In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experiment... more In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti-citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70% of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor κB (NF-κB) inhibitor exposed to four citrullinated peptide antigens, designated "Rheumavax," in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype-positive RA patients with citrullinated peptide-specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observ...
Costimulation-deficient dendritic cells (DCs) prevent autoimmune disease in mouse models. However... more Costimulation-deficient dendritic cells (DCs) prevent autoimmune disease in mouse models. However, autoimmune-prone mice and humans fail to control expansion of peripheral autoreactive effector memory T cells (TEMs), which resist immunoregulation by costimulation-deficient DCs. In contrast, activation of DC costimulation may be coupled with regulatory capacity. To test whether costimulatory DCs control TEMs and attenuate established autoimmune disease, we used RelB-deficient mice, which have multiorgan inflammation, expanded peripheral autoreactive TEMs, and dysfunctional Foxp3+ regulatory T cells (Tregs) cells and conventional DCs. TEMs were regulated by Foxp3+ Tregs when costimulated by CD3/CD28-coated beads or wild-type DCs but not DCs deficient in RelB or CD80/CD86. After transfer, RelB and CD80/CD86-sufficient DCs restored tolerance and achieved a long-term cure of autoimmune disease through costimulation of TEM and Foxp3+ Treg IFN-γ production, as well as induction of IDO by h...
SerpinB2 (plasminogen activator inhibitor-2) is widely described as an inhibitor of urokinase pla... more SerpinB2 (plasminogen activator inhibitor-2) is widely described as an inhibitor of urokinase plasminogen activator; however, SerpinB2−/− mice show no detectable increase in urokinase plasminogen activator activity. In this study, we describe an unexpected immune phenotype in SerpinB2−/− mice. After immunization with OVA in CFA, SerpinB2−/− mice made ≈6-fold more IgG2c and generated ≈2.5-fold more OVA-specific IFN-γ–secreting T cells than SerpinB2+/+ littermate controls. In SerpinB2+/+ mice, high inducible SerpinB2 expression was seen at the injection site and in macrophages low levels in draining lymph nodes and conventional dendritic cells, and no expression was seen in plasmacytoid dendritic, B, T, or NK cells. SerpinB2−/− macrophages promoted greater IFN-γ secretion from wild-type T cells in vivo and in vitro and, when stimulated with anti-CD40/IFN-γ or cultured with wild-type T cells in vitro, secreted more Th1-promoting cytokines than macrophages from littermate controls. Drai...
Existing therapies for rheumatoid arthritis and other autoimmune diseases are not Ag specific, wh... more Existing therapies for rheumatoid arthritis and other autoimmune diseases are not Ag specific, which increases the likelihood of systemic toxicity. We show that egg phosphatidylcholine liposomes loaded with Ag (OVA or methylated BSA) and a lipophilic NF-κB inhibitor (curcumin, quercetin, or Bay11-7082) suppress preexisting immune responses in an Ag-specific manner. We injected loaded liposomes into mice primed with Ag or into mice suffering from Ag-induced inflammatory arthritis. The liposomes targeted APCs in situ, suppressing the cells’ responsiveness to NF-κB and inducing Ag-specific FoxP3+ regulatory T cells. This regulatory mechanism suppressed effector T cell responses and the clinical signs of full-blown Ag-induced arthritis. Thus, liposomes encapsulate Ags and NF-κB inhibitors stably and efficiently and could be readily adapted to deliver Ags and inhibitors for Ag-specific suppression of other autoimmune and allergic diseases.
