Immunopathology of idiopathic pneumonia syndrome (ips) following bone marrow transplant (BMT)

IPS is a major complication following BMT and is accentuated by graft-vshost disease (GVHD). We have found this to be true in our established allogeneic BMT mouse model. B10.BR (H-2k) recipients were lethally irradiated (d.-l) and transplanted (d.O) with 20xl06 anti-Thy+c' treated C57BL/6 (H-2b) marrow with or without ISxlO6 spleen cells (BMS) as a source of GVHD-causing T cells. A parallel set of mice also received cyclophosphamide (cytoxan) (120mg/kg/day) as a conditioning regimen preBMT (daysr3 and -2). Mice were studied on days -2,-l,0,l,3,7,10,14,21,28 and 90. Lung GVHD was associated with an influx of T cells (mostly CD8+), macrophages and neutrophils as early as day 3 post BMT. Mice receiving cytoxan and BMS exhibited an accelerated lethality compared to the control BMS GVHD group. Lung wet/dry ratios and IPS increased in concordance with the development of GVHD. Cytoxan exaccerbated lung injury due to irradiation. Hydroxyproline levels did not differ among the groups, indicating that the injury was not fibrogenic early post-BMT. Frozen lung sections were analyzed for expression of T cell costimulatory and adhesion ligands and cytokines. Lung alterations included upregulation of B7-1, ICAM-1, -2, and MHC class II antigens, as early as day 3 post BMT. Frequencies of cells transcribing the inflammatory proteins TNF-α, IL-Iβ, MIP-la, TGF-β, IFNγ, IL-12p40 and granzymes A + B were increased. Cytoxan accelerated this cellular and cytokine cascade. In summary, early IPS induction is associated with upregulation of T-cell costimulatory ligands and induction of inflammatory and cytolytic proteins concommitant with GVHD development.