Limits...
CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis.

Gilani SR, Vuga LJ, Lindell KO, Gibson KF, Xue J, Kaminski N, Valentine VG, Lindsay EK, George MP, Steele C, Duncan SR - PLoS ONE (2010)

Bottom Line: Most importantly, one-year freedom from major adverse clinical events (either death or lung transplantation) was 56+/-6% among 78 IPF patients with CD4(+)CD28(+)/CD4(total)>or=82%, compared to 9+/-9% among those with more extensive CD28 down-regulation (CD4(+)CD28(+)/CD4(total)<82%) (p = 0.0004).The odds ratio for major adverse events among those with the most extensive CD28 down-regulation was 13.0, with 95% confidence intervals 1.6-111.1.Marked down-regulation of CD28 on circulating CD4 T-cells, a result of repeated antigen-driven proliferations, is associated with poor outcomes in IPF patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: Although the etiology of idiopathic pulmonary fibrosis (IPF) remains perplexing, adaptive immune activation is evident among many afflicted patients. Repeated cycles of antigen-induced proliferation cause T-cells to lose surface expression of CD28, and we hypothesized this process might also occur in IPF.

Methodology/principal findings: Peripheral blood CD4 T-cells from 89 IPF patients were analyzed by flow cytometry and cytokine multiplex assays, and correlated with clinical events. In comparison to autologous CD4(+)CD28(+)cells, the unusual CD4(+)CD28() lymphocytes seen in many IPF patients had discordant expressions of activation markers, more frequently produced cytotoxic mediators perforin (2.4+/-0.8% vs. 60.0+/-7.4%, p<0.0001) and granzyme B (4.5+/-2.8% vs.74.9+/-6.5%, p<0.0001), produced greater amounts of many pro-inflammatory cytokines, and less frequently expressed the regulatory T-cell marker FoxP3 (12.9+/-1.1% vs. 3.3+/-0.6% p<0.0001). Infiltration of CD4(+)CD28() T-cells in IPF lungs was confirmed by confocal microscopy. Interval changes of CD28 expression among subjects who had replicate studies were correlated with conterminous changes of their forced vital capacities (r(s) = 0.49, p = 0.012). Most importantly, one-year freedom from major adverse clinical events (either death or lung transplantation) was 56+/-6% among 78 IPF patients with CD4(+)CD28(+)/CD4(total)>or=82%, compared to 9+/-9% among those with more extensive CD28 down-regulation (CD4(+)CD28(+)/CD4(total)<82%) (p = 0.0004). The odds ratio for major adverse events among those with the most extensive CD28 down-regulation was 13.0, with 95% confidence intervals 1.6-111.1.

Conclusions/significance: Marked down-regulation of CD28 on circulating CD4 T-cells, a result of repeated antigen-driven proliferations, is associated with poor outcomes in IPF patients. The CD4(+)CD28() cells of these patients have potentially enhanced pathogenic characteristics, including increased productions of cytotoxic mediators and pro-inflammatory cytokines. These findings show proliferative T-cell responses to antigen(s) resulting in CD28 down-regulation are associated with progression and manifestations of IPF, and suggest assays of circulating CD4 T-cells may identify patients at greatest risk for clinical deterioration.

Show MeSH

Related in: MedlinePlus

Characteristics of CD4 T-cell subpopulations in IPF patients.A: The proportions of circulating CD4 T-cells that also expressed CD28 (CD28%) were reduced in many IPF patients. The horizontal line denotes the population means. B: In contrast to autologous CD4+CD28+ cells, the CD4+CD28 T-cells of IPF patients more often express major histocompatibility antigen (MHC) Class II (DR), but less frequently express CD25. CD4+CD28 T-cells of IPF patients less frequently produce transcription factor FoxP3 (a putative marker of regulatory T-cells), but much more frequently produce cytotoxic mediators granzyme B (GB) and perforin (Perf). For each measure n = 24, and p values for all intergroup comparisons (CD4+CD28+ vrs. CD4+CD28 cells) are <0.0001.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2813297&req=5

pone-0008959-g001: Characteristics of CD4 T-cell subpopulations in IPF patients.A: The proportions of circulating CD4 T-cells that also expressed CD28 (CD28%) were reduced in many IPF patients. The horizontal line denotes the population means. B: In contrast to autologous CD4+CD28+ cells, the CD4+CD28 T-cells of IPF patients more often express major histocompatibility antigen (MHC) Class II (DR), but less frequently express CD25. CD4+CD28 T-cells of IPF patients less frequently produce transcription factor FoxP3 (a putative marker of regulatory T-cells), but much more frequently produce cytotoxic mediators granzyme B (GB) and perforin (Perf). For each measure n = 24, and p values for all intergroup comparisons (CD4+CD28+ vrs. CD4+CD28 cells) are <0.0001.

Mentions: Eighty-nine (89) IPF subjects had one or more assays of their peripheral blood CD4 T-cells. Unless otherwise specified, only results of their latest determinations are described. Clinical observation periods following their last experimental T-cell assays exceeded 12 months in all subjects who survived and/or did not have lung transplantation. The proportion of total circulating CD4 T-cells that co-expressed CD28 were determined for each subject, and these values are defined here as CD28% [20]. CD28 down-regulation was striking in some IPF patients (Figure 1A), and nineteen (21%) of these subjects had CD28% <90. Ages of the 32 normal, healthy controls (67.9±1.1 years old) were comparable to those of the IPF subjects (p = N.S.). None of the normal controls had CD28% <90, and their aggregate values of this parameter (97.9±0.4) were significantly greater than those of the IPF subjects (Figure 1A).


CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis.

Gilani SR, Vuga LJ, Lindell KO, Gibson KF, Xue J, Kaminski N, Valentine VG, Lindsay EK, George MP, Steele C, Duncan SR - PLoS ONE (2010)

Characteristics of CD4 T-cell subpopulations in IPF patients.A: The proportions of circulating CD4 T-cells that also expressed CD28 (CD28%) were reduced in many IPF patients. The horizontal line denotes the population means. B: In contrast to autologous CD4+CD28+ cells, the CD4+CD28 T-cells of IPF patients more often express major histocompatibility antigen (MHC) Class II (DR), but less frequently express CD25. CD4+CD28 T-cells of IPF patients less frequently produce transcription factor FoxP3 (a putative marker of regulatory T-cells), but much more frequently produce cytotoxic mediators granzyme B (GB) and perforin (Perf). For each measure n = 24, and p values for all intergroup comparisons (CD4+CD28+ vrs. CD4+CD28 cells) are <0.0001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2813297&req=5

pone-0008959-g001: Characteristics of CD4 T-cell subpopulations in IPF patients.A: The proportions of circulating CD4 T-cells that also expressed CD28 (CD28%) were reduced in many IPF patients. The horizontal line denotes the population means. B: In contrast to autologous CD4+CD28+ cells, the CD4+CD28 T-cells of IPF patients more often express major histocompatibility antigen (MHC) Class II (DR), but less frequently express CD25. CD4+CD28 T-cells of IPF patients less frequently produce transcription factor FoxP3 (a putative marker of regulatory T-cells), but much more frequently produce cytotoxic mediators granzyme B (GB) and perforin (Perf). For each measure n = 24, and p values for all intergroup comparisons (CD4+CD28+ vrs. CD4+CD28 cells) are <0.0001.
Mentions: Eighty-nine (89) IPF subjects had one or more assays of their peripheral blood CD4 T-cells. Unless otherwise specified, only results of their latest determinations are described. Clinical observation periods following their last experimental T-cell assays exceeded 12 months in all subjects who survived and/or did not have lung transplantation. The proportion of total circulating CD4 T-cells that co-expressed CD28 were determined for each subject, and these values are defined here as CD28% [20]. CD28 down-regulation was striking in some IPF patients (Figure 1A), and nineteen (21%) of these subjects had CD28% <90. Ages of the 32 normal, healthy controls (67.9±1.1 years old) were comparable to those of the IPF subjects (p = N.S.). None of the normal controls had CD28% <90, and their aggregate values of this parameter (97.9±0.4) were significantly greater than those of the IPF subjects (Figure 1A).

Bottom Line: Most importantly, one-year freedom from major adverse clinical events (either death or lung transplantation) was 56+/-6% among 78 IPF patients with CD4(+)CD28(+)/CD4(total)>or=82%, compared to 9+/-9% among those with more extensive CD28 down-regulation (CD4(+)CD28(+)/CD4(total)<82%) (p = 0.0004).The odds ratio for major adverse events among those with the most extensive CD28 down-regulation was 13.0, with 95% confidence intervals 1.6-111.1.Marked down-regulation of CD28 on circulating CD4 T-cells, a result of repeated antigen-driven proliferations, is associated with poor outcomes in IPF patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: Although the etiology of idiopathic pulmonary fibrosis (IPF) remains perplexing, adaptive immune activation is evident among many afflicted patients. Repeated cycles of antigen-induced proliferation cause T-cells to lose surface expression of CD28, and we hypothesized this process might also occur in IPF.

Methodology/principal findings: Peripheral blood CD4 T-cells from 89 IPF patients were analyzed by flow cytometry and cytokine multiplex assays, and correlated with clinical events. In comparison to autologous CD4(+)CD28(+)cells, the unusual CD4(+)CD28() lymphocytes seen in many IPF patients had discordant expressions of activation markers, more frequently produced cytotoxic mediators perforin (2.4+/-0.8% vs. 60.0+/-7.4%, p<0.0001) and granzyme B (4.5+/-2.8% vs.74.9+/-6.5%, p<0.0001), produced greater amounts of many pro-inflammatory cytokines, and less frequently expressed the regulatory T-cell marker FoxP3 (12.9+/-1.1% vs. 3.3+/-0.6% p<0.0001). Infiltration of CD4(+)CD28() T-cells in IPF lungs was confirmed by confocal microscopy. Interval changes of CD28 expression among subjects who had replicate studies were correlated with conterminous changes of their forced vital capacities (r(s) = 0.49, p = 0.012). Most importantly, one-year freedom from major adverse clinical events (either death or lung transplantation) was 56+/-6% among 78 IPF patients with CD4(+)CD28(+)/CD4(total)>or=82%, compared to 9+/-9% among those with more extensive CD28 down-regulation (CD4(+)CD28(+)/CD4(total)<82%) (p = 0.0004). The odds ratio for major adverse events among those with the most extensive CD28 down-regulation was 13.0, with 95% confidence intervals 1.6-111.1.

Conclusions/significance: Marked down-regulation of CD28 on circulating CD4 T-cells, a result of repeated antigen-driven proliferations, is associated with poor outcomes in IPF patients. The CD4(+)CD28() cells of these patients have potentially enhanced pathogenic characteristics, including increased productions of cytotoxic mediators and pro-inflammatory cytokines. These findings show proliferative T-cell responses to antigen(s) resulting in CD28 down-regulation are associated with progression and manifestations of IPF, and suggest assays of circulating CD4 T-cells may identify patients at greatest risk for clinical deterioration.

Show MeSH
Related in: MedlinePlus