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Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis.

Ma-Krupa W, Jeon MS, Spoerl S, Tedder TF, Goronzy JJ, Weyand CM - J. Exp. Med. (2004)

Bottom Line: Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions.We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA.Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

ABSTRACT
Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4(+) T cells are selectively activated in the adventitia of affected arteries. In human GCA artery-severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83(+) dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia-media border. Adoptive T cell transfer into temporal artery-SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II-matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.

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Therapeutic effects of depleting CD83+ DCs in GCA. Temporal artery–SCID mouse chimeras were generated by implanting SCID mice with segments from a GCA-affected temporal artery. The chimeras were injected on days 9–11 with anti-CD83 Ab or control Ig, and arterial grafts were harvested 1 wk later. Frozen tissue sections were immunostained with anti-CD3 Ab (A). The density of arterial wall T cell infiltrates was determined by counting CD3+ T cells (brown) on cross sections of the arteries (B). cDNA was generated from the explanted temporal arteries to quantify transcripts for β-actin, IFN-γ, and IL-1β by quantitative PCR. All cDNA concentrations were adjusted to 2 × 105 β-actin copies. Copy numbers of IFN-γ– and IL-1β–specific sequences are shown as box plots as described in Fig. 2. Results are from five experiments with tissues from five different patients. Treatment with anti-CD83 Ab induced massive loss of tissue-infiltrating T cells. In parallel, IFN-γ mRNA transcripts decreased to <20% of baseline, and IL-1β mRNA transcripts decreased by >75% (C). Original magnification, 400.
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fig3: Therapeutic effects of depleting CD83+ DCs in GCA. Temporal artery–SCID mouse chimeras were generated by implanting SCID mice with segments from a GCA-affected temporal artery. The chimeras were injected on days 9–11 with anti-CD83 Ab or control Ig, and arterial grafts were harvested 1 wk later. Frozen tissue sections were immunostained with anti-CD3 Ab (A). The density of arterial wall T cell infiltrates was determined by counting CD3+ T cells (brown) on cross sections of the arteries (B). cDNA was generated from the explanted temporal arteries to quantify transcripts for β-actin, IFN-γ, and IL-1β by quantitative PCR. All cDNA concentrations were adjusted to 2 × 105 β-actin copies. Copy numbers of IFN-γ– and IL-1β–specific sequences are shown as box plots as described in Fig. 2. Results are from five experiments with tissues from five different patients. Treatment with anti-CD83 Ab induced massive loss of tissue-infiltrating T cells. In parallel, IFN-γ mRNA transcripts decreased to <20% of baseline, and IL-1β mRNA transcripts decreased by >75% (C). Original magnification, 400.

Mentions: To investigate how DCs contribute to the disease process, we treated temporal artery–SCID mouse chimeras with anti-CD83 Ab. Expression of the CD83 marker in the vasculitic lesion was strictly limited to DCs (Fig. 1, E and F; reference 15). Temporal arteries from five patients were divided into three to five equal pieces. Mice carrying tissue from the same donor were injected with either control Ig or anti-CD83 Ab. Chimeras received Ab injections on days 9–11 after implantation, and the grafts were harvested 1 wk after the completion of the treatment. Histomorphological evaluation showed that anti-CD83 Ab treatment had a marked effect on the density of the T cell infiltrate (Fig. 3, A and B) . After treatment with anti-CD83 Ab, the granulomatous microstructures were destroyed and few T cells were still present in the arterial wall. The remaining T cells were dispersed throughout the vascular tissue. To examine the effect on T cell and macrophage activity, cDNA was generated from tissue extracts, and transcript levels for IFN-γ and IL-1β were semi-quantified. After the administration of anti-CD83 Ab, levels of IFN-γ transcripts, reflective of in situ T cell activation, decreased to <20% of those measured in the grafts from animals treated with control Ig (Fig. 3 C). In parallel, the production of IL-1β, which is derived from macrophages in the vascular lesions, decreased to <300 copies. Thus, targeting CD83+ DCs was highly effective in suppressing vasculitis, suggesting that T cell activation is strictly dependent on DC function.


Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis.

