Pretransplant Complement Inhibitory Graft Therapy Enables Prolonged Cold Storage and Improved Outcomes in Vascularized Composite Allografts
Abstract
There have been nearly 7000 U.S. military fatalities and over 52,000 injuries resulting from the wars in Iraq and Afghanistan. Because of improvements in body armor and battlefield practices, many Soldiers who would have died in previous conflicts now survive. Explosive devices and blast trauma account for the majority of combat-related injuries, and Soldiers who survive often have debilitating injuries to unprotected areas such as the face and limbs. These kinds of injury affect not only physical form and function, but they also represent a significant mental health issue due to their psychological impact. Major disfigurement can lead to embarrassment and/or separation from society, and restoring facial appearance or providing new limbs that can provide mobility and function can dramatically improve quality of life, allowing a patient to perform daily activities and return to the workforce. Restoring form and function also has the potential to provide major psychological benefits and to restore the mental health of a traumatized Soldier. It should also be noted that whereas the number of Soldiers suffering from catastrophic injuries is high, similar injuries are also sustained by a large number of civilians, with over 2 million people in the United States suffering from limb loss. Vascularized composite allotransplantation (VCA) represents a therapeutic option for treating limb/face loss, as well as following tumor excision involving limb loss or large areas of tissue damage. Vascularized tissue composite allografts (e.g., skin, muscle, bone, nerves) are highly immunogenic (especially the skin component), meaning that they are readily attacked by the recipients immune system, requiring the recipients to take aggressive immunosuppression and lifelong treatment to prevent the new limb/face from dying. This places the recipient at substantial risk and shortened life expectancy due to the high toxicity of the immunosuppressive drugs. In view of this, and because VCA is usually life-changing, but not life-saving, a principal research goal is the development of strategies to minimize immunosuppression and, ultimately enable the recipient to no longer need immunosuppressive drugs. Graft loss is principally dependent on T cells; however, there are many other immune factors that can increase graft loss, which are largely activated by factors that occur early in the grafts life. All VCA grafts are harvested from brain dead donors, and immune factors activated during this time are unresponsive to the standard immunosuppressive currently used and contribute to the loss of the graft. We propose to develop a novel therapeutic strategy and to investigate the mechanisms involved in modulating the immune response that occurs during brain death. A mechanistic understanding will be necessary for the clinical development of this therapeutic approach. The strategy to enhance current anti-rejection therapeutics involves inhibiting a biological system that plays an important role in inflammation, immunity, and housekeeping functions. This biological system is known as the complement system, and it comprises a set of blood proteins that act on each other in a sequential order (a pathway) to form activation products that are involved in the aforementioned biological functions. In the studies proposed, we will use a preclinical model of brain death and vascularized composite allograft transplantation in and mice treated with existing and clinically relevant complement inhibitors. We will investigate how complement inhibition changes VCA environment after transplantation, and how these changes subsequently effect the development rejection. These studies will provide important mechanistic data and clinical translational information. There is the potential for the rapid translation of this work to the clinic and for clinical trial approval, since complement inhibitors have been shown to be safe in multiple clinical trials. By
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610783
Entities
People
- Carl Atkinson
Organizations
- Medical University of South Carolina
- United States Army