Introduction: Anti-citrullinated peptide antibodies are found in rheumatoid arthritis (RA) patien... more Introduction: Anti-citrullinated peptide antibodies are found in rheumatoid arthritis (RA) patients with HLA-DRβ chains encoding the shared epitope (SE) sequence. Citrullination increases self-antigen immunogenicity, through increased binding affinity to SE-containing HLA-DR molecules. To characterise T-cell autoreactivity towards citrullinated self-epitopes, we profiled responses of SE + healthy controls and RA patients to citrullinated and unmodified epitopes of four autoantigens. Methods: We compared T-cell proliferative and cytokine responses to citrullinated and native type II collagen 1,237 to 1,249, vimentin 66 to 78, aggrecan 84 to 103 and fibrinogen 79 to 91 in six SE + healthy controls and in 21 RA patients with varying disease duration. Cytokine-producing cells were stained after incubation with peptide in the presence of Brefeldin-A. Results: Although proliferative responses were low, IL-6, IL-17 and TNF were secreted by CD4 + T cells of SE + RA patients and healthy controls, as well as IFNγ and IL-10 secreted by RA patients, in response to citrullinated peptides. Of the epitopes tested, citrullinated aggrecan was most immunogenic. Patients with early RA were more likely to produce IL-6 in response to no epitope or to citrullinated aggrecan, while patients with longstanding RA were more likely to produce IL-6 to more than one epitope. Cytokine-producing CD4 + T cells included the CD45RO + and CD45ROand the CD28 + and CD28subsets in RA patients. Conclusion: Proinflammatory cytokines were produced by CD4 + T cells in SE + individuals in response to citrullinated self-epitopes, of which citrullinated aggrecan was most immunogenic. Our data suggest that the T-cell response to citrullinated self-epitopes matures and diversifies with development of RA.
Objective. Ankylosing spondylitis (AS) is a common inflammatory arthritis affecting primarily the... more Objective. Ankylosing spondylitis (AS) is a common inflammatory arthritis affecting primarily the axial skeleton. IL23R is genetically associated with AS. This study was undertaken to investigate and characterize the role of interleukin-23 (IL-23) signaling in AS pathogenesis. Methods. The study population consisted of patients with active AS (n ؍ 17), patients with psoriatic arthritis (n ؍ 8), patients with rheumatoid arthritis, (n ؍ 9), and healthy subjects (n ؍ 20). IL-23 receptor (IL-23R) expression in T cells was determined in each subject group, and expression levels were compared. Results. The proportion of IL-23R-expressing T cells in the periphery was 2-fold higher in AS patients than in healthy controls, specifically driven by a 3-fold increase in IL-23R-positive ␥/␦ T cells in AS patients. The proportions of CD4؉ and CD8؉ cells that were positive for IL-17 were unchanged. This increased IL-23R expression on ␥/␦ T cells was also associated with enhanced IL-17 secretion, with no observable IL-17 production from IL-23R-negative ␥/␦ T cells in AS patients. Furthermore, ␥/␦ T cells from AS patients were heavily skewed toward IL-17 production in response to stimulation with IL-23 and/or anti-CD3/CD28. Conclusion. Recently, mouse models have shown IL-17-secreting ␥/␦ T cells to be pathogenic in infection and autoimmunity. Our data provide the first description of a potentially pathogenic role of these cells in a human autoimmune disease. Since IL-23 is a maturation and growth factor for IL-17-producing cells, increased IL-23R expression may regulate the function of this putative pathogenic ␥/␦ T cell population. Ankylosing spondylitis (AS), the prototypical spondylarthritis, is strongly familial, with heritability of disease risk estimated to be Ͼ90% (1). Recent genetic association studies have identified a number of genes in the interleukin-23 (IL-23) signaling pathway that contribute to AS, most notably IL23R (encoding the IL-23 pathway-specific receptor subunit [IL-23R]) (2). The same single-nucleotide polymorphisms in IL23R are also associated with inflammatory bowel disease and psoriasis, two conditions that often occur concomitantly with AS, suggesting common pathogenic mechanisms (3). IL-23 signals through a heterodimeric receptor containing the IL-23R subunit (4) and is well documented to initiate and stabilize classic CD4ϩ Th17 responses (5). IL-23 signaling has been demonstrated
In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experiment... more In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti-citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70% of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor κB (NF-κB) inhibitor exposed to four citrullinated peptide antigens, designated "Rheumavax," in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype-positive RA patients with citrullinated peptide-specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observ...