Ma-Krupa W, Jeon MS, Spoerl S, Tedder TF, Goronzy JJ, Weyand CM - J. Exp. Med. (2004)

Therapeutic effects of depleting CD83+ DCs in GCA. Temporal artery–SCID mouse chimeras were generated by implanting SCID mice with segments from a GCA-affected temporal artery. The chimeras were injected on days 9–11 with anti-CD83 Ab or control Ig, and arterial grafts were harvested 1 wk later. Frozen tissue sections were immunostained with anti-CD3 Ab (A). The density of arterial wall T cell infiltrates was determined by counting CD3+ T cells (brown) on cross sections of the arteries (B). cDNA was generated from the explanted temporal arteries to quantify transcripts for β-actin, IFN-γ, and IL-1β by quantitative PCR. All cDNA concentrations were adjusted to 2 × 105 β-actin copies. Copy numbers of IFN-γ– and IL-1β–specific sequences are shown as box plots as described in Fig. 2. Results are from five experiments with tissues from five different patients. Treatment with anti-CD83 Ab induced massive loss of tissue-infiltrating T cells. In parallel, IFN-γ mRNA transcripts decreased to <20% of baseline, and IL-1β mRNA transcripts decreased by >75% (C). Original magnification, 400.
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Related In: Results  -  Collection

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fig3: Therapeutic effects of depleting CD83+ DCs in GCA. Temporal artery–SCID mouse chimeras were generated by implanting SCID mice with segments from a GCA-affected temporal artery. The chimeras were injected on days 9–11 with anti-CD83 Ab or control Ig, and arterial grafts were harvested 1 wk later. Frozen tissue sections were immunostained with anti-CD3 Ab (A). The density of arterial wall T cell infiltrates was determined by counting CD3+ T cells (brown) on cross sections of the arteries (B). cDNA was generated from the explanted temporal arteries to quantify transcripts for β-actin, IFN-γ, and IL-1β by quantitative PCR. All cDNA concentrations were adjusted to 2 × 105 β-actin copies. Copy numbers of IFN-γ– and IL-1β–specific sequences are shown as box plots as described in Fig. 2. Results are from five experiments with tissues from five different patients. Treatment with anti-CD83 Ab induced massive loss of tissue-infiltrating T cells. In parallel, IFN-γ mRNA transcripts decreased to <20% of baseline, and IL-1β mRNA transcripts decreased by >75% (C). Original magnification, 400.
Mentions: To investigate how DCs contribute to the disease process, we treated temporal artery–SCID mouse chimeras with anti-CD83 Ab. Expression of the CD83 marker in the vasculitic lesion was strictly limited to DCs (Fig. 1, E and F; reference 15). Temporal arteries from five patients were divided into three to five equal pieces. Mice carrying tissue from the same donor were injected with either control Ig or anti-CD83 Ab. Chimeras received Ab injections on days 9–11 after implantation, and the grafts were harvested 1 wk after the completion of the treatment. Histomorphological evaluation showed that anti-CD83 Ab treatment had a marked effect on the density of the T cell infiltrate (Fig. 3, A and B) . After treatment with anti-CD83 Ab, the granulomatous microstructures were destroyed and few T cells were still present in the arterial wall. The remaining T cells were dispersed throughout the vascular tissue. To examine the effect on T cell and macrophage activity, cDNA was generated from tissue extracts, and transcript levels for IFN-γ and IL-1β were semi-quantified. After the administration of anti-CD83 Ab, levels of IFN-γ transcripts, reflective of in situ T cell activation, decreased to <20% of those measured in the grafts from animals treated with control Ig (Fig. 3 C). In parallel, the production of IL-1β, which is derived from macrophages in the vascular lesions, decreased to <300 copies. Thus, targeting CD83+ DCs was highly effective in suppressing vasculitis, suggesting that T cell activation is strictly dependent on DC function.

Bottom Line: Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions.We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA.Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

ABSTRACT
Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4(+) T cells are selectively activated in the adventitia of affected arteries. In human GCA artery-severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83(+) dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia-media border. Adoptive T cell transfer into temporal artery-SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II-matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.

Show MeSH
Related in: MedlinePlus