Mechanisms of rejections and tolerance strategies in vascularized composite allotransplantation: a comprehensive review

Vascularized composite allotransplantation (VCA) offers unique reconstructive potential, yet long-term success remains constrained by immune rejection. Acute rejection, driven by T-cell activation following ischemia–reperfusion injury and dendritic-cell priming, is common during the first postoperative year. Concurrent B-cell activation and donor- specific antibody (DSA) formation contribute to antibody-mediated rejection (AMR) and increase the risk of progression toward chronic injury. Chronic rejection is characterized by graft vasculopathy, with endothelial activation, intimal hyperplasia, and gradual luminal narrowing, leading to graft dysfunction.
Patients with burns, transfusions, or temporary skin allografts often have pre-existing sensitization, which increases susceptibility to early AMR and the development of new DSA. In addition, activation of the innate immune system by damage-associated molecules (DAMPs) and pro-inflammatory cytokines further enhances adaptive immune responses, resulting in an environment that is highly prone to rejection. Emerging tolerance-focused strategies aim to lessen lifelong immunosuppression requirements. Approaches such as mixed hematopoietic chimerism, regulatory T-cell (Treg) and mesenchymal stromal cell (MSC) therapies, as well as decellularization/recellularization techniques and machine perfusion, seek to improve graft compatibility and maintain structure.
In this review, we aim to synthesize current evidence on the immunological mechanisms underlying acute and chronic rejection, pathways of sensitization, and emerging strategies designed to reduce immunogenicity and promote long-term tolerance in VCA.