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Constitutively active Stat5b in CD4+ T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses.

ABSTRACT: Overexpression of a constitutively active form of Stat5b (Stat5b-CA) increases regulatory T cells (Tregs). We show that Stat5b-CA transgenic (TG) CD4(+) T cells had a markedly reduced graft-versus-host disease (GVHD) capacity versus wild-type (WT) T cells. Stat5b-CA TG versus WT CD4(+) T cells had a higher proportion of Tregs, which were superior in suppressing alloresponses mediated by CD4(+)CD25(-) effector T cells (Teffs). By day 5 after transplantation, Stat5b-CA TG Tregs had expanded approximately 3-fold more than WT Tregs. Purified Stat5b-CA TG Tregs added to WT CD4(+)CD25(-) Teffs were superior on a per-cell basis for inhibiting GVHD versus WT Tregs. Surprisingly, rigorously Treg-depleted Stat5b-CA TG versus WT CD4(+)CD25(-) Teffs caused less GVHD lethality associated with diminished Teff proinflammatory and increased Th2 anti-inflammatory cytokine responses. Reduced GVHD by Stat5b-CA TG versus WT Teffs could not be explained by conversion into Tregs in day 10 posttransplantation spleen or small intestine. In addition, Stat5b-CA TG Teffs retained a graft-versus-leukemia response. These results indicate a major role for Stat5 in Treg expansion and potency along with a lesser but significant role in Teff activation and suggest a strategy of pharmacologic Stat5b up-regulation as a means of decreasing GVHD while retaining a graft-versus-leukemia effect.

SUBMITTER: Vogtenhuber C

PROVIDER: S-EPMC2913456 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Constitutively active Stat5b in CD4+ T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses.

Vogtenhuber Christine C Bucher Christoph C Highfill Steven L SL Koch Lisa K LK Goren Emily E Panoskaltsis-Mortari Angela A Taylor Patricia A PA Farrar Michael A MA Blazar Bruce R BR

Blood 20100504 3

Overexpression of a constitutively active form of Stat5b (Stat5b-CA) increases regulatory T cells (Tregs). We show that Stat5b-CA transgenic (TG) CD4(+) T cells had a markedly reduced graft-versus-host disease (GVHD) capacity versus wild-type (WT) T cells. Stat5b-CA TG versus WT CD4(+) T cells had a higher proportion of Tregs, which were superior in suppressing alloresponses mediated by CD4(+)CD25(-) effector T cells (Teffs). By day 5 after transplantation, Stat5b-CA TG Tregs had expanded approx ...[more]

PMID: 20442366

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Project description:BackgroundInsertion force has been shown to significantly reduce chondrocyte viability during osteochondral allograft transplantation. How graft size influences the required insertion force and chondrocyte viability has yet to be determined. Hypothesis/Purpose: The purpose was to characterize how graft size influences insertion force requirements and chondrocyte viability during osteochondral transplantation. The hypothesis was that larger grafts would require greater force and reduce chondrocyte viability.Study designControlled laboratory study.MethodsFour graft sizes-15 × 5 mm, 15 × 10 mm, 25 × 5 mm, and 25 × 10 mm (diameter × depth)-were harvested from 13 thawed fresh-frozen human cadaveric distal femurs. Average, maximum, and cumulative force and number of impacts were recorded for 44 grafts by a surgical mallet embedded with a calibrated force sensor. In a separate experiment, fresh osteochondral tissues were subjected to mechanical loading. To capture a range of clinically important forces, categories were selected to correspond to impaction force data. Chondrocyte viability was assessed with confocal laser microscopy and live/dead staining.ResultsTotal force for all grafts averaged 4576 N. Median number of impacts for all grafts was 20 (range, 7-116). The mean number of impacts for 5-mm-deep grafts was 14.2 (95% CI, 10.8-18.6), as compared with 26.3 (95% CI, 19.9-34.4) for 10-mm-deep grafts ( P < .001). The mean cumulative force for 5-mm-deep grafts was 2128 N (95% CI, 1467-3087), as opposed to 4689 N (95% CI, 3232-6803) for 10-mm-deep grafts ( P = .001). For every 1 mm in graft depth, an average of 13.1% (95% CI, 6.2%-20.3%) more impacts are required when controlling for diameter and density ( P < .001). For every 1 mm in graft depth, the force required increases on average by 17.1% (95% CI, 7.7%-27.4%) when controlling for diameter and density ( P = .001). There was a significant reduction in chondrocyte viability for the forces required for graft thickness values >10 mm. Only forces associated with graft thickness <10 mm had chondrocyte viabilities consistently >70%.ConclusionInsertion force increases significantly with increasing graft depth. Controlling for diameter and bone density, a 1-mm increase in graft depth is associated with 13.1% more impacts and 17.1% more force. Chondrocyte viability was significantly reduced to <70% at average forces associated with grafts thicker than 10 mm.Clinical relevanceBased on the current data, graft depth is an important consideration for surgeons when sizing osteochondral allograft transplant for chondral lesions of the knee.

Dataset Information

Constitutively active Stat5b in CD4+ T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses.

Publications

Constitutively active Stat5b in CD4+ T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses.

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