Chronic Rejection in Facial Vascularized Composite Allotransplantation (fVCA).

Chronic rejection (CR) remains a major barrier to long-term success in facial vascularized composite allotransplantation (fVCA), particularly in facial transplants. Unlike acute rejection, CR is a gradual, progressive process marked by vasculopathy, fibrosis, and functional graft decline. Histopathologic features include intimal hyperplasia, dermal sclerosis, adnexal atrophy, and telangiectasia. Immune mechanisms driving CR involve persistent activation of Th1 and Th17 T cells, macrophages, and, to a lesser extent, B cells, which form tertiary lymphoid structures. Dysregulated cytokines and chemokines, such as IFN-γ, IL-17, and IL-6, perpetuate inflammation and fibrosis, whereas the downregulation of regulatory mediators like IL-10 impairs immune resolution. Chronic antigen exposure, complement activation, and the presence of tissue-resident memory T cells further sustain graft injury. Clinically, CR presents with tightening of facial tissue, pigmentary changes, pain, and impaired oral and facial function, which can sometimes progress to necrosis and graft failure. Diagnostic challenges persist due to heterogeneous presentation and a lack of standardized criteria. Early detection through protocol biopsies, mucosal sampling, and vascular imaging is essential. Future directions emphasize the need for molecular diagnostics, targeted immunomodulation, and antifibrotic therapies. A deeper understanding of CR pathophysiology is critical to improving graft longevity and patient quality of life in fVCA.