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Modifiers of complement activation for prevention of antibody-mediated injury to allografts

Hughes, Peter D.a; Cohney, Solomon J.a,b

Current Opinion in Organ Transplantation: August 2011 - Volume 16 - Issue 4 - p 425–433
doi: 10.1097/MOT.0b013e3283489a5a
Histocompatibility: Edited by Stanley Jordan
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Purpose of review 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.

Recent findings 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.

Summary 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.

aDepartment of Nephrology, Royal Melbourne Hospital

bWestern Hospitals, Parkville, Victoria, Australia

Correspondence to Dr Solomon J. Cohney, Department of Nephrology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia E-mail: solomon.cohney@mh.org.au

© 2011 Lippincott Williams & Wilkins, Inc.