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Mar 03, 2011
 |  BC Innovations  |  Targets & Mechanisms

Targeting T cell metabolism

Researchers at the University of Michigan have shown that modulating ATP synthase activity can selectively kill alloreactive T cells and arrestgraft-versus-host disease.1Lycera Corp.has licensed the findings, which may provide a new indication for the small molecule partial inhibitors ofATP synthase that the company plans to advance into the clinic this year.

The findings also suggest that targeting cellular metabolism may be a viable therapeutic strategy to treat other immune diseases.

Each year, physicians perform more than 25,000 allogeneic hematopoietic stem cell transplants worldwide, and GvHD is a major cause of morbidity and mortality in transplant recipients.2The disease manifests when a subset ofdonor T cells detects differences in histocompatibility antigens and becomes alloreactive, proliferating and attacking their new host. This leads to tissue damage and in severe cases can cause organ failure and death.

Standard care for GvHD includes corticosteroids and inhibitors of

mammalian target of rapamycin (mTOR; FRAP; RAFT1), although these broadly immunosuppressive drugs leave patients highly susceptible to infections and induce complete remissions in <50% of patients.

Researchers at the University of Michigan led by Gary Glick and James Ferrara think they have found a way to selectively eliminate the disease-causing alloreactive T cells while leaving the rest of the immune system intact. Glick is a professor of chemistry at the university, and Ferrara is a professor of pediatric oncology at the medical school.

The team's key observation is that alloreactive T cells have different metabolic requirements from nonreactive T cells. In mouse models...

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