While microvascular injury is associated with chronic rejection, the cause of tissue ischemia during alloimmune injury is not yet elucidated.
We investigated the contribution of T lymphocytes and complement to microvascular injury-associated ischemia during acute rejection of mouse tracheal transplants.
Methods and Results:
Using novel techniques to assess microvascular integrity and function, we evaluated how lymphocyte subsets and complement specifically affect microvascular perfusion and tissue oxygenation in MHC-mismatched transplants. To characterize T cell effects on microvessel loss and recovery, we transplanted functional airway grafts in the presence and absence of CD4 + and CD8 + T cells. To establish the contribution of complement-mediated injury to the allograft microcirculation, we transplanted C3-deficient and C3-inhibited recipients. We demonstrated that CD4 + T cells and complement are independently sufficient to cause graft ischemia. CD8 + T cells were required for airway neovascularization to occur following CD4-mediated rejection. Activation of antibody-dependent complement pathways mediated tissue ischemia even in the absence of cellular rejection. Complement inhibition by CR2-Crry attenuated graft hypoxia, complement/antibody deposition on vascular endothelium and promoted vascular perfusion by enhanced angiogenesis. Finally, there was a clear relationship between the burden of tissue hypoxia (ischemia×time duration) and the development of subsequent airway remodeling.
These studies demonstrated that CD4 + T cells and complement operate independently to cause transplant ischemia during acute rejection and that sustained ischemia is a precursor to chronic rejection.