title: Modifiers of complement activation for prevention of antibody-mediated injury to allografts.
abstract: OBJECTIVE
  Improvements in prevention and management of cellular rejection of solid organ transplants, coupled with increasing numbers of sensitized patients, have focused attention on antibody-mediated rejection (AbMR). Complement is a critical component of AbMR, in addition to interfacing between innate and adaptive immunity and the coagulation cascade. This article reviews complement biology and strategies to overcome complement in AbMR, cognisant that antibody can act independently of complement.
  
  
  RESULTS
  The past decade has witnessed an improvement in the prevention and treatment of AbMR as a result of solid-phase assays to determine antibody specificity, definition of histopathological criteria, and use of plasmapheresis and/or intravenous immunoglobulin (IVIG). Nonetheless, AbMR continues to impact adversely on short- and long-term graft survival. Use of B and/or T-lymphocyte-depleting therapies has not shown measurable benefit, and the need remains for therapies that deplete antibody, or provide better protection from complement-mediated damage. Disordered complement activity in human diseases such as paroxysmal nocturnal haemoglobinuria, has provided additional impetus to pursuing therapeutic complement inhibition. Preliminary data from C5 inhibition with eculizumab in the treatment and prevention of AbMR have shown promise. Trials with recombinant human inhibitors of C1 (effective in angioedema) to prevent or treat AbMR are beginning.
  
  
  CONCLUSIONS
  Despite current limitations, 'protection' of the transplant through plasmapheresis and/or IVIG enables many allografts to survive in sensitized recipients. Elucidating the pathways mediating graft acceptance, by constitutive antibody deletion, or 'accommodation' (wherein donor organ remains uninjured despite antibody binding), or other local protective mechanism(s), is an equally important challenge in the quest to overcome AbMR.
authors.affiliation: Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Hughes
authors.forename: Solomon J
authors.initials: SJ
authors.lastname: Cohney
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000187:drug effects*; D015935:Complement C4b / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007518:Isoantibodies / Q000097:blood*; D016377:Organ Transplantation / Q000009:adverse effects; D010446:Peptide Fragments / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D006680:HLA Antigens; D007155:Immunologic Factors; D007518:Isoantibodies; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d