Therapeutic vaccines in autoimmunity

Sela, Michael; Mozes, Edna

doi:10.1073/pnas.0404826101

Cited by 48 publications

(29 citation statements)

References 78 publications

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“…However, most helminth antigens reportedly contain a large mixture of proteins, glycol‐proteins, and glycol‐lipids or whole protein 7, 8, 32. These mixture molecules or whole proteins may cross‐link adjacent IgE on mast cells and basophils, or activate pathogenic B and T cells, thereby exacerbating the allergy or autoimmune response 33, 34. By contrast, a short linear peptide generally avoids the above deficiencies and can antagonize the inflammatory responses of allergy and autoimmune diseases 33, 34.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Wang

et al. 2016

J Cellular Molecular Medi

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Helminth‐derived products have recently been shown to prevent the development of inflammatory diseases in mouse models. However, most identified immunomodulators from helminthes are mixtures or macromolecules with potentially immunogenic side effects. We previously identified an immunomodulatory peptide called SJMHE1 from the HSP60 protein of Schistosoma japonicum. In this study, we assessed the ability of SJMHE1 to affect murine splenocytes and human peripheral blood mononuclear cells (PBMCs) stimulated by toll‐like receptor (TLR) ligands in vitro and its treatment effect on mice with collagen‐induced arthritis (CIA). We show that SJMHE1 not only modulates the cytokine production of murine macrophage (MΦ) and dendritic cell but also affects cytokine production upon coculturing with allogeneic CD4+ T cell. SJMHE1 potently inhibits the cytokine response to TLR ligands lipopolysaccharide (LPS), CpG oligodeoxynucleotides (CpG) or resiquimod (R848) from mouse splenocytes, and human PBMCs stimulated by LPS. Furthermore, SJMHE1 suppressed clinical signs of CIA in mice and blocked joint erosion progression. This effect was mediated by downregulation of key cytokines involved in the pathogenesis of CIA, such as interferon‐γ (IFN‐γ), tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6, IL‐17, and IL‐22 and up‐regulation of the inhibitory cytokine IL‐10, Tgf‐β1 mRNA, and CD4+ CD25+Foxp3+ Tregs. This study provides new evidence that the peptide from S. japonicum, which is the ‘safe’ selective generation of small molecule peptide that has evolved during host–parasite interactions, is of great value in the search for novel anti‐inflammatory agents and therapeutic targets for autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Wang

et al. 2016

J Cellular Molecular Medi

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“…Immune deviation by TCR antagonism seems to have the potential to be used therapeutically to significantly delay undesired T cell responses that ultimately lead to disease (41). Alternatively, peptides able to stimulate regulatory T cells might also represent valuable candidates for deviating a proinflammatory autoimmune pattern to a more regulatory functional phenotype.…”

Section: Discussionmentioning

confidence: 99%

Selective Modulation of CD4+ T Cells from Lupus Patients by a Promiscuous, Protective Peptide Analog

Monneaux

Hoebeke

Sordet

et al. 2005

The Journal of Immunology

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A peptide encompassing residues 131–151 of the spliceosomal U1-70K protein and its analog phosphorylated at Ser140 were synthesized as potential candidates for the treatment of patients with lupus. Studies in the MRL/lpr and (NZB × NZW)F1 lupus models have demonstrated that these sequences contain a CD4+ T cell epitope but administration of the phosphorylated peptide only ameliorates the clinical manifestations of treated MRL/lpr mice. Binding assays with soluble HLA class II molecules and molecular modeling experiments indicate that both peptides behave as promiscuous epitopes and bind to a large panel of human DR molecules. In contrast to normal T cells and T cells from non-lupus autoimmune patients, we found that PBMCs from 40% of lupus patients selected randomly and CFSE-labeled CD4+ T cells proliferate in response to peptide 131–151. Remarkably, however, we observed that phosphorylation of Ser140 prevents CD4+ T cells proliferation but not secretion of regulatory cytokines, suggesting a striking immunomodulatory effect of phosphorylated analog on lupus CD4+ T cells that was unique to patients. The analog might act as an activator of regulatory T cells or as a partial agonist of TCR.

