Pathways analysis of differential gene expression induced by engrafting doses of total body irradiation for allogeneic bone marrow transplantation in mice

Xinjian Chen; Yuanyuan Wang; Qiuxia Li; Schickwann Tsai; Alun Thomas; Judith A. Shizuru; Thai M. Cao

doi:10.1007/s00251-013-0710-0

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Pathways analysis of differential gene expression induced by engrafting doses of total body irradiation for allogeneic bone marrow transplantation in mice

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Pathways analysis of differential gene expression induced by engrafting doses of total body irradiation for allogeneic bone marrow transplantation in mice

Xinjian Chen, Yuanyuan Wang, Qiuxia Li, Schickwann Tsai, Alun Thomas, Judith A. Shizuru and Thai M. Cao

Immunogenetics (New York), Vol.65(8), pp.597-607

05/24/2013

DOI: 10.1007/s00251-013-0710-0

PMCID: PMC3713107

PMID: 23703256

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https://www.ncbi.nlm.nih.gov/pmc/articles/3713107View

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Abstract

A major challenge in allogeneic bone marrow (BM) transplantation is overcoming engraftment resistance to avoid the clinical problem of graft rejection. Identifying gene pathways that regulate BM engraftment may reveal molecular targets for overcoming engraftment barriers. Previously, we developed a mouse model of BM transplantation that utilizes recipient conditioning with non-myeloablative total body irradiation (TBI). We defined TBI doses that lead to graft rejection, that conversely are permissive for engraftment, and mouse strain variation with regards to the permissive TBI dose. We now report gene expression analysis, using Agilent Mouse 8x60K microarrays, in spleens of mice conditioned with varied TBI doses for correlation to the expected engraftment phenotype. The spleens of mice given engrafting doses of TBI, compared with non-engrafting TBI doses, demonstrated substantially broader gene expression changes, significant at the multiple testing-corrected P < .05 level and with fold change ≥ 2. Functional analysis revealed significant enrichment for a down-regulated canonical pathway involving B-cell development. Genes enriched in this pathway suggest that suppressing donor antigen processing and presentation may be pivotal effects conferred by TBI to enable engraftment. Regardless of TBI dose and recipient mouse strain, pervasive genomic changes related to inflammation was observed and reflected by significant enrichment for canonical pathways and association with upstream regulators. These gene expression changes suggest that macrophage and complement pathways may be targeted to overcome engraftment barriers. These exploratory results highlight gene pathways that may be important in mediating BM engraftment resistance.

Bone marrow

gene expression

graft rejection

Details

Title: Subtitle: Pathways analysis of differential gene expression induced by engrafting doses of total body irradiation for allogeneic bone marrow transplantation in mice
Creators: Xinjian Chen - University of Utah
Yuanyuan Wang - University of Utah
Qiuxia Li - University of Utah
Schickwann Tsai - University of Utah
Alun Thomas - University of Utah
Judith A. Shizuru - Stanford University
Thai M. Cao - University of Utah
Resource Type: Journal article
Publication Details: Immunogenetics (New York), Vol.65(8), pp.597-607
DOI: 10.1007/s00251-013-0710-0
PMID: 23703256
PMCID: PMC3713107
NLM abbreviation: Immunogenetics
ISSN: 0093-7711
eISSN: 1432-1211
Grant note: R01 AI076652 || AI / National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
Language: English
Date published: 05/24/2013
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984359902102771

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