Graft-versus-host disease (GvHD) is a serious complication following allogeneic hematopoietic cell transplantation and is characterized by the dysregulated immune response to allogeneic antigen stimulation after donor immune reconstitution, followed by the subsequent destruction of host tissues. Despite prophylactic measures, the incidence of acute GvHD remains substantially high. Primary prophylaxis and treatment relies on immunosuppression, elevating the risk of infection. New approaches are thus critically needed and biologic approaches hold the promise to help without immunosuppression. Regulatory T cells (Tregs) are key mediators of immunity and tolerance, and have been the recent focus in the study of GvHD, as well as a promising cellular therapy for reducing the risk of GvHD. An early phase clinical trial using ex vivo expanded Tregs demonstrated the safety of Treg infusion in GvHD patients; however, the efficacy for reducing the severity of GvHD was modest. Several factors, however, limit their clinical application. There is increasing evidence suggesting that optimal Treg function is impaired by inflammatory factors. Our preliminary studies have demonstrated a novel role for IL-27 in enhancing the suppressive function of Tregs in this context. In a murine model of T-cell mediated intestinal inflammation, we demonstrated that IL-27 signaling in Tregs is essential for Treg function in vivo. While wild-type Tregs are fully capable of suppressing T cell mediated intestinal inflammation, Tregs deficient in IL-27 receptors are unable to suppress inflammation. We further demonstrated that pre-stimulating Tregs with IL-27 significantly enhances their suppressive function in both intestinal inflammation and allogeneic GvHD. Based on these observations, we hypothesize that IL-27 pre- stimulation enhance Treg suppressive function and will have the capability of effectively preventing GvHD development.
Two specific aims are proposed to address this hypothesis.
Aim 1 will test the role of IL-27 signaling in Tregs in preventing GvHD in a murine allogeneic GvHD model.
Aim 2 will test the therapeutic role of IL-27 pre-stimulation in human Tregs in a xenogenic model of GvHD. This study will generate proof-of- concept results for the development of highly efficacious IL-27 based Treg therapy for the prevention and attenuation of GvHD.

Public Health Relevance

Graft-versus-host disease is a serious complication after allogeneic hematopoietic cell transplant with limited treatment options. Novel therapies are critically needed, and cellular therapies such as regulatory T cells hold much promise without the damaging effects of corticosteroid immunosuppressive therapy. This proposal studies a novel role for IL-27 in enhancing regulatory T cell function under inflammatory conditions, and will provide a pre- clinical basis for the development of IL-27 based regulatory T cell therapy for the prevention and treatment of GvHD..

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI121524-02
Application #
9335255
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Nabavi, Nasrin N
Project Start
2016-08-19
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Pathology
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195