach to the treatment of diverse autoimmune diseases. To address this hypothesis, we propose two complementary projects. One project will examine Treg therapy in an antigen-non-specific autoimmune disease (systemic lupus erythematosus)(SLE), and one will examine Treg therapy in an antigen-specific autoimmune disease (pemphigus vulgaris)(PV). The selection of these two diseases affords us the following important opportunities: (i) to examine whether this therapeutic approach is generally applicable across clinically distinct autoimmune diseases;(ii) to compare safety, efficacy, and mechanism of action across both antigen-specific and antigen-non-specific autoimmune diseases;(iii) to compare polyclonal and antigen-specific Treg therapy in the same disease (PV);and (iv) to examine the same target tissue (skin) in both lupus and PV disease.
The specific aims are: Primary Project - Conduct a phase l-ll development program designed to test the feasibility, safety, and potential efficacy of Treg therapy in patients with cutaneous manifestations of lupus. Alternate Project - Conduct a phase l-ll development program designed to compare autologous polyclonal versus enriched antigen-specific Treg therapy in patients with PV. Through these projects, we aim to demonstrate the presence and persistence of transferred Tregs in blood and target tissue;perform T cell receptor sequencing to determine whether infused Tregs proliferate;assess biomarkers in blood and skin;and generate efficacy data to lay the foundation for eventual pivotal trials.

Public Health Relevance

The broad aim of the UCSF ACE program is to work collaboratively with other ACE sites to translate advances in immunology and molecular biology into practical, safe , and effective therapies for people with autoimmune diseases. Within this umbrella, the UCSF site will focus on examing the prospects of using autologous regulatory T cells as a novel appraoch to the treatment of autoimmune diseases. By so doing, we will be examining an approach that may have broad applicability across diverse autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
1UM1AI110498-01
Application #
8680659
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Johnson, David R
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Fernando, Roshini; Grisolia, Ana Beatriz Diniz; Lu, Yan et al. (2018) Slit2 Modulates the Inflammatory Phenotype of Orbit-Infiltrating Fibrocytes in Graves' Disease. J Immunol 200:3942-3949
Mader, Simone; Brimberg, Lior; Soltys, John N et al. (2018) Mutations of Recombinant Aquaporin-4 Antibody in the Fc Domain Can Impair Complement-Dependent Cellular Cytotoxicity and Transplacental Transport. Front Immunol 9:1599
Liu, Yiting; Given, Katherine S; Owens, Gregory P et al. (2018) Distinct patterns of glia repair and remyelination in antibody-mediated demyelination models of multiple sclerosis and neuromyelitis optica. Glia 66:2575-2588
Wein, Marc N; Foretz, Marc; Fisher, David E et al. (2018) Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential. Trends Endocrinol Metab 29:723-735
Shimizu, Fumitaka; Schaller, Kristin L; Owens, Gregory P et al. (2017) Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica. Sci Transl Med 9:
Soltys, John N; Meyer, Stephanie A; Schumann, Hannah et al. (2017) Determining the Spatial Relationship of Membrane-Bound Aquaporin-4 Autoantibodies by STED Nanoscopy. Biophys J 112:1692-1702
Vogel, Anna-Lena; Knier, Benjamin; Lammens, Katja et al. (2017) Deletional tolerance prevents AQP4-directed autoimmunity in mice. Eur J Immunol 47:458-469
Haddon, D James; Wand, Hannah E; Jarrell, Justin A et al. (2017) Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment. J Rheumatol 44:631-638
Alberga, Domenico; Trisciuzzi, Daniela; Lattanzi, Gianluca et al. (2017) Comparative molecular dynamics study of neuromyelitis optica-immunoglobulin G binding to aquaporin-4 extracellular domains. Biochim Biophys Acta Biomembr 1859:1326-1334
Bennett, Jeffrey L; Owens, Gregory P (2017) Neuromyelitis Optica: Deciphering a Complex Immune-Mediated Astrocytopathy. J Neuroophthalmol 37:291-299

Showing the most recent 10 out of 16 publications