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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

Immunotherapy of murine inflammatory arthritis. Groups of 8 mice were injected sc at the base of tail with 1 x 106 untreated,LPS activated or TNF-α  treated DC 3 days prior to immunization with CII in CFA and again 3 days before the booster immunisation.Control mice received injections of PBS. Mice were scored for clinical signs of disease until day 40. (A) The % of mice with arthritis in each group over time. (B) The mean arthritis severity score in each group over time. *= p < 0.05 by Mann Whitney test. (C) Transverse section through stifle joint of PBS treated mouse stained with H&E demonstrating inflammatory cell infiltration. (D) Transverse section through stifle joint of TNF-αtreated DC injected mouse indicating much reduced cellular infiltration. Magnification x10.
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Figure 4: Immunotherapy of murine inflammatory arthritis. Groups of 8 mice were injected sc at the base of tail with 1 x 106 untreated,LPS activated or TNF-α treated DC 3 days prior to immunization with CII in CFA and again 3 days before the booster immunisation.Control mice received injections of PBS. Mice were scored for clinical signs of disease until day 40. (A) The % of mice with arthritis in each group over time. (B) The mean arthritis severity score in each group over time. *= p < 0.05 by Mann Whitney test. (C) Transverse section through stifle joint of PBS treated mouse stained with H&E demonstrating inflammatory cell infiltration. (D) Transverse section through stifle joint of TNF-αtreated DC injected mouse indicating much reduced cellular infiltration. Magnification x10.

Mentions: Collagen induced arthritis is established by a pro-inflammatory response directed towards CII and the production of antigen-specific complement fixing Ab. Skewing the immune system towards a more anti-inflammatory CII response can prevent or interrupt CIA development. CIA therefore, represents an ideal model to investigate the disease modulating capacity of TNF-α treated DC bearing in mind the caveat that the stability of the DC phenotype in vivo is unknown. Previous studies have shown that DC are poor APC for CII [26-28]. We were able to confirm these observations (data not shown) and also demonstrate the inability of DC to efficiently present CIIp (Fig. 3A). In light of these findings, the capacity of unpulsed TNF-α treated DC to modulate disease in CIA was investigated. For this purpose unstimulated, LPS activated or TNF-α treated DC were injected 3 days prior to immunization with CII in CFA and again 3 days before the booster immunization. Mice that were injected with TNF-α treated DC had a delayed onset of arthritis compared to those injected with PBS, unstimulated DC or LPS activated DC (Fig. 4A). A lower incidence of arthritis in the group of mice given TNF-α treated DC occurred for up to 32 days post CII/CFA injection. Notably at day 29, considerable protection was still observed in the TNF-α treated DC group, whereas at this time point all control mice had developed arthritis. Moreover, in addition the mean severity score was significantly reduced in the TNF-α treated DC mice at day 29 and remained statistically significantly less than all other groups throughout the course of the experiment (Fig. 4B). In the mice that had received TNF-α treated DC the mean clinical score reached at the end of the experiment was 6.25 ± 0.59 compared with 11.63 ± 0.70 for mice injected with PBS. These results are supported by histology of the affected joints. Sections from PBS injected mice demonstrated pannus formation, significant cellular infiltration of soft tissue and cartilage erosion (Fig. 4C). In contrast, joints from mice receiving TNF-α treated DC appeared relatively unaffected (Fig. 4D). These results clearly demonstrate the capacity of TNF-α treated DC to modulate disease in CIA.


Systemic administration of tolerogenic dendritic cells ameliorates murine inflammatory arthritis.

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

Immunotherapy of murine inflammatory arthritis. Groups of 8 mice were injected sc at the base of tail with 1 x 106 untreated,LPS activated or TNF-α  treated DC 3 days prior to immunization with CII in CFA and again 3 days before the booster immunisation.Control mice received injections of PBS. Mice were scored for clinical signs of disease until day 40. (A) The % of mice with arthritis in each group over time. (B) The mean arthritis severity score in each group over time. *= p < 0.05 by Mann Whitney test. (C) Transverse section through stifle joint of PBS treated mouse stained with H&E demonstrating inflammatory cell infiltration. (D) Transverse section through stifle joint of TNF-αtreated DC injected mouse indicating much reduced cellular infiltration. Magnification x10.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Immunotherapy of murine inflammatory arthritis. Groups of 8 mice were injected sc at the base of tail with 1 x 106 untreated,LPS activated or TNF-α treated DC 3 days prior to immunization with CII in CFA and again 3 days before the booster immunisation.Control mice received injections of PBS. Mice were scored for clinical signs of disease until day 40. (A) The % of mice with arthritis in each group over time. (B) The mean arthritis severity score in each group over time. *= p < 0.05 by Mann Whitney test. (C) Transverse section through stifle joint of PBS treated mouse stained with H&E demonstrating inflammatory cell infiltration. (D) Transverse section through stifle joint of TNF-αtreated DC injected mouse indicating much reduced cellular infiltration. Magnification x10.
Mentions: Collagen induced arthritis is established by a pro-inflammatory response directed towards CII and the production of antigen-specific complement fixing Ab. Skewing the immune system towards a more anti-inflammatory CII response can prevent or interrupt CIA development. CIA therefore, represents an ideal model to investigate the disease modulating capacity of TNF-α treated DC bearing in mind the caveat that the stability of the DC phenotype in vivo is unknown. Previous studies have shown that DC are poor APC for CII [26-28]. We were able to confirm these observations (data not shown) and also demonstrate the inability of DC to efficiently present CIIp (Fig. 3A). In light of these findings, the capacity of unpulsed TNF-α treated DC to modulate disease in CIA was investigated. For this purpose unstimulated, LPS activated or TNF-α treated DC were injected 3 days prior to immunization with CII in CFA and again 3 days before the booster immunization. Mice that were injected with TNF-α treated DC had a delayed onset of arthritis compared to those injected with PBS, unstimulated DC or LPS activated DC (Fig. 4A). A lower incidence of arthritis in the group of mice given TNF-α treated DC occurred for up to 32 days post CII/CFA injection. Notably at day 29, considerable protection was still observed in the TNF-α treated DC group, whereas at this time point all control mice had developed arthritis. Moreover, in addition the mean severity score was significantly reduced in the TNF-α treated DC mice at day 29 and remained statistically significantly less than all other groups throughout the course of the experiment (Fig. 4B). In the mice that had received TNF-α treated DC the mean clinical score reached at the end of the experiment was 6.25 ± 0.59 compared with 11.63 ± 0.70 for mice injected with PBS. These results are supported by histology of the affected joints. Sections from PBS injected mice demonstrated pannus formation, significant cellular infiltration of soft tissue and cartilage erosion (Fig. 4C). In contrast, joints from mice receiving TNF-α treated DC appeared relatively unaffected (Fig. 4D). These results clearly demonstrate the capacity of TNF-α treated DC to modulate disease in CIA.

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