Idiopathic pneumonia syndrome after bone marrow transplantation: the role of pre-transplant radiation conditioning and local cytokine dysregulation in promoting lung inflammation and fibrosis

Abstract

Pulmonary complications and graft-vs.-host disease (GVHD) remain severe threats to survival after bone marrow transplantation (BMT). Idiopathic pneumonia syndrome (IPS) accounts for nearly 50% of all the cases of interstitial pneumonitis after BMT. IPS is characterized by an early inflammatory phase followed by chronic inflammation and fibrosis of lung tissue; however, the immunopathogenesis of this disease is not yet clearly understood. This biphasic syndrome has been reported to be associated with pre-transplant radiation conditioning in some studies while others have suggested that GVHD or autoimmune phenomena may be responsible for its development. The early post-BMT phase is characterized by the presence of inflammatory cytokines whose net effect is to promote lymphocyte influx into lungs with minimal fibrosis, that leads to an acute form of graft-vs.-host reaction-mediated pulmonary tissue damage. Gradual changes over time in leucocyte influx and activation lead to dysregulated wound repair mechanisms resulting from the shift in the balance of cytokines that promote fibrosis. Using data from new animal models of IPS and information from studies of human IPS, we hypothesize that cytokine-modulated immunological mechanisms which occur during the acute and chronic phases after bone marrow transplantation lead to the development of the progressive, inflammatory, and fibrotic lung disease typical of idiopathic pneumonia syndrome.

Figure 1

Pre-transplant irradiation can induce cytokines that lead to the expression of MHC, costimulatory and/or cell adhesion molecules on pulmonary tissue. Cytokine networks may induce an environment that promotes homing and activation of allogeneic T cells in the lungs.

Figure 2

The initial inflammatory phase in the lungs after bone marrow transplantation is an antifibrotic phase. Homing and activation of alloreactive T cells to the lungs results in a cytokine milieu that promotes cellular influx into lungs while maintaining a nonfibrotic microenvironment.

Figure 3

The late phase of IPS is characterized by a chronic fibrotic phase in the lungs. The balance of cytokines in the pulmonary microenvironment shifts to higher expression of tumour necrosis factor (TNF) and reduced expression of IFN-γ which promotes collagen secretion by interstitial fibroblasts, thereby leading to lung fibrosis.