A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4<sup>+</sup>CD25<sup>+</sup>cells and TGF-β

Sharabi, Amir; Zinger, Heidy; Zborowsky, Maya; Sthoeger, Zev; Mozes, Edna

doi:10.1073/pnas.0603201103

Cited by 85 publications

(106 citation statements)

References 38 publications

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“…CD4 ϩ CD25 ϩ regulatory cells represent a well characterized population of cells that play crucial roles in immunological tolerance and in autoimmunity (28)(29)(30). The role of CD4 ϩ CD25 ϩ cells in the control of autoimmune diseases was clearly demonstrated in experimental models in which elimination of CD25 ϩ T cells resulted in acceleration of disease progression including inflammatory bowel disease, experimental autoimmune encephalomyelitis, autoimmune diabetes (31), and lupus (32). In previous studies performed in our laboratory, we demonstrated that inhibition of ERK1,2 in CD4 ϩ CD25 ϩ cells abrogated their ability to suppress IFN-␥ secretion by LN cells of immunized mice (H.B.-D., B.V.A., M.S., and E.M., unpublished work).…”

Section: Discussionmentioning

confidence: 99%

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Ben-David¹,

Aruna²,

Seger

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are T cell-dependent antibody-mediated autoimmune diseases. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogues of two myasthenogenic peptides, p195-212 and p259 -271, down-regulated in vitro and in vivo MG-associated autoreactive responses. The dual APL was shown to exert its beneficial effects by up-regulating ERK1,2 in CD4 ؉ CD25 ؉ regulatory cells. In this study, we investigated a novel 50-kDa ERK-like protein (ERK-50) that is up-regulated significantly in addition to ERK1,2 after treatment with the dual APL. We report here that ERK-50 was upregulated in LN cells and in LN-derived T cells of mice that were immunized with the myasthenogenic peptides and treated with the dual APL. Moreover, ERK-50 was up-regulated in dual-APLtreated mice that were immunized with the Torpedo acetylcholine receptor. ERK-50 was demonstrated to be recognized by antibodies directed against the C and N termini of ERK1, against the C terminus of ERK2, and against general ERK. The 50-kDa ERK was shown to be stimulated by Con A, and inhibition of MEK1 down-regulated the 50-kDa ERK as was shown for ERK1,2. However, 4␤-phorbol 12-myristate 13-acetate (TPA) did not stimulate ERK-50. Finally, the activated ERK-50 was up-regulated in the dual-APL-induced CD4 ؉ CD25 ؉ regulatory cells. Thus, ERK-50 is suggested to be a novel ERK isoform, being up-regulated in response to treatment with the dual APL.autoimmunity ͉ immunomodulation ͉ kinase

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Section: Discussionmentioning

confidence: 99%

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Ben-David¹,

Aruna²,

Seger

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…These unaltered, native peptide epitopes halt progression of lupus nephritis upon tolerization in high-dose soluble form and importantly for human therapy, the peptides are also effective in delaying/preventing lupus nephritis in subnanomolar doses (ϳ0.37 nM or 1 g), administered s.c. to lupus-prone SNF 1 mice (2,3,15). This dose is 300-to 1000-fold less than peptides from other nucleoproteins or unrelated peptides from Ig V regions (CDR) that are being tried as therapeutic agents (4,5,16,17).…”

Section: Low-dose Peptide Tolerance Therapy Of Lupus Generates Plasmamentioning

confidence: 99%

“…T olerance therapy for systemic lupus erythematosus using autoantigenic peptides that specifically target pathogenic autoimmune cells is a highly desirable goal (1)(2)(3)(4)(5). Due to intrinsic defects in lupus immune system, nucleosomes from apoptotic cells become major immunogens initiating cognate interactions between autoimmune CD4 ϩ Th cells and B cells leading to production of somatically mutated, class-switched autoantibodies that form pathogenic immune complexes with diverse nuclear Ags (6 -11).…”

