Amelioration of proteolipid protein 139–151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms

Stern, Joel N. H.; Illés, Zsolt; Reddy, