Organ-Derived Dendritic Cells Have Differential Effects on Alloreactive T Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE5503 | GEO | 2007/10/31
SECONDARY ACCESSION(S): PRJNA96151
REPOSITORIES: GEO
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Project description:Transcriptional response of murine allogeneic T cells (B10.BR) after; stimulation with different organ-derived (spleen, liver, peripheral and; mesenteric lymph nodes) dendritic cells (C57BL/6) in vitro Experiment Overall Design: We stimulated B10.BR T cells with dendritic cells derived from different C57BL/6 organs for four days and then performed array experiments on the T cells.
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Project description:Divergence has occured between the B10.BR-H2k H2-T18a/SgSnJJrep and B10.BR-H2k H2-T18a/SgSnJ (drifted) mouse strains, resulting in altered antigenic recognition and differential bone marrow engraftment capability. The microarray data demonstrate that the transcriptional profile of genes associated with hematopoiesis differs between lineage negative (as a marker for hematopoietic stem cells) bone marrow cells isolated from the B10.BR-H2k H2-T18a/SgSnJJrep and B10.BR-H2k H2-T18a/SgSnJ (drifted) mouse strains.
2009-09-16 | GSE17471 | GEO
Project description:To identify novel mechanisms regulating allogeneic hematopoietic cell engraftment, we previously used a forward genetic approach and described identification, in mice, of the Bmgr5 bone marrow (BM) engraftment quantitative trait locus (QTL). This QTL confers dominant and large allele effects for engraftment susceptibility. It was localized to chromosome 16 by classical quantitative genetic techniques in a segregating backcross bred from susceptible BALB.K and resistant B10.BR mice. We now report verification of the Bmgr5 QTL using reciprocal chromosome 16 consomic strains. The BM engraftment phenotype in these consomic mice shows that Bmgr5 susceptibility alleles are not only sufficient but also indispensable for conferring permissiveness for allogeneic BM engraftment. Using panels of congenic mice, we resolved the Bmgr5 QTL into two separate subloci, termed Bmgr5a and Bmgr5b, each conferring permissiveness for the engraftment phenotype and both fine mapped to an interval amenable to positional cloning. Candidate Bmgr5 genes were then prioritized using whole exome DNA sequencing and microarray gene expression profiling. Further studies are needed to elucidate the genetic interaction between Bmgr5a and Bmgr5b and identify causative genes and underlying gene variants. This may lead to new approaches for overcoming the problem of graft rejection in clinical hematopoietic cell transplantation. B10.BALBChr16 and BALB.B10Chr16 consomic strain mice were constructed in our laboratory for validation of bone marrow engraftment and graft-vs-host diseaes QTLs. The parental strains for consomic line construction were B10.BR (B10.BR-H2k H2-T18a/SgSnJJrep) and BALB.K (C.C3-H2k/LilMcdJ). The JAX Mouse Diveristy 620K SNP Array was used to verify adequate removal of residual background heterozygosity. Liver DNA was delivered to JAX Mouse Diversity Genotyping Array Service (Jackson Laboratory) for the SNP Array genotyping.
2013-01-10 | E-GEOD-43377 | biostudies-arrayexpress
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Project description:A major challenge in bone allogeneic marrow (BM) transplantation is overcoming engraftment resistance to avoid the clinical problem of graft rejection. Identifying genes and pathways that regulate BM engraftment may reveal molecular targets for overcoming these engraftment barriers. Previously, we developed a mouse model of BM transplantation that utilizes recipient conditioning with non-myeloablative total body irradiation followed by transplantation of allogeneic BM cells. We defined TBI doses that lead to graft rejection, that are permissive for engraftment, and mouse strain variation with regards to the permissive TBI dose. We now report gene expression analysis, using the Agilent Mouse 8x60K v3 expression arrays, in spleen of mice conditioned with TBI doses for evaluation in correlation to the expected engraftment phenotype. The spleens of mice given TBI demonstrated extensive differential gene expression, compared with un-irradiated controls, at both multiple testing-corrected P < .05 and fold change greater than or equal to 2 levels. Functional analysis revealed significant enrichment for up-regulation of canonical pathways involved in inflammation, even when treated with TBI doses not permissive for engraftment. Consistent with this the most significantly associated upstream regulators included lipopolysaccharide, tumor necrosis factor, and a toll-like receptor. Unique to engrafting mice, however, were enrichment for a down-regulated canonical pathway related to B-cell development. Results from this analysis have identified canonical pathways and upstream regulators of BM engraftment in mice and may lead to new approaches to overcome the problem of graft rejection complicating clinical BM transplantation. Each individual sample was pooled from 3 mice and performed in triplicate for each experimental group (TBI 300 cGy, 400 cGy, or 500 cGy) and for each strain mice (BALB.K or B10.BR) for statistical analysis. Additional arrays were perfromed for TBI 800 cGy (BALB.K) and TBI 900 cGy (B10.BR) for anlaysis of gene expressive after myeloablative condition.
