Defining the Impact of Donor and Recipient Microbiota on VCA Alloimmunity
Abstract
Thousands of Americans suffer from severe and irreplaceable tissue loss secondary to combat-related injuries, other traumatic events or surgical resections. Where tissue loss involves the extremities, prosthetics can be used to restore some mechanical function, but are of limited use in that they lack sensation, are difficult to handle, and look unnatural. For patients with this type of injury, vascularized composite allotransplantation (VCA) has shown superior results. A VCA is a collection of different types of tissue – skin, muscle, bone – that is transplanted as a whole unit and contains blood vessels that can be connected to the recipient’s blood vessels to allow blood flow to the transplant. The major problem facing the VCA field is that medications used in traditional solid organ transplantation remain too toxic for VCA. Immunosuppression is critical for the survival of the transplant otherwise the recipients’ immune system will reject the new tissue within days. Unfortunately, currently used drugs are not specific to the immune cells causing rejection but affect every cell in the body. These side effects can damage vital organs, increase the likelihood of certain cancers and other opportunistic infections. This also poses a difficult ethical decision many recipients of these transplants are otherwise healthy individuals and current immunosuppression pose huge health risks. If this barrier could be overcome, VCA would become the new standard of care and greatly improve the quality of life in many individuals. Recently, environmental factors, such as microbiota, i.e., the fecal matter of the gastrointestinal tract (bacteria, viruses, and fungi) has been shown important for nutrition, immunity, and effects on the brain and behavior. It has been also associated with a number of diseases that cause a disturbance in the normal balance of microbes. Indeed, the community of commensal microorganisms in the human gut is a diverse ecosystem of ca. 100 trillion bacteria (1–2 kg in mass), with a genome of ca. 150-fold greater than the human genome itself. Its role in organ transplantation remains largely unknown, while studying microbiota in VCA is of particular interest as it involves both the effects of recipient gut microbes as well as skin-specific microbes of the VCA donor. The current project arises from long-term and complementary experiences of the UCLA and the Johns Hopkins transplant research teams. The UCLA is one of the largest solid organ transplant centers in the country. Its research group, headed by Dr. Kupiec-Weglinski, had been leading the effort to improve outcomes in liver transplant recipients, both experimentally and clinically. Recently, the UCLA-led team has found that giving mice antibiotics for 10 days prior to a liver transplant leads to better liver function after the surgery. Importantly, the same phenomenon appears to hold true in humans. The researchers concluded that the antibiotics inhibited bacteria that cause inflammation, which in turn can lead to organ rejection. As a result, liver function was better than in the mice and human patients who did not receive antibiotics prior to surgery. To further substantiate the beneficial effect of the antibiotics, the researchers transplanted fecal matter from the untreated mice into those that had been given the medication. The mice that received the fecal transplants suffered inflammatory damage to their livers, despite the fact that they had been given antibiotics earlier in the experiment. The data on the UCLA patients covered 264 people who had received liver transplants — 156 who, because they were sicker before their surgeries, received antibiotics for 10 or more days, and 108 who were given antibiotics for less than 10 days or not at all. Remarkably, livers functioned much better after transplantation in those patients who were very sick and required prolonged antibiotic treatment prior to receiving life-saving liver t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210898
Entities
People
- Gerald Brandacher
Organizations
- Johns Hopkins University
- United States Army