The long-term goal of this project is to develop a regulatory T cell (Treg)-based approach for the induction of donor-specific immunologic tolerance in liver transplant recipients. Liver transplantation can be life-saving therapy for live failure. However, the maintenance of the transplanted liver requires continuous immunosuppression to prevent rejection by the host immune system. Although ongoing refinement of immunosuppression regimens has substantially reduced the incidence of acute rejection after transplantation, long-term outcomes have stagnated partly due to morbidity and mortality associated with immunosuppression. Therefore, a main focus of research has been to promote tolerance to transplanted livers so that immunosuppression can be minimized or completely withdrawn. In the past decade, we have learned that tolerance in organ transplantation is linked to the development and persistence of Tregs. In multiple preclinical models, therapeutic administration of Tregs has proven efficacy in controlling allograft rejection and inducing donor-specific tolerance. Alloantigen-specific Treg are more effective and potentially safer than non-specific Treg by offering targeted therapy instead of indiscriminate regulation. A key point in Treg-based regimens in the transplant setting is that, because of the exceptionally high frequency of donor-reactive T cells, "debulking" of the host alloreactive repertoire and adjunct immunosuppression are needed to create a more favorable setting for Tregs to control alloimmunity and to ensure long-term graft tolerance.
We aim to translate these basic and clinical findings into a practical and effective clinical protocol. We plan to test the ue of donor- alloantigen-reactive Tregs in the context of a Treg-supportive immunosuppression regimen as an approach to induce liver transplant tolerance. As a first step, we propose to conduct an open-label, two-center, phase I, dose escalation trial to determine the safety of administering a single escalating dose of donor-specific Tregs in liver transplant patients. We will perform mechanistic analyses of the study patients to assess the impact of the Treg therapy on recipient's immune reactivity to the donor. We have finalized the clinical trial protocol, Treg manufacturing process, and detailed plan for mechanistic studies. FDA has reviewed the Investigational New Drug (IND) application for this trial and the IND is currently open. This proposal represents the first application of donor alloantigen-reactiveTregs in solid organ transplantation to induce graft tolerance. It is strongly aligned with NIAID's goal to "evaluate approaches that include tolerogenic, anti-inflammatory, and immunomodulatory strategies to treat and prevent immune-mediated diseases".

Public Health Relevance

Regulatory T cells (Tregs) have recently been shown to be critical for the development of natural and acquired immunologic tolerance in a variety of settings, suggesting that Treg administration may be useful for the therapeutic induction of immunologic tolerance. Organ transplant recipients continue to suffer from immunologic rejection as well as serious side effects from non-specific immunosuppressive medication. Our long-term objective is to develop Treg cell therapy to induce transplant tolerance so that immunosuppression can be minimized or withdrawn. We therefore propose to develop the first clinical trial in solid organ transplantation to test the safety of an immunosuppression regimen that favors the development of Tregs, in conjunction with an infusion of donor-reactive Tregs in the liver transplant setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI110658-01
Application #
8672260
Study Section
Special Emphasis Panel (ZAI1-QV-I (J3))
Program Officer
Hayes, Deborah
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$983,209
Indirect Cost
$188,930
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Tang, Qizhi; Kang, Sang-Mo (2014) Interpretation of transplant biopsies and immune responses following Treg cell therapy. Curr Opin Organ Transplant 19:616-20