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Systemic administration of tolerogenic dendritic cells ameliorates murine inflammatory arthritis.

Healy LJ, Collins HL, Thompson SJ - Open Rheumatol J (2008)

Bottom Line: Mice receiving TNF-α treated DC but not LPS matured DC had a delayed onset, and significantly reduced severity, of arthritis.Disease suppression was associated with reduced levels of collagen specific IgG2a and decreased inflammatory cell infiltration into affected joints.In summary the treatment of DC with TNF-α generates an antigen presenting cell with a phenotype that can reduce the pro-inflammatory response and direct the immune system towards a disease modifying, anti-inflammatory state.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Infection and Inflammatory Diseases, King's College London, London, UK.

ABSTRACT
The expression of various cell surface molecules and the production of certain cytokines are important mechanisms by which dendritic cells (DC) are able to bias immune responses. This paper describes the effects of the inflammatory cytokine tumor necrosis factor (TNF)-α on DC phenotype and function. TNF-α treatment resulted in upregulation of MHC class II and CD86 in the absence of increased cell surface CD40 and CD80 or the production of IL-12. Additionally TNF-α treated cells were able to bias T cell responses towards an anti-inflammatory profile. On a note of caution this tolerogenic phenotype of the DC was not stable upon subsequent TLR-4 ligation as a 4 hour pulse of the TNF-α treated DC with lipopolysaccharide (LPS) resulted in the restoration of IL-12 production and an enhancement of their T cell stimulatory capacity which resulted in an increased IFN-γ production. However, TNF-α treated DC, when administered in vivo, were shown to ameliorate disease in collagen induced arthritis, an experimental model of inflammatory joint disease. Mice receiving TNF-α treated DC but not LPS matured DC had a delayed onset, and significantly reduced severity, of arthritis. Disease suppression was associated with reduced levels of collagen specific IgG2a and decreased inflammatory cell infiltration into affected joints. In summary the treatment of DC with TNF-α generates an antigen presenting cell with a phenotype that can reduce the pro-inflammatory response and direct the immune system towards a disease modifying, anti-inflammatory state.

No MeSH data available.


Related in: MedlinePlus

TNF-α  treated DC bias T cells towards an anti-inflammatory phenotype. Groups of mice were injected sc at the base of tail with 1 x 106 DC that had been LPS activated or TNF treated and pulsed with CIIp (A) or Ova (B). Control mice received injections of PBS.Ten days later, spleen and draining lymph nodes were removed. Cell cultures were prepared and stimulated with CIIp (A) or ova (80µg/ml) (B, C, D). After 4 days proliferation was assessed and cytokine production (IFN-γ, and IL-10) measured. Bars represent the mean ± SEM (* = p < 0.05 by Mann Whitney test).
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Figure 3: TNF-α treated DC bias T cells towards an anti-inflammatory phenotype. Groups of mice were injected sc at the base of tail with 1 x 106 DC that had been LPS activated or TNF treated and pulsed with CIIp (A) or Ova (B). Control mice received injections of PBS.Ten days later, spleen and draining lymph nodes were removed. Cell cultures were prepared and stimulated with CIIp (A) or ova (80µg/ml) (B, C, D). After 4 days proliferation was assessed and cytokine production (IFN-γ, and IL-10) measured. Bars represent the mean ± SEM (* = p < 0.05 by Mann Whitney test).

Mentions: In order to investigate the antigen presenting function of each of the DC types in vivo, mice were injected with LPS activated or TNF-α treated DC that had been pulsed with the immunodominant epitope corresponding to amino acids 259-270 of collagen (CIIp) or OVA. Ten days after immunization, cells from spleen and lymph nodes were assessed for their responses to restimulation with OVA or CIIp.Cells from mice that had received CIIp pulsed DC, regardless of their pretreatment, failed to respond to CIIp, suggesting that BM-DC are poor antigen presenting cells for CIIp in vivo (Fig. 3A) confirming the in vitro observations by Holmdahl and colleagues [26]. However, spleen and lymph node cells were capable of vigorous proliferation to the T cell mitogen Con A (data not shown) thus demonstrating their viability. By contrast, both LPS activated and TNF-α treated DC were clearly capable of presenting OVA in vivo ascells from mice that were injected with OVA pulsed DC proliferated in response to antigen in vitro (Fig. 3B). The quality of the immune response generated by the differentially treated DC was assessed by measuring the levels of cytokines produced by spleen and lymph node cells stimulated with OVA in vitro. The production of the Th2- associated cytokine IL-4 was below the detection limit of the assay for all groups tested. However, as illustrated in Fig. (3C) cells from mice that had received OVA pulsed TNF-α treated DC produced higher levels of IL-10 as compared to cells derived from mice receiving OVA pulsed LPS matured DC although this difference did not reach statistical significance. However, cells from mice receiving antigen pulsed TNF-α treated DC produced significantly less IFN-γ than cells derived from mice injected with LPS matured DC (Fig. 3D). These results indicate that TNF-α treated DC bias the resulting immune response towards an anti-inflammatory phenotype as characterized by significantly lower IFN-γ production and elevated levels of IL-10.


