Clinical Manifestation, Mechanisms, and Potential Targets of Intervention for Chronic Rejection in Vascularized Composite Allotransplantation

As the field of vascularized composite allograft (VCA) has matured, chronic rejection (CR) has emerged as the major cause of late graft loss, albeit occurring at a lower frequency than in many solid organ transplants. VCAs differ from conventional solid organ transplants in that they have multiple tissue targets and CR types. Exposure to environmental, physical, or thermal trauma has been shown to start or worsen both acute and CR in VCA recipients. This overview will cover the clinical presentation of CR in human and animal models, how that differs between VCA components such as skin, vessels, and adnexa, followed by a description of the pathologic presentation of CR, the resulting working pathologic classification of CR, and finally, a discussion of the pathophysiology and potential treatment or monitoring directions of CR in VCAs. These studies provide some exciting avenues where current and future research should be targeted to improve diagnosis and prognosis and find new treatment approaches, which include targeting complement and checkpoint inhibitors. The mechanisms of vasculopathy in disease states outside the field of transplantation, such as pulmonary arterial hypertension, are included, which may provide novel perspectives on CR in transplant recipients. Finally, we propose working points to summarize the current understanding of CR in VCAs and provide directions for future investigations, prevention, and possible treatment.