DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

In Vivo Imaging of Bone Marrow Regulatory T Cells and Their Role in the Prevention of Bone Marrow Failure

Principal Investigator: LIN, CHARLES P
Institution Receiving Award: MASSACHUSETTS GENERAL HOSPITAL
Program: BMFRP
Proposal Number: BM090093
Award Number: W81XWH-10-1-0217
Funding Mechanism: Exploration - Hypothesis Development Award
Partnering Awards:
Award Amount: $172,907.00


PUBLIC ABSTRACT

Acquired aplastic anemia (AA) is a fatal bone marrow (BM) failure caused by immune cells in the body that destroys its own blood-forming (hematopoietic) stem cells, but the exact mechanism how this happens has not been worked out. We hypothesize that the BM, where the adult hematopoietic stem cells reside, provides a protective sanctuary where the stem cells are protected from immune attack. We further hypothesize that a group of protective T lymphocytes called regulatory T cells accumulate at this location and shield the stem cells from other immune cells. Breakdown of this protective mechanism can result in autoimmune reaction against the stem cells leading to BM failure.

To test these hypotheses, we propose to generate a mouse model where the regulatory T cells are unable to form the protective shield in the BM stem cell niche. We will examine if AA develops in these mice in the absence of appropriate immune protection. We will use state-of-the-art imaging technology to track individual regulatory T cells in the BM of live mice to study their migration, spatial distribution, and interaction with stem cells and other immune cells in the BM. We will examine if infusion of additional regulatory T cells can prevent AA and if manipulating the ability of regulatory T cells to migrate to the BM changes the outcome of the disease.

If successful, our studies will uncover a new and important role of immune protection in the BM and the role of regulatory T cells in this protective mechanism. Enhancing regulatory T cell trafficking to BM may be a potential new strategy for treatment of AA.