The Role of Tissue-Resident Macrophages in Transplant Immunity

Successful engraftment of Vascular Composite Allotransplantation (VCA), including face transplants, provides functional and quality of life benefits to the recipient. There is significant interest in developing predictive biomarkers that will identify rejection episodes at the earliest possible moment thereby enabling clinicians to preemptively treat rejection episodes, safely guide maintenance immunosuppression minimization or withdrawal, and improve rejection surveillance for investigational therapies. Tissue-resident macrophages (TRMs) are a population of sentinel phagocytes that are present in virtually all tissues, particularly at barrier sites such as skin that are substantial components of VCA, and arise from yolk-sac not bone marrow derived precursors. We are testing whether a powerful immunoregulatory CD169+ population of TRMs that was previously identified in mice is present in humans. We hypothesize that maintenance of the immunoregulatory phenotype of CD169+ TRMs will correlate with a healthy vascular composite allograft whereas the loss of CD169+ TRMs or their immunoregulatory properties will coincide with incipient and ongoing allograft rejection. Face transplant skin samples from 4 patients were stained for tissue resident macrophage markers and the anticipated immunoregulatory phenotype. We demonstrated the existence of potentially immunoregulatory population of dermal resident macrophages in normal skin from healthy individuals and quiescent skin in face transplant patients, their disappearance in inflamed conditions and ambiguous behavior upon rejection episodes. While our data is preliminary we suspect that through evolution a class of TRMs that are cytoprotective in the quiescent state die or lose immunosuppressive properties in response to danger signals. The results suggest further and more detailed examination of undescribed subsets of tissue resident macrophage population. These studies have the potential to provide a powerful new biomarker that will guide clinical care by accurately measuring allograft health and may offer new mechanistic insights into the earliest events that precipitate VCA rejection thereby identifying novel TRM-related therapeutic targets for the establishment of drug-free VCA transplant tolerance.