If a Soldier is injured in battle or in the course of duty, the expectation is that he/she will receive the best care available, and that is the way their caregivers approach their management. In the case of those who require surgery, the aim is return them to a normal, healthy state or as near to normal as currently possible. However, many Soldiers experience explosive or traumatic limb injuries that lead to loss of a limb. The decreased mobility, quality of life, and self-image that some experience as a result of amputations of one or more limbs can be devastating. At the moment, if they are otherwise healthy, they may be fitted with a prosthesis or trained to use a wheelchair. However, injured Soldiers are typically not offered a limb transplant to try and put them back into the state they were pre-injury in the way that they would if they suffered end-stage organ failure, since the act of transplantation currently requires the recipient to take drug immunosuppression for the rest of the person's life so as to avoid rejection. The downside of this is that the drugs used to try and prevent rejection can increase the risks of infection, malignancy, and organ failure, as well as leading to financial and other burdens.

In other words, the treatment is too toxic for a normal person to reasonably undertake.

The current project arises from the applicant's research into how a subpopulation of cells of the body's immune system that are called T-regulatory (Treg) cells can be used to provide protective effects post-transplant. The applicant has shown that normal Tregs can prevent graft rejection and that this effect can be made even stronger by genetic removal or drug inhibition of enzymes, called histone/protein deacetylases (HDACs).

The work proposed involves establishing in basic systems, that is, in mice, whether or not HDAC targeting can promote Treg cell function and lead to long-term limb transplant survival without the recipient continuously taking immunosuppressive drugs. Indeed, no such regular immunosuppressive drugs are required or used in our studies. Our work will establish whether this does or does not work. If it does, all the reagents are at hand, or are currently in clinical trials in people, to test this approach in preclinical or clinical studies.

To summarize, we propose to bring limb transplants, and other forms of tissue transplants that are non-life-supporting, out of the too-hard basket and into a practical and viable treatment that doctors throughout the country can use to help improve the quality of life of Veterans.