Bone marrow (BM) transplantation (BMT) is the treatment of choice for many malignancies and specific nherited disorders. Unfortunately, infections such as Pseudomonas aeruginosa (P. aeruginosa) occur frequently even post-engraftment. Little is known about the mechanisms responsible for the increased risk of lung infections in BMT patients. We have shown that mice undergoing syngeneic BMT are more susceptible to pulmonary infection with P. aeruginosa than are non-transplanted mice despite complete donor leukocyte reconstitution. We found defects in the ability of alveolar macrophages (AMs) and polymorphonuclear leukocytes (PMNs) from BMT mice to phagocytose and/or kill bacteria and release tumor necrosis factor-a (TNFa). In addition, AMs and PMNs from BMT mice produce up to 125-times more prostaglandin E2 (PGE2) than cells from control mice. PGE2 is able to limit AM phagocytosis and to limit AM and PMN bacterial killing via interactions with the E prostanoid 2 (EP2) receptor. Thus, PGE2 is an attractive candidate to play a central role in the dysfunctional activity of AMs and PMNs from BMT mice. In vivo confirmation comes from our studies where pharmacologic blockade of PGE2 production (using indomethacin) restores lung host defense against P. aeruginosa post-BMT. These data have led to our hypothesis that over-production of PGE2 in the lung post-BMT, acting via EP2 receptor signaling, suppresses lung phagocyte function leading to impaired pulmonary host defense against P. aeruginosa. Our current studies will determine whether increased production of granulocyte-macrophage colony-stimulating factor (GM-CSF) post-BMT leads to increased production of PGE2 and whether the donor vs. host origin of the lung phagocytes or the BMT-conditioned lung environment contributes to impaired host defense. Finally, we will explore the role that the phosphatase and tensin homolog on chromosome ten (PTEN) and IL-1 receptor-associated kinase (IRAK)-M play as mediators of the PGE2-induced suppression. Using molecular, cellular and animal modeling strategies, we will address the following aims:
Aim 1) To determine the role of increased GM-CSF in determining PGE2 elevation and impaired host-defense post- BMT;
Aim 2) To determine whether the origin of the AMs (donor vs. host) dictates function post-BM;
Aim 3 To determine whether the BMT lung microenvironment is inhibitory to AM function;
Aim 4) To determine the roles that PTEN activation and/or IRAK-M elevation play in mediating the PGE2-induced immunosuppression post-BMT. This work provides mechanistic insight into the persistent immunosuppression seen post-BMT and provides a proof of concept for the development of new therapeutic strategies (neutralization of GM- CSF, inhibition of PGE2 synthesis/signaling and pharmacologic inhibition of PTEN activation) which may result in effective new treatments to prevent pulmonary infections in patients post-stem cell transplant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI065543-03S1
Application #
7793247
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Kehn, Patricia J
Project Start
2007-05-15
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
3
Fiscal Year
2009
Total Cost
$33,312
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Domingo-Gonzalez, Racquel; Moore, Bethany B (2014) Innate Immunity Post-Hematopoietic Stem Cell Transplantation: Focus on Epigenetics. Adv Neuroimmune Biol 5:189-197
Zas?ona, Zbigniew; Okunishi, Katsuhide; Bourdonnay, Emilie et al. (2014) Prostaglandin E? suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells. J Allergy Clin Immunol 133:379-87
Zas?ona, Zbigniew; Przybranowski, Sally; Wilke, Carol et al. (2014) Resident alveolar macrophages suppress, whereas recruited monocytes promote, allergic lung inflammation in murine models of asthma. J Immunol 193:4245-53
Domingo-Gonzalez, Racquel; Moore, Bethany B (2013) Defective pulmonary innate immune responses post-stem cell transplantation; review and results from one model system. Front Immunol 4:126
Domingo-Gonzalez, Racquel; Huang, Steven K; Laouar, Yasmina et al. (2012) COX-2 expression is upregulated by DNA hypomethylation after hematopoietic stem cell transplantation. J Immunol 189:4528-36
Naik, Payal N; Horowitz, Jeffrey C; Moore, Thomas A et al. (2012) Pulmonary fibrosis induced by ?-herpesvirus in aged mice is associated with increased fibroblast responsiveness to transforming growth factor-?. J Gerontol A Biol Sci Med Sci 67:714-25
Ballinger, Megan N; Newstead, Michael W; Zeng, Xianying et al. (2012) TLR signaling prevents hyperoxia-induced lung injury by protecting the alveolar epithelium from oxidant-mediated death. J Immunol 189:356-64
Coomes, Stephanie M; Hubbard, Leah L N; Moore, Bethany B (2011) Impaired pulmonary immunity post-bone marrow transplant. Immunol Res 50:78-86
Coomes, Stephanie M; Farmen, Sara; Wilke, Carol A et al. (2011) Severe gammaherpesvirus-induced pneumonitis and fibrosis in syngeneic bone marrow transplant mice is related to effects of transforming growth factor-?. Am J Pathol 179:2382-96
Stoolman, Joshua S; Vannella, Kevin M; Coomes, Stephanie M et al. (2011) Latent infection by ?herpesvirus stimulates profibrotic mediator release from multiple cell types. Am J Physiol Lung Cell Mol Physiol 300:L274-85

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