Amelioration of Idiopathic Pneumonia Syndrome (IPS) and GVHD by KGF-Pretreatment Is Partly Mediated Via a STAT-6-Dependent Pathway in the Host.
Authors: Panoskaltsis-Mortari Angela , Price Andrew , Tram Kevin , McFadden Rita , Ehrhardt Michael J. , Grusby Michael J. , Blazar Bruce R. 
Published: October 2019

Abstract
KGF (FGF-7), an epithelial cell growth factor, can lessen the injurious effects of post-BMT lung injury (IPS) and GVHD when given prior to conditioning of the recipient. We reported that mice treated with KGF pre-conditioning had elevated systemic levels of Th2-type cytokines at the time of BM infusion which was associated with less GVHD. In non-conditioned SCID mice that developed lethal GVHD from allogeneic T cells, KGF pretreatment also increased Th2 cytokines implying that KGF alone was responsible for the systemic Th2 milieu and not a response that was dependent on conditioning. In the post-BMT lung, KGF pretreatment did not alter the cellular composition of the inflammatory infiltrate but resulted in decreased levels of immune activation markers compared to non-treated control IPS mice. The mechanism of this immunomodulatory effect is unknown. Since Th2 responses are dependent on the STAT-6 transcription factor, we studied the effects of KGF in our established murine IPS model using lethally-conditioned STAT-6−/− mice (B6 background) as recipients of allogeneic B10.BR BM and T cells and compared to WT hosts. STAT-6−/− mice pretreated with KGF (5 mg/kg s.c. for 3 days) had an accelerated mortality rate and poorer survival compared to WT recipients. Examination of GVHD target organs revealed that KGF pretreatment ameliorated liver GVHD in WT and STAT-6−/− recipients. In contrast, the benefit of KGF for GVHD of the colon was only seen in the WT but not in STAT-6−/− recipients, consistent with post-BMT body weights and survival. Whole body plethysmograph was done to evaluate lung function at 30 cm water pressure on day 7 post-BMT, a time when acute IPS is manifested in this model. WT but not STAT-6−/− mice pretreated with KGF had improved lung compliance compared to their non-treated counterparts (p<0.05). KGF-pretreated STAT-6−/− recipients also had increased lung weights compared to control- or KGF-treated WT mice with IPS (p<0.05). Histological analysis of lung cryosections taken on day 7 post-BMT showed that all recipients of allogeneic BM and T cells had increased inflammatory cells in their lungs, consistent with acute IPS. However, STAT-6−/− hosts with IPS had elevated numbers of CD4+ T cells in their lungs compared to WT hosts with IPS (18.3%±1.5 vs 11.6%±2.7, p=0.01). Other cell phenotypes did not differ. However, KGF-pretreated STAT-6−/− mice had significantly elevated levels (10-fold) of IL-17, CCL2 and CCL8 in their bronchoalveolar lavage fluid on day 7 post-BMT compared to their WT KGF-treated counterparts implying a skewing to a Th17 inflammatory response in STAT-6−/− mice. These data indicate that the STAT-6 pathway plays a role in the cytoprotective function of KGF and this STAT-6-dependency is tissue-specific. To achieve the full benefits of KGF and other cytoprotective agents, it will be important to take into account the immune modulatory mechanisms operative in individual GVHD target organs.