title: CD4+ T cells and complement independently mediate graft ischemia in the rejection of mouse orthotopic tracheal transplants.
abstract: BACKGROUND
  While microvascular injury is associated with chronic rejection, the cause of tissue ischemia during alloimmune injury is not yet elucidated.
  
  
  OBJECTIVE
  We investigated the contribution of T lymphocytes and complement to microvascular injury-associated ischemia during acute rejection of mouse tracheal transplants.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Veterans Affairs Palo Alto Health Care System/Stanford University School of Medicine, CA 94304, USA.
authors: Mohammad A
authors: MA
authors: Khan
authors: Xinguo
authors: X
authors: Jiang
authors: Gundeep
authors: G
authors: Dhillon
authors: Joshua
authors: J
authors: Beilke
authors: V Michael
authors: VM
authors: Holers
authors: Carl
authors: C
authors: Atkinson
authors: Stephen
authors: S
authors: Tomlinson
authors: Mark R
authors: MR
authors: Nicolls
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015687:Cell Hypoxia; D003176:Complement C3 / Q000172:deficiency; D003165:Complement System Proteins / Q000276:immunology*; D016654:Genes, RAG-1; D006084:Graft Rejection / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics; D007511:Ischemia / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D018919:Neovascularization, Physiologic; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014132:Trachea / Q000098:blood supply / Q000637:transplantation*
chemical_list: C527099:CR2-Crry fusion protein, mouse; D003176:Complement C3; D018398:Homeodomain Proteins; D011993:Recombinant Fusion Proteins; C064658:RAG-1 protein; D003165:Complement System Proteins