IL-12 p80 is an innate epithelial cell effector that mediates chronic allograft dysfunction

Area of Science:

• Transplantation immunology
• Innate immunity
• Allograft dysfunction

Background:

• Bronchiolitis obliterans syndrome (BOS) is the primary cause of chronic lung allograft dysfunction.
• Respiratory viral infections are identified risk factors for BOS.
• Virus-induced airway epithelial injury upregulates innate immune genes, including the interleukin (IL)-12 family.

Purpose of the Study:

• To investigate the role of epithelial cell-derived IL-12 family members in lung allograft dysfunction.
• To evaluate the impact of viral infection on IL-12 family member expression and subsequent allograft outcomes.

Main Methods:

• Characterization and manipulation of murine and human IL-12 family members in lung allografts.
• Correlation of IL-12 family member expression with epithelial cell injury, immune cell infiltration, and collagen deposition.
• Utilized mouse models of lung transplantation and analyzed human allograft specimens.

Main Results:

• Concurrent viral infection and transplantation in mice exacerbated epithelial injury, macrophage accumulation, and collagen deposition.
• Virus-driven dysfunction was linked to increased epithelial production of IL-12 p80, a macrophage chemoattractant.
• Blocking or overexpressing epithelial p80 modulated macrophage infiltration and allograft dysfunction.
• Human recipients with viral infections showed elevated epithelial p80 expression correlating with increased macrophage accumulation.

Conclusions:

• An enhanced epithelial innate immune response is a key mechanism in lung allograft dysfunction.
• The macrophage chemoattractant IL-12 p80 is identified as a critical innate epithelial effector in disease progression.
• Targeting epithelial p80 may offer a therapeutic strategy for preventing or treating lung allograft dysfunction.