Human and Murine Obliterative Bronchiolitis in Transplant

Abstract

Obliterative bronchiolitis is a devastating illness that limits the longterm 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.

The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation

“…Furthermore, even in a s.c. tracheal transplant model of OB, the trafficking of effector T cells to the lung has been reported (31). This evidence suggests the important role of the lung as a "reservoir" of effector and effector memory T cells that may contribute to allograft airway rejection after lung transplantation (19).…”

“…Increasing evidence suggests that the lung might be an important reservoir of effector and effector memory T cells (17,18). In a s.c. tracheal transplant model of OB, preferential localization of effector memory CD4 ϩ and CD8 ϩ T cells to the lung parenchyma and airways has been demonstrated (19).…”

CTLA-4-mediated regulatory phenotype of T-cells in tolerant lung recipients

“…At the histological level, OB is characterised at the early stage by the infiltration of the bronchiolar wall with lymphocytes, monocytes and histiocytes, followed by a fibrosis process, leading to obliteration of small airways [3]. Although the understanding of risk factors associated with the occurrence of OB has increased in the recent years [4], immune characteristics distinguishing tolerant recipients from patients with BOS remain largely unknown [5,6].…”

Lung Diseases - Selected State of the Art Reviews

“…Protein levels of IL-6 and IL-1β and mRNA levels for TGF-β, IL-17, IL-23 and IL-8 in BAL fluid were increased in lung transplant recipients with BOS when compared to controls (Vanaudenaerde, Wuyts et al 2008). CXCL8, a potent chemoattractant for neutrophils, has previously been associated with BOS, but it was unclear whether the presence of neutrophils was just a marker of general inflammation or a key mediator of obliterative bronchiolitis (McDyer 2007). Since IL-17 promotes neutrophil chemotaxis, the presence of neutrophils has been suggested to be secondary to a Th17-mediated alloimmune or autoimmune response (Shilling and Wilkes 2011).…”