Role of complement activation in obliterative bronchiolitis post-lung transplantation

Area of Science:

• Immunology
• Transplantation Biology
• Pulmonary Medicine

Background:

• Obliterative bronchiolitis (OB) is a major cause of lung allograft failure.
• IL-17 and autoimmunity to type V collagen are implicated in OB pathogenesis.
• The role of complement activation in OB remains unclear.

Purpose of the Study:

• To investigate the role of complement activation in OB development and IL-17 production.
• To elucidate the interplay between complement, IL-17, and complement-regulatory proteins (CRPs) in lung allografts.

Main Methods:

• Analysis of CRP expression and C3a levels in human and murine OB samples.
• In vitro studies on IL-17's effect on CRP expression in airway epithelial cells.
• In vivo experiments using IL-17 neutralization and C5 blockade in murine lung transplantation models.

Main Results:

• CRP expression was downregulated, and C3a was upregulated in OB lungs.
• IL-17 suppressed CRP expression, while IL-17 neutralization restored CRP and reduced C3a.
• Exogenous C3a boosted IL-17 production.
• C5 blockade prevented OB, reduced rejection, normalized CRP, and decreased IL-17 and IL-6 levels.

Conclusions:

• Complement activation, driven by IL-17-mediated CRP downregulation, contributes to OB pathogenesis.
• A positive feedback loop exists between C3a and IL-17, promoting CRP suppression.
• Complement inhibition presents a potential therapeutic strategy for preventing OB after lung transplantation.