An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin

Abstract

Idiopathic pneumonia syndrome (IPS) refers to diffuse, non-infectious pneumonia that occurs after allogeneic bone marrow transplantation (BMT). We have developed a model of IPS using a well-characterized murine BMT system (B10.BR-->CBA) in which lung injury after BMT can be induced by minor histocompatibility (H) antigenic differences between donor and host. Lung pathology and broncho-alveolar lavage (BAL) fluid were analyzed in transplant recipients before and after both syngeneic and allogeneic BMT. At 2 weeks after BMT, no specific pathologic abnormalities were noted; at 6 weeks, both pneumonitis and mononuclear cell infiltration around vessels and bronchioles were observed only in mice receiving allogeneic BMT. This injury was associated with elevated BAL fluid levels of endotoxin (lipopolysaccharide [LPS]), neutrophils, and tumor necrosis factor alpha. No pathologic organisms were isolated from the respiratory tract of any animal. We also tested the role of endotoxin in the development of this injury. Injection of LPS 6 weeks after transplantation caused profound lung injury only in mice with moderate graft-versus-host disease; dramatic increases in BAL neutrophils and tumor necrosis factor alpha were observed, with alveolar hemorrhage occurring in 4 of 12 of these mice but in no other group. We conclude that (1) this murine BMT system is a potentially useful model of clinical IPS; (2) minor H differences between donor and recipient can be important stimuli in the pathogenesis of IPS; and (3) endotoxin in BAL fluid is associated with lung injury, and excess endotoxin can cause the development of alveolar hemorrhage in this model.

An Official American Thoracic Society Research Statement: Noninfectious Lung Injury after Hematopoietic Stem Cell Transplantation: Idiopathic Pneumonia Syndrome

“…Acute GVHD often precedes IPS, suggesting a possible causal relationship between the two disorders (3,33,56,57). Although IPS can also occur when signs and symptoms of GVHD are limited or absent, the consistent association between lung injury and GVHD in experimental models also supports such an etiology (1,3,6,7,15,(20)(21)(22)58).…”

“…In a practical sense, the diagnosis of IPS is based on exclusion of infectious organisms, cardiac dysfunction, acute renal failure, or iatrogenic fluid overload in the setting of pulmonary dysfunction after HSCT. IPS encompasses a spectrum of clinical presentations, in both children and adults, and is thought to result from a variety of lung insults, including toxic effects of HSCT conditioning regimens, immunologic cell-mediated injury, inflammatory cytokines, and occult pulmonary infections (1,(4)(5)(6)(7)(8)(9)(10)(11).…”

“…Several murine models of lung injury after HSCT have been established using a variety of strain combinations and conditioning regimens (Table 4). They include a lethally irradiated major histocompatibility complex (MHC)-matched, multiple minor antigen mismatch (6,20,68,172); a complete MHC mismatch model with and without cyclophosphamide (7, 69), lethally irradiated, haploidentical, parent into F1 model (20,146,147,165); a MHC class I mismatch (68,70); a MHC class II mismatch (68); and a syngeneic HSCT model using high-dose chemotherapy (71).…”

“…Regardless of strain combination, two primary, reproducible abnormalities are apparent in these experimental models: a dense mononuclear cell infiltrate around both pulmonary vessels and bronchioles and an acute pneumonitis involving the interstitium and alveolar spaces representing each of the three anatomic categories outlined in Figure 1. When measured, alterations in pulmonary function are associated with lung histopathology demonstrating that the observed lung inflammation is physiologically relevant (6,7,75). The alveolar infiltrate is composed of macrophages, lymphocytes, epithelial cells, and scattered polymorphonuclear cells within a fibrin matrix, whereas the periluminal (around vascular and bronchial structures) infiltrates are composed primarily of activated donor T cells.…”

“…The only exception to this is when mice are challenged with lipopolysaccharide (LPS). In this scenario, hemorrhage is only observed in mice with advanced GVHD and is associated with large increases in BAL fluid levels of neutrophils, TNF-a, and LPS (6,11).…”