Costimulation-deficient dendritic cells (DCs) prevent autoimmune disease in mouse models. However... more Costimulation-deficient dendritic cells (DCs) prevent autoimmune disease in mouse models. However, autoimmune-prone mice and humans fail to control expansion of peripheral autoreactive effector memory T cells (TEMs), which resist immunoregulation by costimulation-deficient DCs. In contrast, activation of DC costimulation may be coupled with regulatory capacity. To test whether costimulatory DCs control TEMs and attenuate established autoimmune disease, we used RelB-deficient mice, which have multiorgan inflammation, expanded peripheral autoreactive TEMs, and dysfunctional Foxp3+ regulatory T cells (Tregs) cells and conventional DCs. TEMs were regulated by Foxp3+ Tregs when costimulated by CD3/CD28-coated beads or wild-type DCs but not DCs deficient in RelB or CD80/CD86. After transfer, RelB and CD80/CD86-sufficient DCs restored tolerance and achieved a long-term cure of autoimmune disease through costimulation of TEM and Foxp3+ Treg IFN-γ production, as well as induction of IDO by h...
SerpinB2 (plasminogen activator inhibitor-2) is widely described as an inhibitor of urokinase pla... more SerpinB2 (plasminogen activator inhibitor-2) is widely described as an inhibitor of urokinase plasminogen activator; however, SerpinB2−/− mice show no detectable increase in urokinase plasminogen activator activity. In this study, we describe an unexpected immune phenotype in SerpinB2−/− mice. After immunization with OVA in CFA, SerpinB2−/− mice made ≈6-fold more IgG2c and generated ≈2.5-fold more OVA-specific IFN-γ–secreting T cells than SerpinB2+/+ littermate controls. In SerpinB2+/+ mice, high inducible SerpinB2 expression was seen at the injection site and in macrophages low levels in draining lymph nodes and conventional dendritic cells, and no expression was seen in plasmacytoid dendritic, B, T, or NK cells. SerpinB2−/− macrophages promoted greater IFN-γ secretion from wild-type T cells in vivo and in vitro and, when stimulated with anti-CD40/IFN-γ or cultured with wild-type T cells in vitro, secreted more Th1-promoting cytokines than macrophages from littermate controls. Drai...
Existing therapies for rheumatoid arthritis and other autoimmune diseases are not Ag specific, wh... more Existing therapies for rheumatoid arthritis and other autoimmune diseases are not Ag specific, which increases the likelihood of systemic toxicity. We show that egg phosphatidylcholine liposomes loaded with Ag (OVA or methylated BSA) and a lipophilic NF-κB inhibitor (curcumin, quercetin, or Bay11-7082) suppress preexisting immune responses in an Ag-specific manner. We injected loaded liposomes into mice primed with Ag or into mice suffering from Ag-induced inflammatory arthritis. The liposomes targeted APCs in situ, suppressing the cells’ responsiveness to NF-κB and inducing Ag-specific FoxP3+ regulatory T cells. This regulatory mechanism suppressed effector T cell responses and the clinical signs of full-blown Ag-induced arthritis. Thus, liposomes encapsulate Ags and NF-κB inhibitors stably and efficiently and could be readily adapted to deliver Ags and inhibitors for Ag-specific suppression of other autoimmune and allergic diseases.
