Local intragraft humoral immune responses in chronic lung allograft dysfunction

Area of Science:

• Transplantation immunology
• Allograft rejection mechanisms
• Pulmonary medicine

Background:

• Donor human leukocyte antigen (HLA)-specific antibodies (DSA) and non-HLA antibodies contribute to lung allograft injury and chronic lung allograft dysfunction (CLAD).
• The origin of these antibodies, whether produced locally within the graft or systemically, remains unclear.

Purpose of the Study:

• To investigate the hypothesis that DSA and non-HLA antibodies are produced locally within CLAD lungs.
• To determine the site of antibody production in the context of lung allograft dysfunction.

Main Methods:

• Lung tissue was collected from 15 CLAD patients.
• Lung tissue cultures were performed with and without stimulation (lipopolysaccharide or CD40L) to collect lung culture supernatant (LCS).
• Protein eluates were obtained from lung tissue, and antibody levels (MFI) were measured using Luminex and antigen microarray.

Main Results:

• LCS from patients with serum DSA were positive for DSA, with increased levels after CD40L stimulation.
• Non-HLA antibody levels in LCS correlated with lung eluate but not serum, suggesting local production.
• Higher frequencies of activated lung B cells and increased IgG+ plasma cells and IL-21 expression were observed in lymphoid aggregates within CLAD lungs.

Conclusions:

• Donor-specific antibodies (DSA) and non-HLA antibodies can be produced within activated B cell-rich lung allografts.
• This local production contributes to the pathogenesis of chronic lung allograft dysfunction (CLAD).