Interferon-Gamma Signaling in the Pathogenesis of Idiopathic Pneumonia Syndrome Following Allogeneic Bone Marrow Transplantation

Idiopathic pneumonia syndrome (IPS) is a life-threatening acute noninfectious diffuse lung injury occurring after allogeneic bone marrow transplantation (BMT). We have recently shown that absence of STAT1 signaling in recipient APC leads to accelerated Graft Versus Host Disease (GVHD) and Transplant-associated mortality and morbidity after lethal irradiation in fully MHC-mismatched allogeneic or in non-irradiated P→F1 BMT models. We now addressed the impact of recipient Type II interferon signaling on the development of lung injury after allogeneic BMT using a non-irradiated P→F1 model. 1x10 7 BMCs plus 2.5x10 7 SPCs from C57BL/6 (B6) mice were i.v. injected into IFNγR-deficient CB6F1 (F1.GRKO) or CB6F1 wild type (WT) mice. F1.GRKO recipients had significantly reduced survival (MST 32 days post-BMT vs. not reached p 5 vs.4x10 4 , p + BAL cells were donor derived in the F1.GRKO recipients, compared to only 10% in the wild type recipients. Furthermore, the absolute cell number of donor CD4 + and CD8 + cells in the knockout mice significantly outnumbered that in their wild type counterparts (p -/- mice, the activation, proliferation, and differentiation status of donor lymphocytes were assessed by Flowcytometry after BMT. In line with the lung infiltration, there was significantly increased donor cell engraftment in PBMC, spleen, lymph nodes, and bone marrow in F1.GRKO recipients (all with p high CD62L low cells), Th1 and Tc1 differentiation of donor CD4 and CD8 cells (p + T reg cell differentiation was noticed. Interestigly, we observed significantly lower PD-L1 expression on recipient APC in the F1.GRKO mice compared to wild type mice, suggesting that absence of PD-L1 expression may contribute to reduced contraction of activated donor T cells. Interestingly, in line with these findings we also observed significantly reduced PD-L1 expression when single cell suspension from lung tissues were analyzed by flow. Reduced PD-L1 expression was observed on both recipient CD45 + , and CD45 - cells in F1.GRKO when tested on day 22 post-BMT, meanwhile there was no difference in PD-L1 expression pattern in the cells isolated from small intestine. These results suggest that IFN-γ induced PD-L1 expression on hematopoietic and non-hematopoietic cells in the lung may be of significance in protecting recipients against acute donor-cell mediated lung injury and IPS. Disclosures Lentzsch: Celgene: Membership on an entity9s Board of Directors or advisory committees; Axiom: Speakers Bureau; Novartis: Membership on an entity9s Board of Directors or advisory committees; BMS: Membership on an entity9s Board of Directors or advisory committees; Janssen: Membership on an entity9s Board of Directors or advisory committees.