Preventive azithromycin treatment reduces noninfectious lung injury and acute graft-versus-host disease in a murine model of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2015 Jan;21(1):30-8
Date
12/03/2014Pubmed ID
25445642DOI
10.1016/j.bbmt.2014.09.025Scopus ID
2-s2.0-84927125235 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
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.
Author List
Radhakrishnan SV, Palaniyandi S, Mueller G, Miklos S, Hager M, Spacenko E, Karlsson FJ, Huber E, Kittan NA, Hildebrandt GCAuthor
Sabarinath Venniyil Radhakrishnan MD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acute DiseaseAnimals
Anti-Bacterial Agents
Azithromycin
Bone Marrow Transplantation
Cytokines
Dendritic Cells
Disease Models, Animal
Female
Graft vs Host Disease
Intestines
Liver
Lung
Lung Injury
Mice
Primary Cell Culture
Respiratory Function Tests
Spleen
Survival Analysis
T-Lymphocytes
Transplantation, Homologous
Whole-Body Irradiation