AN EXPERIMENTAL-MODEL OF IDIOPATHIC PNEUMONIA SYNDROME AFTER BONE-MARROW TRANSPLANTATION .1. THE ROLES OF MINOR H-ANTIGENS AND ENDOTOXIN

Idiopathic pneumonia syndrome (IPS) refers to diffuse, noninfectious p neumonia that occurs after allogeneic bone marrow transplantation (BMT ). We have developed a model of IFS using a well-characterized murine BMT system (B10.BR --> CBA) in which lung injury after BMT can be indu ced by minor histocompatibility (H) antigenic differences between dono r and host. Lung pathology and broncho-alveolar lavage (BAL) fluid wer e analyzed in transplant recipients before and after both syngeneic an d allogeneic BMT. At 2 weeks after BMT, no specific pathologic abnorma lities were noted; at 6 weeks, both pneumonitis and mononuclear cell i nfiltration 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, an d tumor necrosis factor alpha. No pathologic organisms were isolated f rom the respiratory tract of any animal. We also tested the role of en dotoxin in the development of this injury. Injection of LPS 6 weeks af ter transplantation caused profound lung injury only in mice with mode rate graft-versus-host disease; dramatic increases in BAL neutrophils and tumor necrosis factor alpha were observed, with alveolar hemorrhag e occurring in 4 of 12 of these mice but in no other group. We conclud e that (1) this murine BMT system is a potentially useful model of cli nical 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. (C) 1996 by The American Society of Hematology.