title: Preventive azithromycin treatment reduces noninfectious lung injury and acute graft-versus-host disease in a murine model of allogeneic hematopoietic cell transplantation.
abstract: Noninfectious lung injury and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with significant morbidity and mortality. Azithromycin is widely used in allogeneic HCT recipients for pulmonary chronic GVHD, although current data appear controversial. We induced GVHD and noninfectious lung injury in lethally irradiated B6D2F1 mice by transplanting bone marrow and splenic T cells from allogeneic C57BL/6 mice. Experimental groups were treated with oral azithromycin starting on day 14 until the end of week 6 or week 14 after transplantation. Azithromycin treatment resulted in improved survival and decreased lung injury; the latter characterized by improved pulmonary function, reduced peribronchial and perivascular inflammatory cell infiltrates along with diminished collagen deposition, and a decrease in lung cytokine and chemokine expression. Azithromycin also improved intestinal GVHD but did not affect liver GVHD at week 6 early after transplantation. At week 14, azithromycin decreased liver GVHD but had no effect on intestinal GVHD. In vitro, allogeneic antigen-presenting cell (APC)- dependent T cell proliferation and cytokine production were suppressed by azithromycin and inversely correlated with relative regulatory T cell (Treg) expansion, whereas no effect was seen when T cell proliferation occurred APC independently through CD3/CD28-stimulation. Further, azithromycin reduced alloreactive T cell expansion but increased Treg expansion in vivo with corresponding downregulation of MHC II on CD11c(+) dendritic cells. These results demonstrate that preventive administration of azithromycin can reduce the severity of acute GVHD and noninfectious lung injury after allo-HCT, supporting further investigation in clinical trials.
authors.affiliation: Department of Internal Medicine, Louisiana State University Health Sciences Center, Shreveport, Shreveport, Louisiana; Division of Hematology and Hematologic Malignancies, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah.
authors.forename: Sabarinath Venniyil
authors.initials: SV
authors.lastname: Radhakrishnan
authors.affiliation: Division of Hematology and Hematologic Malignancies, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah; Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Feist-Weiller Cancer Center, Shreveport, Louisiana.
authors.forename: Senthilnathan
authors.initials: S
authors.lastname: Palaniyandi
authors.affiliation: Division of Hematology and Oncology, University of Regensburg, Regensburg, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Mueller
authors.affiliation: Division of Hematology and Oncology, University of Regensburg, Regensburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Miklos
authors.affiliation: Division of Hematology and Oncology, University of Regensburg, Regensburg, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Hager
authors.affiliation: Division of Hematology and Oncology, University of Regensburg, Regensburg, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Spacenko
authors.affiliation: Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Feist-Weiller Cancer Center, Shreveport, Louisiana.
authors.forename: Fridrik J
authors.initials: FJ
authors.lastname: Karlsson
authors.affiliation: Department of Pathology, University of Regensburg, Regensburg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Huber
authors.affiliation: Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Feist-Weiller Cancer Center, Shreveport, Louisiana.
authors.forename: Nicolai A
authors.initials: NA
authors.lastname: Kittan
authors.affiliation: Division of Hematology and Hematologic Malignancies, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah; Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Feist-Weiller Cancer Center, Shreveport, Louisiana. Electronic address: Gerhard.hildebrandt@hci.utah.edu.
authors.forename: Gerhard C
authors.initials: GC
authors.lastname: Hildebrandt
mesh_terms: D000208:Acute Disease; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D007422:Intestines / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D055370:Lung Injury / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D061251:Primary Cell Culture; D012129:Respiratory Function Tests; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D017963:Azithromycin
keywords: Acute graft-versus-host disease; Azithromycin; Noninfectious lung injury; Regulatory T cell