Vaccination, prevention, and treatment of experimental autoimmune neuritis (EAN) by an oligomerized T cell epitope

Stienekemeier, Martina; Falk, Kirsten; Rötzschke, Olaf; Weishaupt, Andreas; Schneider, Carsten Q.; Toyka, Klaus V.; Gold, Ralf; Strominger, Jack L.

doi:10.1073/pnas.241504598

Cited by 22 publications

(19 citation statements)

References 33 publications

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“…Our previous studies have shown that repeat antigens consisting of linear copies of T cell epitopes are able to induce antigen-specific tolerance and suppress the clinical signs in various experimental autoimmune model systems (Rotzschke et al, 1997;Falk et al, 2000b;Falk et al, 2000a;Mack et al, 2001;Stienekemeier et al, 2001;Piaggio et al, 2007;Puentes et al, 2013). Their suppressive effect has been correlated with the induction of anergy (Falk et al, 2000a), expansion of regulatory cells (Piaggio et al, 2007) and induction of active suppression (Puentes et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies have shown that repeat antigens consisting of linear copies of T cell epitopes are able to suppress the clinical disease in various autoimmune model systems (Rotzschke et al, 1997;Falk et al, 2000b;Falk et al, 2000a;Mack et al, 2001;Stienekemeier et al, 2001;Piaggio et al, 2007;Puentes et al, 2013). In the present study, we wanted to investigate the suppressive capacity of parasite derived repeat structures linked to encephalitogenic epitopes in an experimental mouse model of multiple sclerosis.…”

Section: Parasite Tandem Repeats Linked To Single-encephalitogenic T mentioning

confidence: 99%

“…Briefly, female SJL/J and C57BL/6 mice were immunized by subcutaneous injection on the dorsal region The therapeutic effect of SAg fusion proteins was examined before and after disease induction. Concentration, dosing frequency and route of administration were based on our previous studies using repetitive self-peptides (oligomerized peptides), which showed that a single intravenous treatment with a low dosage of oligomers induced protective effect on experimental models of autoimmune diseases (Falk et al, 2000b;Stienekemeier et al, 2001;Puentes et al, 2013). SAg fusion proteins applied on the range of the peptide-concentration used to induce disease (dosages between 50 and 70 g), were shown to be safe and effective.…”

Section: Induction Of Eae and Therapeutic Effect Of S-antigen Fusion mentioning

confidence: 99%

“…This protection was shown to be antigen-specific and mediated by the induction of active suppression involving the action of anti-inflammatory cytokines like IL-10 and TGF-β. Multimerized antigens, initially thought to increase antigenicity by crosslinking MHC class II complexes on the surface of antigen presenting cells (APCs) and thereby leading to an enhanced T cell activation, have shown to suppress the clinical symptoms in experimental animal models of human autoimmune disease, like multiple sclerosis, autoimmune neuritis and type I diabetes (Falk et al, 2000b;Stienekemeier et al, 2001;Piaggio et al, 2007;Puentes et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Puentes

Dickhaut

Hofstätter

et al. 2016

J Neuroimmune Pharmacol

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Parasite proteins containing repeats are essential invasion ligands, important for their ability to evade the host immune system and to induce immunosuppression. Here, the intrinsic suppressive potential of repetitive structures within parasite proteins was exploited to induce immunomodulation in order to establish self-tolerance in an animal model of autoimmune neurological disease.We tested the tolerogenic potential of fusion proteins containing repeat sequences of parasites linked to self-antigens. The fusion constructs consist of a recombinant protein containing repeat sequences derived from the S-antigen protein (SAg) of Plasmodium falciparum linked to a CD4 T cell epitope of myelin. They were tested for their efficacy to control the development of experimental autoimmune encephalomyelitis (EAE), In addition, we used the DO11.10 transgenic mouse model to study the immune mechanisms involved in tolerance induced by SAg fusion proteins.We found that repeated sequences of P. falciparum SAg protein linked to self-epitopes markedly protected mice from EAE. These fusion constructs were powerful tolerizing agents not only in a preventive setting but also in the treatment of ongoing disease. The tolerogenic effect was shown to be antigen-specific and strongly dependent on the physical linkage of the T cell epitope to the parasite structure and on the action of anti-inflammatory cytokines like IL-10 and TGF-β. Other mechanisms include down-regulation of TNF-α accompanied by increased numbers of FoxP3 + cells. This study describes the use of repetitive structures from parasites linked to defined T cell epitopes as an effective method to induce antigen-specific tolerance with potential applicability for the treatment and prevention of autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Parasite Tandem Repeats Linked To Single-encephalitogenic T mentioning

confidence: 99%

Section: Induction Of Eae and Therapeutic Effect Of S-antigen Fusion mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Puentes

Dickhaut

Hofstätter

et al. 2016

J Neuroimmune Pharmacol

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“…BPNMinduced EAN (19) is also a mild disease with a maximal score of Ϸ1.5-2. After immunization with BPNM alone, all mice in the group developed signs of EAN between days 17 and 18 with a mean score of 1.7 (Fig.…”

Section: Adoptive Transfer (Atx) Of Copolymer-specific Regulatory T Cmentioning

confidence: 99%

Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice

Stern

Keskin

Zhang

et al. 2008

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

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IL-10-secreting regulatory T cell lines specific to glatiramer acetate [poly(Y,E,A,K)n] or poly(Y,F,A,K)n have been established from the enlarged spleen and lymph nodes that result from copolymer treatment of SJL mice in which experimental autoimmune encephalomyelitis was induced by PLP139-151. These CD4+CD25+T cell lines secrete high levels of IL-10 and IL-13 but only small amounts of IL-4 and virtually no TGF-β, IL-17, IL-6, IFN-γ, or TNF-α. Their phenotypes are particularly characterized by the absence of Foxp3 and the presence of two TNFR family members, CD30 and GITR. The lines proliferated specifically to the immunizing copolymers but were autoantigen-nonspecific, in that the same T cell line could suppress autoimmunity induced by three different autoantigens in SJL mice, i.e., PLP139-151(EAE), MBP85-99 (EAE), and bovine peripheral nerve myelin (experimental autoimmune neuritis), indicating they function by bystander suppression.

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Experimental Treatment of Acquired and Inherited Neuropathies

Sereda

Fledrich

Stassart

2014

Pathological Potential of Neuroglia

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Vaccination, prevention, and treatment of experimental autoimmune neuritis (EAN) by an oligomerized T cell epitope

Cited by 22 publications

References 33 publications

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice

Experimental Treatment of Acquired and Inherited Neuropathies

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