Complement activation is not required for obliterative airway disease induced by antibodies to major histocompatibility complex class I: Implications for chronic lung rejection

  • J Heart Lung Transplant. 2012 Nov;31(11):1214-22. doi: 10.1016/j.healun.2012.08.011.
Masashi Takenaka  1 ,  Vijay Subramanian ,  Venkataswarup Tiriveedhi ,  Donna Phelan ,  Ramsey Hachem ,  Elbert Trulock ,  Andrew E Gelman ,  G Alexander Patterson ,  Kiyotaka Hoshinaga ,  Thalachallour Mohanakumar
Affiliations
  • 1. Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
PMID: 22980951 DOI: 10.1016/j.healun.2012.08.011
Abstract

Background: The role of non-complement activating antibodies (ncAbs) to mismatched donor human leukocyte antigen (HLA) in the pathogenesis of chronic lung rejection is not known. We used a murine model of obliterative airway disease (OAD) induced by Abs to major histocompatibility major histocompatibility complex (MHC) class I and serum from donor-specific Abs developed in human lung transplant (LTx) recipients to test the role of ncAbs in the development of OAD and bronchiolitis obliterans syndrome (BOS).

Methods: Anti-MHC ncAbs were administered intrabronchially in B.10 mice or in C3 knockout (C3KO) mice. Lungs were analyzed by histopathology. Lymphocytes secreting interleukin (IL)-17, interferon-γ, or IL-10 to Collagen V and K-α1 tubulin (Kα1T) were enumerated by enzyme-linked immunospot assay. Serum antibodies to Collagen V and Kα1T were determined by enzyme-linked immunosorbent assay. Cytokine and growth factor expression in Lungs was determined by real-time polymerase chain reaction. Donor-specific Abs from patients with BOS and control BOS-negative LTx recipients were analyzed by C1q assay.

Results: Administration of ncAbs in B.10 mice or C3KO resulted in OAD lesions. There were significant increases in IL-17- and interferon-γ-secreting cells to Collagen V and Kα1T, along with serum Abs to these Antigens. There was also augmented expression of monocyte chemotactic protein-1, IL-6, IL-1β, vascular endothelial growth factor, transforming growth factor-β, and fibroblastic growth factor in mice administered ncAbs by Day 3. Among 5 LTx recipients with BOS, only 1 had C1q binding donor-specific Abs.

Conclusion: Complement activation by Abs to MHC class I is not required for development of OAD and human BOS. Therefore, anti-MHC binding to epithelial and endothelial cells can directly activate pro-fibrotic and pro-inflammatory cascades leading to immune response to self-antigens and chronic rejection.

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