The primary objective of this project is to examine the feasibility, safety, and potential therapeutic efficacy of autologous antigen-specific Treg therapy in patients with pemphigus vulgaris (PV). To accomplish this objective, we will conduct a phase I-II development program. PV is an excellent model disease for these investigations because the autoantigens are well-defined, and mechanistic analyses can readily be performed with peripheral blood and with diseased tissue. This program is designed to complement the primary project by comparing enriched antigen-specific Treg therapy with polyclonal Treg therapy in the treatment of a severe autoimmune disease.
The specific aims are:
Specific Aim #1 : Conduct a phase I dose-escalation study of Treg therapy in patients with PV. By so doing, we seek to: (1) generate sufficient preliminary safety data on Treg infusion in patients with PV to enable us to move to a phase II efficacy trial during the course of the 5-year ACE cycle; (2) demonstrate the presence, and assess the persistence, of transferred Tregs in blood and in target tissue (skin); (3) assess disease-specific and immunologic biomarkers in blood and skin; and (4) generate preliminary efficacy data using the Pemphigus Disease Activity Index (PDAl).
Specific Aim #2 : Conduct a phase II trial of Treg therapy in patients with PV based on the results of the phase I studies. In its simplest form, the phase II trial would have three groups - a control group, a group that receives polyclonal Tregs, and a group that receives antigen-specific Tregs. However, there are other design options to consider depending on the results of phase I and new data that may become available including (1) multiple dose groups; (2) additional treatment groups to assess the impact of simultaneous administration of low-dose interleukin 2 (IL-2) in an effort to enhance Treg activity; and (3) additional experimental groups utilizing IVIG as the background therapy, as this modality does not suppress T cell function. In addition to the primary clinical outcomes, molecular mechanisms described above will be included in this phase II trial.

Public Health Relevance

This project explores a novel approach to PV that is based on Tregs; the body's own regulatory mechanisms to control autoimmunity; rather than traditional toxic therapies. As PV is a well characterized; antigen-specific disease; it provides a unique opportunity to compare the therapeutic efficacy of antigen-specific versus polyclonal Tregs. This approach is particularly relevant to the goals of the ACE program because it involves a strategy that may have broad applicability across diverse autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project with Complex Structure Cooperative Agreement (UM1)
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Special Emphasis Panel (ZAI1-PA-I (J1))
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University of California San Francisco
San Francisco
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