Systemic administration of tolerogenic dendritic cells ameliorates murine inflammatory arthritis.

Healy LJ, Collins HL, Thompson SJ - Open Rheumatol J (2008)

TNF-α  treated DC bias T cells towards an anti-inflammatory phenotype. Groups of mice were injected sc at the base of tail with 1 x 106 DC that had been LPS activated or TNF treated and pulsed with CIIp (A) or Ova (B). Control mice received injections of PBS.Ten days later, spleen and draining lymph nodes were removed. Cell cultures were prepared and stimulated with CIIp (A) or ova (80µg/ml) (B, C, D). After 4 days proliferation was assessed and cytokine production (IFN-γ, and IL-10) measured. Bars represent the mean ± SEM (* = p < 0.05 by Mann Whitney test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2627532&req=5

Figure 3: TNF-α treated DC bias T cells towards an anti-inflammatory phenotype. Groups of mice were injected sc at the base of tail with 1 x 106 DC that had been LPS activated or TNF treated and pulsed with CIIp (A) or Ova (B). Control mice received injections of PBS.Ten days later, spleen and draining lymph nodes were removed. Cell cultures were prepared and stimulated with CIIp (A) or ova (80µg/ml) (B, C, D). After 4 days proliferation was assessed and cytokine production (IFN-γ, and IL-10) measured. Bars represent the mean ± SEM (* = p < 0.05 by Mann Whitney test).
Mentions: In order to investigate the antigen presenting function of each of the DC types in vivo, mice were injected with LPS activated or TNF-α treated DC that had been pulsed with the immunodominant epitope corresponding to amino acids 259-270 of collagen (CIIp) or OVA. Ten days after immunization, cells from spleen and lymph nodes were assessed for their responses to restimulation with OVA or CIIp.Cells from mice that had received CIIp pulsed DC, regardless of their pretreatment, failed to respond to CIIp, suggesting that BM-DC are poor antigen presenting cells for CIIp in vivo (Fig. 3A) confirming the in vitro observations by Holmdahl and colleagues [26]. However, spleen and lymph node cells were capable of vigorous proliferation to the T cell mitogen Con A (data not shown) thus demonstrating their viability. By contrast, both LPS activated and TNF-α treated DC were clearly capable of presenting OVA in vivo ascells from mice that were injected with OVA pulsed DC proliferated in response to antigen in vitro (Fig. 3B). The quality of the immune response generated by the differentially treated DC was assessed by measuring the levels of cytokines produced by spleen and lymph node cells stimulated with OVA in vitro. The production of the Th2- associated cytokine IL-4 was below the detection limit of the assay for all groups tested. However, as illustrated in Fig. (3C) cells from mice that had received OVA pulsed TNF-α treated DC produced higher levels of IL-10 as compared to cells derived from mice receiving OVA pulsed LPS matured DC although this difference did not reach statistical significance. However, cells from mice receiving antigen pulsed TNF-α treated DC produced significantly less IFN-γ than cells derived from mice injected with LPS matured DC (Fig. 3D). These results indicate that TNF-α treated DC bias the resulting immune response towards an anti-inflammatory phenotype as characterized by significantly lower IFN-γ production and elevated levels of IL-10.

Bottom Line: Mice receiving TNF-α treated DC but not LPS matured DC had a delayed onset, and significantly reduced severity, of arthritis.Disease suppression was associated with reduced levels of collagen specific IgG2a and decreased inflammatory cell infiltration into affected joints.In summary the treatment of DC with TNF-α generates an antigen presenting cell with a phenotype that can reduce the pro-inflammatory response and direct the immune system towards a disease modifying, anti-inflammatory state.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Infection and Inflammatory Diseases, King's College London, London, UK.

ABSTRACT
The expression of various cell surface molecules and the production of certain cytokines are important mechanisms by which dendritic cells (DC) are able to bias immune responses. This paper describes the effects of the inflammatory cytokine tumor necrosis factor (TNF)-α on DC phenotype and function. TNF-α treatment resulted in upregulation of MHC class II and CD86 in the absence of increased cell surface CD40 and CD80 or the production of IL-12. Additionally TNF-α treated cells were able to bias T cell responses towards an anti-inflammatory profile. On a note of caution this tolerogenic phenotype of the DC was not stable upon subsequent TLR-4 ligation as a 4 hour pulse of the TNF-α treated DC with lipopolysaccharide (LPS) resulted in the restoration of IL-12 production and an enhancement of their T cell stimulatory capacity which resulted in an increased IFN-γ production. However, TNF-α treated DC, when administered in vivo, were shown to ameliorate disease in collagen induced arthritis, an experimental model of inflammatory joint disease. Mice receiving TNF-α treated DC but not LPS matured DC had a delayed onset, and significantly reduced severity, of arthritis. Disease suppression was associated with reduced levels of collagen specific IgG2a and decreased inflammatory cell infiltration into affected joints. In summary the treatment of DC with TNF-α generates an antigen presenting cell with a phenotype that can reduce the pro-inflammatory response and direct the immune system towards a disease modifying, anti-inflammatory state.

No MeSH data available.


Related in: MedlinePlus