Introduction: Anti-citrullinated peptide antibodies are found in rheumatoid arthritis (RA) patien... more Introduction: Anti-citrullinated peptide antibodies are found in rheumatoid arthritis (RA) patients with HLA-DRβ chains encoding the shared epitope (SE) sequence. Citrullination increases self-antigen immunogenicity, through increased binding affinity to SE-containing HLA-DR molecules. To characterise T-cell autoreactivity towards citrullinated self-epitopes, we profiled responses of SE + healthy controls and RA patients to citrullinated and unmodified epitopes of four autoantigens. Methods: We compared T-cell proliferative and cytokine responses to citrullinated and native type II collagen 1,237 to 1,249, vimentin 66 to 78, aggrecan 84 to 103 and fibrinogen 79 to 91 in six SE + healthy controls and in 21 RA patients with varying disease duration. Cytokine-producing cells were stained after incubation with peptide in the presence of Brefeldin-A. Results: Although proliferative responses were low, IL-6, IL-17 and TNF were secreted by CD4 + T cells of SE + RA patients and healthy controls, as well as IFNγ and IL-10 secreted by RA patients, in response to citrullinated peptides. Of the epitopes tested, citrullinated aggrecan was most immunogenic. Patients with early RA were more likely to produce IL-6 in response to no epitope or to citrullinated aggrecan, while patients with longstanding RA were more likely to produce IL-6 to more than one epitope. Cytokine-producing CD4 + T cells included the CD45RO + and CD45ROand the CD28 + and CD28subsets in RA patients. Conclusion: Proinflammatory cytokines were produced by CD4 + T cells in SE + individuals in response to citrullinated self-epitopes, of which citrullinated aggrecan was most immunogenic. Our data suggest that the T-cell response to citrullinated self-epitopes matures and diversifies with development of RA.
Objective. Ankylosing spondylitis (AS) is a common inflammatory arthritis affecting primarily the... more Objective. Ankylosing spondylitis (AS) is a common inflammatory arthritis affecting primarily the axial skeleton. IL23R is genetically associated with AS. This study was undertaken to investigate and characterize the role of interleukin-23 (IL-23) signaling in AS pathogenesis. Methods. The study population consisted of patients with active AS (n ؍ 17), patients with psoriatic arthritis (n ؍ 8), patients with rheumatoid arthritis, (n ؍ 9), and healthy subjects (n ؍ 20). IL-23 receptor (IL-23R) expression in T cells was determined in each subject group, and expression levels were compared. Results. The proportion of IL-23R-expressing T cells in the periphery was 2-fold higher in AS patients than in healthy controls, specifically driven by a 3-fold increase in IL-23R-positive ␥/␦ T cells in AS patients. The proportions of CD4؉ and CD8؉ cells that were positive for IL-17 were unchanged. This increased IL-23R expression on ␥/␦ T cells was also associated with enhanced IL-17 secretion, with no observable IL-17 production from IL-23R-negative ␥/␦ T cells in AS patients. Furthermore, ␥/␦ T cells from AS patients were heavily skewed toward IL-17 production in response to stimulation with IL-23 and/or anti-CD3/CD28. Conclusion. Recently, mouse models have shown IL-17-secreting ␥/␦ T cells to be pathogenic in infection and autoimmunity. Our data provide the first description of a potentially pathogenic role of these cells in a human autoimmune disease. Since IL-23 is a maturation and growth factor for IL-17-producing cells, increased IL-23R expression may regulate the function of this putative pathogenic ␥/␦ T cell population. Ankylosing spondylitis (AS), the prototypical spondylarthritis, is strongly familial, with heritability of disease risk estimated to be Ͼ90% (1). Recent genetic association studies have identified a number of genes in the interleukin-23 (IL-23) signaling pathway that contribute to AS, most notably IL23R (encoding the IL-23 pathway-specific receptor subunit [IL-23R]) (2). The same single-nucleotide polymorphisms in IL23R are also associated with inflammatory bowel disease and psoriasis, two conditions that often occur concomitantly with AS, suggesting common pathogenic mechanisms (3). IL-23 signals through a heterodimeric receptor containing the IL-23R subunit (4) and is well documented to initiate and stabilize classic CD4ϩ Th17 responses (5). IL-23 signaling has been demonstrated
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