Allogeneic stem cell transplantation (allo-SCT) remains the most effective therapy for patients with high risk acute leukemia, specific low-grade lymphoid malignancies, and other malignant diseases. Widespread use is limited by the immunological consequence of allo-SCT, graft-versus-host disease (GvHD), which accounts for 15-30% of mortality in recipients. As a result, only 25-30% of patients who could benefit from allo-SCT receive this treatment. The effectiveness of allo-SCT is dependent upon elimination of tumor cells via conditioning therapy and the immunologic targeting of tumor cells by donor immune cells termed the graft-versus-leukemia (GvL) response. The desired effect, GvL and the unwanted side effect, acute GvHD (aGvHD) are mediated in part by donor T cells that recognize minor or major MHC disparities between donor and recipient/tumor. This leads to an immunological cascade in which T cells and other immune effector cells migrate and expand in host GvHD target organs leading to the unfortunate clinical consequence of a GvHD. The particular subset of T cells that mediates aGvHD is not clear. Several studies have implicated Th1 and/or Th17 T cells in the pathogenesis of aGvHD. Pre-clinical data suggest that IFN-? producing Th1 cells are perhaps more important for GI tract aGvHD whereas IL-17 producing Th17 cells are more important for skin and lung pathology. However, both murine models and clinical data indicate that suppression of Th1 and Th17 responses by shifting to a Th2 T cell phenotype limits aGvHD. One potential mechanism for the enhanced Th1 tropism of the lower GI tract is the role of conditioning therapy on the release of cytokines and bacterial products tha may polarize nave T cells toward a Th1. Our laboratory has shown that co-infusion of Tregs cells, reduces aGvHD by suppressing Th1 responses. The recent explosion of data surrounding innate immune cells, such as type 2 innate lymphoid cells (ILC2) and type 2 multipotent progenitors (MPP2) has increased the possibility of discovering additional candidate suppressive cells. Type 2 ILCs express significant quantities of Th2 cytokines, as well as regulatory receptors that are constitutively expressed on Tregs. The goal of this proposal is to evaluate the ability of type 2 innate cells to suppress allo-activated inflammatory Th1/Th17 cells, increase Th2 cell activation and enhance the development of anti-inflammatory M2 macrophages and myeloid-dervied suppressor cells (MDSC), suppressing aGvHD. For the first aim of this proposal we will investigate the hypothesis that the absence of host ILC2/MPP2 cells is critically important in the Th1 response in the GI tract and that infusion of ILC2/MPP2 cells wil alter the host cytokine profile, suppress Th1/Th17 cells and expand the Th2 population reducing GvHD without altering the GvL response. In addition, our second aim will investigate the mechanism(s) by which these cells function to prevent aGvHD and the hypothesis that co-transplantation of activated ILC2 and MPP2 cells alters the development of M2 macrophages and MDSCs as a result of the generation of a type 2 micro-environment.

Public Health Relevance

The transplantation of stem cells or bone marrow from one individual to another is a standard approach for the treatment of acute leukemia, bone marrow failure problems and lymphoid malignancies. However, this process is limited by the immune reactivity of donor cells against the host, termed acute graft-versus-host disease (aGvHD). How the loss of host innate cells as a result of conditioning therapy affects the development of particular groups of donor immune cells and the development of aGvHD remains unclear. The focus of this proposal is to understand the role that type 2 innate cells play in the occurrence of aGvHD, focusing on their ability to alter donor T cell responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL126365-01
Application #
8835686
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Welniak, Lisbeth A
Project Start
2015-04-02
Project End
2016-04-01
Budget Start
2015-04-02
Budget End
2016-04-01
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599