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Complement-Mediated Microvascular Injury Leads to Chronic Rejection

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Complement Therapeutics

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 735))

Abstract

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.

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, VA Palo Alto/Stanford University School of Medicine, 300 Pasteur Dr A283 MC 5351, Stanford, CA, 94305, USA

    Mohammad A. Khan & Mark R. Nicolls

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  1. Mohammad A. Khan
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  2. Mark R. Nicolls
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Correspondence to Mark R. Nicolls .

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Editors and Affiliations

  1. Medicine, University Of Pennsylvania Department Of Pathology Laboratory Of, Philadelphia, Pennsylvania, USA

    John D. Lambris

  2. University of Colorado School of Medicin, Aurora, Colorado, USA

    V. Michael Holers

  3. Department of Pathology & Laboratory Med, University of Pennsylvania School of Med, Philadelphia, Pennsylvania, USA

    Daniel Ricklin

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Khan, M.A., Nicolls, M.R. (2013). Complement-Mediated Microvascular Injury Leads to Chronic Rejection. In: Lambris, J., Holers, V., Ricklin, D. (eds) Complement Therapeutics. Advances in Experimental Medicine and Biology, vol 735. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4118-2_16

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