Microvascular loss may be an unappreciated root cause of chronic rejection for all solid organ transplants. As the only solid organ transplant that does not undergo primary systemic arterial revascularization at the time of surgery, lung transplants rely on the establishment of a microcirculation and are especially vulnerable to the effects of microvascular loss. Microangiopathy, with its attendant
ischemia, can lead to tissue
infarction and airway
fibrosis. Maintaining healthy vasculature in lung allografts may be critical for preventing terminal airway
fibrosis, also known as the
bronchiolitis obliterans syndrome (BOS). BOS is the major obstacle to lung transplant success and affects up to 60% of patients surviving 5 years. The role of
complement in causing acute microvascular loss and
ischemia during rejection has recently been examined using the mouse orthotopic tracheal
transplantation; this is an ideal model for parsing the role of airway vasculature in rejection. Prior to the development of airway
fibrosis in rejecting tracheal allografts, C3 deposits on the vascular endothelium just as tissue
hypoxia is first detected. With the eventual destruction of vessels, microvascular blood flow to the graft stops altogether for several days.
Complement deficiency and
complement inhibition lead to markedly improved tissue oxygenation in transplants, diminished
airway remodeling, and accelerated vascular repair. CD4+ T cells and antibody-dependent
complement activity independently mediate vascular destruction and sustained tissue
ischemia during acute rejection. Consequently, interceding against
complement-mediated microvascular injury with adjunctive
therapy during acute rejection episodes, in addition to standard immunosuppression which targets CD4+ T cells, may help prevent the subsequent development of chronic rejection.