2013-01-08 | E-GEOD-43310 | biostudies-arrayexpress
Project description:Introduction: Expansion of antigen (Ag)-specific natural occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloAg-specific nTregs. Methods: A highly enriched nTreg-fraction (CD4+CD25brightCD127- T cells) was alloAg-specific expanded using HLA-mismatched immature, mature monocyte-derived dendritic cells (moDC) or peripheral blood mononuclear cells (PBMC). The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the TSDR of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4 and cytokines. In addition, the antigen-specific suppressive capacity of these expanded nTregs was tested. Results: Allogeneic mature moDC and skin-derived DC were superior in inducing nTreg-expansion compared to immature moDC or PBMC in an HLA-DR and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2, could facilitate optimal mature moDC-induced nTreg-expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (<1:320), potent suppressors of alloAg-induced proliferation without significant suppression of completely HLA-mismatched-Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the TSDR within the FOXP3 gene and highly expressed of FOXP3, HELIOS and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-g and TNF-a but very few IL-17 producing nTregs were found. Next generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Conclusions: Human allogeneic mature moDC are highly efficient stimulator cells, in presence of exogenous IL-15, for expansion of stable alloAg-specific nTregs with superior suppressive function. Four different batches of highly pure regulatory T cells (all from the same donor) were expanded in two different ways, and compared to non-expanded samples.
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Project description:Divergence has occured between the B10.BR-H2k H2-T18a/SgSnJJrep and B10.BR-H2k H2-T18a/SgSnJ (drifted) mouse strains, resulting in altered antigenic recognition and differential bone marrow engraftment capability. The microarray data demonstrate that the transcriptional profile of genes associated with hematopoiesis differs between lineage negative (as a marker for hematopoietic stem cells) bone marrow cells isolated from the B10.BR-H2k H2-T18a/SgSnJJrep and B10.BR-H2k H2-T18a/SgSnJ (drifted) mouse strains. Bone marrow cells from ten male mice of each strain, aged 10-12 weeks, were harvested. One pooled sample was analyzed for each strain.
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Project description:Introduction: Expansion of antigen (Ag)-specific natural occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloAg-specific nTregs. Methods: A highly enriched nTreg-fraction (CD4+CD25brightCD127- T cells) was alloAg-specific expanded using HLA-mismatched immature, mature monocyte-derived dendritic cells (moDC) or peripheral blood mononuclear cells (PBMC). The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the TSDR of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4 and cytokines. In addition, the antigen-specific suppressive capacity of these expanded nTregs was tested. Results: Allogeneic mature moDC and skin-derived DC were superior in inducing nTreg-expansion compared to immature moDC or PBMC in an HLA-DR and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2, could facilitate optimal mature moDC-induced nTreg-expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (<1:320), potent suppressors of alloAg-induced proliferation without significant suppression of completely HLA-mismatched-Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the TSDR within the FOXP3 gene and highly expressed of FOXP3, HELIOS and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-g and TNF-a but very few IL-17 producing nTregs were found. Next generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Conclusions: Human allogeneic mature moDC are highly efficient stimulator cells, in presence of exogenous IL-15, for expansion of stable alloAg-specific nTregs with superior suppressive function.
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