Vascularized composite allotransplantation (VCA), such as hand and face transplants, is a valid reconstructive option for people that have suffered traumatic limb loss or severe disfigurements. However, hand and face grafts are subject to graft rejection, and people receiving such transplants must commit to lifelong drug treatment in order to avoid the loss of the graft. The use of these immunosuppressive drugs is associated with the development of severe side effects, such as kidney dysfunction, cancer, and high infection risk. Therefore, the aesthetic and functional improvements of these reconstructive approaches come at a high cost to the patient. In order to reduce the risks associated with lifelong immunosuppression, we need to develop innovative therapeutic strategies aimed at minimizing drug intake and promoting transplant tolerance. VCA differs from other organ transplantations because the graft is composed of different tissues (skin, muscle, bone, cartilage, etc.). Since the lymphatic system is able to coordinate the immunological response over the multiple tissues of a VCA, it represents an accessible system for drug delivery and tissue engineering. Therefore, in this project, we will target the lymphatic vessels and lymph nodes of the VCA grafts to reduce tissue inflammation and promote tolerance. This study will provide new perspectives for the design of effective immunotherapies targeted towards VCA. We predict that by specifically targeting the lymphatic system, the clinical outcome in VCA will significantly improve, promoting immunoregulation across the different tissues. The ultimate goal is to reduce or eliminate lifelong immunosuppression, boosting the clinical adoption of VCA and improving the wellness and overall quality of life of patients receiving reconstructive transplants. The project addresses the following Fiscal Year 2016 Reconstructive Transplant Research Focus Areas: Immune system regulation as specifically applied to VCA and Immunomodulation approaches and mechanisms.