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Gene Expression Profiles of PBMC Subsets in Acute GVHD Following Cord Blood Transplantation (IMS v.2)

ABSTRACT: In comparison with allogeneic hematopoietic stem cell transplantation using other sources, umbilical cord blood transplantation (UCBT) offers substantial clinical advantages including a lower incidence and severity of acute graft-versus-host disease (GVHD) despite the use of allogeneic UCB stem cells with more disparate HLA. However, detailed pathophysiology of acute GVHD developed after UCBT has not yet been clarified. Here, we examined the roles of inflammatory cells in the pathogenesis of acute GVHD following UCBT, by expression profiling of a total of 615 genes in each of 4 subsets (CD4+, CD8+, CD14+, and CD56+) of peripheral blood mononuclear cells (PBMCs), which were taken from 5 patients with hematologic malignancy, in whom acute GVHD had developed after UCBT. By comparing expression profiles measured during acute GVHD with those measured upon discharge (recovery phase), for each subset of PBMCs, we identified immuno-regulatory genes which were assumed to be linked to the pathogenesis of acute GVHD. Keywords: disease state analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE10513 | GEO | 2008/12/22

SECONDARY ACCESSION(S): PRJNA108939

REPOSITORIES: GEO

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Project description:Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems benefi cial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL / 6 mice were lethally irradiated and reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6 M-bM-^@M-^S 9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The diff erence between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25 + CD4 + regulatory T cells since their depletion did not abrogate the therapeutic eff ect of ICOSL blockade. Microarray analysis revealed IFN- M-NM-3 and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction. B6 recipients were irradiated with 10.0 Gray, administered from a 137 Cs source. Splenocytes from C3H mice were prepared as single cell suspensions in PBS, depleted of red blood cells and counted. 2 M-bM-^@M-^S 3 M-CM-^W 10^7 C3H splenocytes in a volume of 200 M-NM-<l were transplanted into B6 recipients via tail vein injection (4 mice per group per experiment) 4 M-bM-^@M-^S 6 h after irradiation. Mice in the treatment group with anti-ICOSL mAb and their respective controls, received 500 M-NM-<g mAb i. p starting at day 0 or day 3, followed by subsequent injections of 200 M-NM-<g of mAb every other day. At day 4 after transplantation RNA of spleen cells was prepared and subjected to microarray analysis. Combined RNA from allogeneic transplanted mice was hybridized onto 2 independent arrays.

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Gene Expression Profiles of PBMC Subsets in Acute GVHD Following Cord Blood Transplantation (IMS v.2)

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