Human and murine obliterative bronchiolitis in transplant

Abstract

Obliterative bronchiolitis is a devastating illness that limits the long-term success of lung transplantation. Its high prevalence and overall poor response to current therapeutic measures demands further research to elucidate pathogenic mechanisms. Toward this goal, there is a role for animal models to study the mechanisms of obliterative bronchiolitis, such as the murine heterotopic tracheal allograft model. This review compares the tracheal allograft model to human obliterative bronchiolitis pathology and highlights the important mechanisms of airway rejection described using this model. Although certain limitations exist, the pursuit of proof-of-concept studies in this model, as well as other animal models, can provide the basis for genetic and cellular translational human studies directed toward post-transplant obliterative bronchiolitis pathogenesis. To meet these challenges, we call for the establishment of a National Institutes of Health-supported Lung Transplant Network to better orchestrate translational research efforts in obliterative bronchiolitis pathogenesis and treatment, and to advance the field of lung transplantation.

Figure 1.

Similarities in early/late murine obliterative airway disease (OAD) pathology compared with human lymphocytic bronchiolitis and obliterative bronchiolitis. Images of human pathology courtesy of Dr. Rubin Tuder.

Figure 1.

Similarities in early/late murine obliterative airway disease (OAD) pathology compared with human lymphocytic bronchiolitis and obliterative bronchiolitis. Images of human pathology courtesy of Dr. Rubin Tuder.

Figure 1.

Similarities in early/late murine obliterative airway disease (OAD) pathology compared with human lymphocytic bronchiolitis and obliterative bronchiolitis. Images of human pathology courtesy of Dr. Rubin Tuder.

Figure 1.

Similarities in early/late murine obliterative airway disease (OAD) pathology compared with human lymphocytic bronchiolitis and obliterative bronchiolitis. Images of human pathology courtesy of Dr. Rubin Tuder.

Figure 2.

Pluripotent allospecific CD8⁺ effector T cells contribute to murine OAD. On Day 14 post-transplant, tracheal allograft mononuclear cells from CD45.1⁺B6 recipients were isolated and cocultured with/without donor (BALB/c, CD45.2⁺) splenocytes for 6 h followed by determination of IFN-γ, tumor necrosis factor (TNF)-α, and granzyme B expression using intracellular cytokine staining (anticytokine or isotype antibody staining) and flow cytometric analysis gating on CD45.1⁺CD8⁺ T cells.