Faculty Collaboration Database

The Prolyl Hydroxylase Inhibitor Dimethyl Oxalyl Glycine Decreases Early Gastrointestinal GVHD in Experimental Allogeneic Hematopoietic Cell Transplantation. Transplantation 2020 Dec;104(12):2507-2515

Date

07/09/2020

Pubmed ID

32639407

Pubmed Central ID

PMC8139022

DOI

10.1097/TP.0000000000003383

Scopus ID

2-s2.0-85096509107 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

BACKGROUND: Prolyl hydroxylase inhibitors (PHI) promote stabilization of hypoxia-inducible factor-1 alpha and affect signaling cascades of inflammation and cell death. Their beneficial use in experimental models of ulcerative colitis and lung allograft rejection led us to test the effect of the PHI dimethyl oxalyl glycine (DMOG) in the pathophysiology of graft versus host disease (GVHD).

METHODS: Acute GVHD was induced in lethally irradiated BALB/c mice. DMOG was administered intraperitoneally on alternate days for the first 2-weeks posttransplant, and then twice a week till day +50, while controls received vehicle only. Animals were monitored for clinical GVHD and analyzed at day +7 and at day +50.

RESULTS: DMOG treatment of allogeneic recipients improved survival by day +50, which was associated with decreased early gut injury and serum tumor necrosis factor-α compared with allogeneic controls. DMOG treatment of allogeneic recipients resulted in increased hypoxia-inducible factor-1 alpha expression and reduced apoptosis in the terminal ileum via Fas-associated protein with death domain protein repression along with decreased T-cell infiltration. Reduced pathology in colon after DMOG treatment associates with intestinal epithelium integrity and reduced damage caused by diminished recruitment of neutrophils.

CONCLUSIONS: Taken together, we show protective effects of DMOG on early gut GVHD and improved survival in a model of allogeneic hematopoietic cell transplantation, providing the rationale for further evaluation of PHIs, in the prevention and treatment of acute GVHD.

Author List

Palaniyandi S, Kumari R, Venniyil Radhakrishnan S, Strattan E, Hakim N, Munker R, Kesler MV, Hildebrandt GC

Author

Sabarinath Venniyil Radhakrishnan MD Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acids, Dicarboxylic
Animals
Apoptosis
Cells, Cultured
Colon
Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Hypoxia-Inducible Factor 1, alpha Subunit
Ileum
Intestinal Diseases
Mice, Inbred BALB C
Mice, Inbred C57BL
Prolyl Hydroxylases
Prolyl-Hydroxylase Inhibitors
Time Factors
Transplantation, Homologous
Treatment Outcome
Whole-Body Irradiation