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“…SJMHE1 is 66% identical to P277, a fragment of the human HSP60, which can arrest the spontaneous diabetogenic process in NOD mice [28]. Additionally, a sequence in SJMHE1 contained a random polymer of four amino acids (GLAT) also present in myelin basic protein that has been proven to be an effective treatment for MS [38,44]. Whether SJMHE1 can be used as a peptide-based therapy for allergic and autoimmune disease treatment requires further analysis.…”

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confidence: 99%

CD4⁺CD25⁺ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

et al. 2009

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Chronic schistosome infection results in the suppression of host immune responses, allowing long-term schistosome survival and restricting pathology. Current theories suggest that Treg play an important role in this regulation. However, the mechanism of Treg induction during schistosome infection is still unknown. The aim of this study was to determine the mechanism behind the induction of CD4 1 CD25 1 T cells by Schistosoma japonicum HSP60 (SjHSP60)-derived peptide SJMHE1 as well as to elucidate the cellular and molecular basis for the induction of CD4 1 CD25 1 T cells during S. japonicum infection. Mice immunized with SJMHE1 or spleen and LN cells from naïve mice pretreated with SJMHE1 in vitro all displayed an increase in CD4 1 CD25 1 T-cell populations. Release of IL-10 and TGF-b by SJMHE1 stimulation may contribute to suppression. Adoptively transferred SJMHE1-induced CD4 1 CD25 1 T cells inhibited delayed-type hypersensitivity in BALB/c mice. Additionally, SJMHE1-treated APC were tolerogenic and induced CD4 1 cells to differentiate into suppressive CD4 1 CD25 1 Treg. Furthermore, our data support a role for TLR2 in SJMHE1-mediated CD4 1 CD25 1 Treg induction. These findings provide the basis for a more complete understanding of the S. japonicum-host interactions that contribute to host homeostatic mechanisms, preventing an excessive immune response.Key words: CD4 1 CD25 1 Treg . Immunomodulation . Schistosomes . SJMHE1 . TLR2 Supporting Information available online IntroductionImmune regulation associated with protective immunity is intricate and entails the effective elimination of the pathogen without causing serious damage to the host. Conversely, effective pathogens have developed multiple mechanisms for modulating or suppressing host immunity as survival and dissemination strategies. Therefore, during the course of an infection, a struggle between host defense mechanisms and the pathogen's immunomodulatory processes results in a complex interplay that may result in pathogen eradication or damage to the host (and persistence of the pathogen). One of the survival strategies used by pathogens involves the induction of immunosuppressive cell populations, e.g. Treg [1,2]. 3052The first observations suggesting that Treg induction occurs during infections with certain pathogens were made in mice infected with Bordetella pertussis [3] and in humans infected with HCV [4] or the nematode Onchocerca volvulus [5]. More recently, Treg induction has been described in chronic infections caused by Candida albicans [6], Mycobacterium tuberculosis [7], HIV [8], Leishmania major [9], Litomosoides sigmodontis [10], and Helicobacter pylori [11]. Treg induction has also been associated with Schistosome infection. Schistosomiasis is a major human disease primarily caused by one of the three species of Schistosome endemic to parts of Asia, South America, and Africa, i.e. S. mansoni, S. haematobium, and S. japonicum. Mortality rates resulting from these types of parasitic infections are second only to malaria. Chronic schis...

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Therapeutic vaccines in autoimmunity

Cited by 48 publications

References 78 publications

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Selective Modulation of CD4+ T Cells from Lupus Patients by a Promiscuous, Protective Peptide Analog

CD4⁺CD25⁺ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

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Therapeutic vaccines in autoimmunity

Cited by 48 publications

References 78 publications

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Selective Modulation of CD4+ T Cells from Lupus Patients by a Promiscuous, Protective Peptide Analog

CD4+CD25+ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

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CD4⁺CD25⁺ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent