T Cell-Mediated Expression of S100A4 Is Associated with Cartilage Disruption in Transplanted Bronchi

 

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Objectives: Chronic lung allograft dysfunction (CLAD) is a major limiting factor for long-term survival after lung transplantation (LTx). Increased levels of the calcium-binding S100 protein family have been reported in lung allograft tissue and bronchoalveolar lavage fluid of patients with CLAD, although little is known about their pathogenetic role. The subtype S100A4 has recently gained increased attention in oncology as it is associated with an aggressive phenotype and metastasis-promoting properties if expressed in cancer. We sought to investigate S100A4 expression human bronchus grafts.

Methods: Long segments of the tracheas in immunocompetent Brown Norway (BN) and T cell-deficient athymic nude (RNU) rats were replaced by similar-sized human bronchi. Grafts were harvested on day 7 (BN₇, n = 6; RNU₇, n = 7) or day 28 (BN₂₈, n = 6; RNU₂₈, n = 6) for histology, S100A4 expression, and quantification of immune activation.

Results: In the BN group, the graft tissue showed infiltration of CD68+ and CD3+ lymphocytes, while the mononuclear infiltrate in RNU rats consisted of similar amounts of CD68-positive macrophages but showed only scarce CD3+ cells. The accumulation of S100A4+ cells at 28 days was significantly denser in BN grafts and mostly observed surrounding the cartilage. S100A4+ cells infiltrated into the cartilage only in the BN group and were associated with a significant destruction of the cartilage architecture. S100A4 expression was abundant in cartilage-invading cells. The donor-specific splenocyte IFNγ-response and the donor-specific antibody response were vastly higher in BN rats than in RNU rats, accounting for a strong lymphocyte-induced immune response. Grafts in BN developed marked peri-bronchial fibrosis and substantial subepithelial proliferative disease over 28 days with reduction of the airway cross-sectional area, while changes in RNU were more subtle. In vitro co-culture experiments showed that the expression of S100A4 protein in fibroblasts was significantly higher when stimulated with mononuclear cells from BN than from RNU. S100A4 expression was directly dependent on lymphocytic stimulation and could not be induced by CD3-depleted mononuclear cells.

Conclusion: Cartilage infiltration by S100A4+ cells in transplanted bronchi is driven by T cell-dependent mechanisms and is associated with disruption of its architecture. This yet ill-defined phenomenon may contribute to the progression of graft dysfunction in CLAD.