Section: Low-dose Peptide Tolerance Therapy Of Lupus Generates Plasmamentioning

confidence: 99%

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Kang

Liu

Datta

2007

The Journal of Immunology

186

206

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Subnanomolar doses of an unaltered, naturally occurring nucleosomal histone peptide epitope, H471–94, when injected s.c. into lupus-prone mice, markedly prolong lifespan by generating CD4+25+ and CD8+ regulatory T cells (Treg) producing TGF-β. The induced Treg cells suppress nuclear autoantigen-specific Th and B cells and block renal inflammation. Splenic dendritic cells (DC) captured the s.c.-injected H471–94 peptide rapidly and expressed a tolerogenic phenotype. The DC of the tolerized animal, especially plasmacytoid DC, produced increased amounts of TGF-β, but diminished IL-6 on stimulation via the TLR-9 pathway by nucleosome autoantigen and other ligands; and those plasmacytoid DC blocked lupus autoimmune disease by simultaneously inducing autoantigen-specific Treg and suppressing inflammatory Th17 cells that infiltrated the kidneys of untreated lupus mice. Low-dose tolerance with H471–94 was effective even though the lupus immune system is spontaneously preprimed to react to the autoepitope. Thus, H471–94 peptide tolerance therapy that preferentially targets pathogenic autoimmune cells could spare lupus patients from chronically receiving toxic agents or global immunosuppressants and maintain remission by restoring autoantigen-specific Treg cells.

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“…17 Accordingly, adoptive transfer of in vitro-expanded T reg cells, or administration of histone-derived peptides or peptides derived from the complementarity-determining region 1 of anti-double-strand DNA immunoglobulin has been shown to ameliorate the disease in BWF1 mice by a mechanism involving T reg cells. [17][18][19][20] These studies suggest that the function of endogenous T reg cells is, at least partially, abrogated by unidentified mechanisms in BWF1 mice.…”

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confidence: 99%

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Abe

Ueha

Suzuki

et al. 2008

The American Journal of Pathology

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Foxp3 ؉ CD4 ؉ regulatory T (T reg ) cells play a pivotal role in the maintenance of dominant self tolerance. Understanding how the failures of immune control by T reg cells are involved in autoimmune diseases is important for the development of effective immunotherapies. In the present study, we analyzed the characteristics of endogenous T reg cells in (NZB ؋ NZW) F1 (BWF1) mice, a murine model of systemic lupus erythematosus. Unexpectedly, T reg number and frequency in aged BWF1 mice with developing lupus nephritis were increased, not decreased, and in vitro suppressive activity in lymphoid organs was intact. In addition, T reg cells trafficked to target organs because cells were present in the kidney and lung. T reg cells of aged BWF1 mice exhibited altered localization within lymph organs, however, and an altered phenotype, with higher expression levels of chemokine receptors and activation markers, suggesting a highly activated cellular state. Notably, the expression levels of costimulatory molecules were also markedly enhanced in the T reg cells of aged BWF1 mice. Furthermore, T reg cells of BWF1 mice did not show any suppressive effects on antibody production in vitro. Taken together, we conclude that T reg cells in BWF1 mice are not predisposed to functional incompetence but rather are present in a highly activated state. Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology characterized by a massive production of autoantibodies against various nuclear antigens. The deposit of immune complexes in the target organs, ie, skin, kidney, lung, joints, and central nervous system, is thought to cause fatal dysfunction of the body system. (NZB ϫ NZW) F1 (BWF1) is a mouse strain that has been widely used as a model for SLE since the 1960s. These mice spontaneously develop severe autoimmune disease highly resembling human SLE in terms of serological and hematological abnormalities, and severe nephritis accompanying massive production of antinuclear antibodies. 1 Reconstitution of SCID (severe combined immunodeficiency) mice with cultured pre-B cells of BWF1 mice recapitulates many symptoms of the disease of BWF1 mice. Cultured pre-B cells alone, however, are not sufficient to fully reproduce the disease. 2 These data suggest that cellular subset(s) in addition to B cells are necessary for the development of the lupus-like syndrome of BWF1 mice, although abnormalities of the immune system predominantly lie within B cells. One of the possible candidates is CD4 ϩ T cells, because depletion of CD4 ϩ T cells with anti-CD4 antibody from 5 months old, slightly before the disease onset, prevents the development of the disease. 3,4 CD4 ϩ T cells are, therefore, also required for the development of the disease in BWF1 mice, possibly by providing help for the production of high-affinity autoantibodies.Studies in this decade have clearly shown the key roles of naturally occurring regulatory T (T reg ) cells in the maintenance of dominant self tolerance of the immune system. 5 T reg cells in normal mi...

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A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4⁺CD25⁺cells and TGF-β

Cited by 85 publications

References 38 publications

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

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A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+cells and TGF-β

Cited by 85 publications

References 38 publications

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

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A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4⁺CD25⁺cells and TGF-β