A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

Abstract

Obliterative bronchiolitis is a frequent, morbid, and usually refractory complication of lung transplantation. Mechanistic study of obliterative bronchiolitis would be aided by development of a relevant model that uses human immune effector cells and airway targets. Our objective was to develop a murine chimera model that mimics obliterative bronchiolitis of lung allograft recipients in human airways in vivo. Human peripheral blood mononuclear cells were adoptively transferred to immunodeficient mice lacking activity of T, B, and NK cells, with and without concurrent transplantations of human small airways dissected from allogeneic cadaveric lungs. Chimerism with human T cells occurred in the majority of recipient animals. The chimeric T cells became highly activated, rapidly infiltrated into the small human airway grafts, and caused obliterative bronchiolitis. In contrast, airways implanted into control mice that did not also receive human peripheral blood mononuclear cell transfers remained intact. In vitro proliferation assays indicated that the chimeric T cells had enhanced specific proliferative responses to donor airway alloantigens. This model confirms the critical role of T cells in development of obliterative bronchiolitis among human lung allograft recipients and provides a novel and easily implemented mechanism for detailed, reductionist in vivo studies of human T-cell responses to allogeneic human small airways. Chronic lung allograft rejection typically manifests with obliterative bronchiolitis (OB), a small airway fibroproliferative disease process characterized by varying degrees of airway luminal obliteration with fibrinous granulation tissue. 1 Lung transplant recipients with OB develop expiratory airflow obstruction, which is often inexorably progressive, and have increased predilection for infection. 2 Despite extensive investigation, as well as incremental advances in donor organ preservation, surgical techniques, immunosuppressive regimens, and infection prophylaxis, OB remains the single most frequent cause of late graft dysfunction and death after lung transplantation. 2 Current limitations in prevention and treatment of OB likely reflect incomplete understanding of the responsible immunopathogenic mechanisms. Accordingly, having a model to generate novel insights regarding the disease paradigm, and a ready means to test these hypotheses, could be a boon for the development of more effective modalities to prevent or counter this frequent complication of lung transplantation.Animal models have been immeasurably important in advancing our understanding of many disease processes, including allograft rejection mechanisms. 3 With particular respect to pulmonary transplantation, heterotopic tracheal allografts in mice undergo histological abnormalities that reproduce the progression of OB in humans, including an initial lymphocytic infiltration, followed by successive stages of epithelial metaplasia and denudation and, ultimately, intraluminal fibroproliferation. [3][4][5][6][7] Although this mo...

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…Another potentially powerful model takes advantage of humanized mice by transplanting human airways and peripheral blood mononuclear cells into an immunodeficient mouse (108,109). These models are promising for studying peripherally derived human leukocytes but have challenges due to the limited supply of human bronchi available.…”

Rattus Model Utilizing Selective Pulmonary Ischemia Induces Bronchiolitis Obliterans Organizing Pneumonia

“…(7) These models include orthotopic and heterotopic lung transplant rodent models, a chimeric T cell mouse model, heterotopic tracheal allografts, inhalational injury, viral infection, bone marrow transplant, and tracheal transplant. (9, 23, 25-60) Only a few models have implicated ischemia as a mechanism for BOOP in either via tracheal transplant, inhaled papaverine, or interruption of circulation. (7, 48, 52) Such models have systemic influence and affect both lungs simultaneously.…”

Lung Diseases - Selected State of the Art Reviews

“…Another group, from the University of Pittsburgh, has developed a human-mouse chimeric model of BOS in which the allograft and immune effector cells are of human origin. (Xue et al 2011) They state that the formation of chimeric allogenic T cells, and the resulting infiltration into small human airways is definitive in delineating the role T cells play in the development of BOS.…”