Dr. Coopersmith and Dr. Ford Receive Third R01

July 2015

Dr. Craig Coopersmith, vice chair of research of the Emory Department of Surgery, and Dr. Mandy Ford, scientific director of the Emory Transplant Center, have received their third Co-PI NIH R01 grant, which will fund the study, "Targeting 2B4 Coinhibitory Signals During Sepsis-Induced Immune Dysregulation." This grant will join the team's other two ongoing R01s in addressing an aspect of the immunological host response in sepsis.

The prior studies are investigating the interplay between cancer and sepsis and the impact of chronic alcohol abuse on the pathophysiology of the highly lethal disease, while the new study will dig deeper into the roots of the systemic immune dysregulation that switches on the immune suppression that is a major contributor to sepsis-induced mortality.

"Certain studies in models of chronic viral infection have found that coinhibitory molecules each play distinct and non-redundant roles in weakening T cells, suggesting that the particular constellation of distinct coinhibitory molecules expressed on the surface of T cells when an immune response is triggered correlates to different stages and degrees of T cell function and/or exhaustion," says Dr. Ford. "With that in mind, we sought to determine which novel coinhibitory molecules might participate in the immunosuppressive phase that increases the risk of mortality during sepsis."

Drs. Ford and Coopersmith are focusing on the 2B4 molecule, which encodes a cell surface receptor expressed on immune cells that play a significant role in the host-rejection of both tumors and virally infected cells. After a series of animal studies, the scientists found that the absence of 2B4 rendered the test subjects six times less likely to experience mortality after sepsis. Preliminary data also suggested that 2B4 modifies immune dysregulation during sepsis, and analysis of human T cells during acute septic injury revealed an increase in the expression of 2B4.

Building on these conclusions, the study aims to determine how 2B4 contributes to sepsis-induced mortality, the cell type(s) by which it mediates its effects, and when it contributes to sepsis-induced mortality during the disease process. An innovative feature of the proposal is that the mice used will have developed memory T cells at a frequency similar to that of adult humans due to having survived various acute infections—standard laboratory mice only contain a very small percentage of memory T cells.

"Interrogation of the mechanisms by which inhibition of 2B4-mediated coinhibitory signals protects mice from death during sepsis is critical for the potential future translation of immunomodulatory strategies to target this pathway to prevent death in septic patients," says Dr. Ford.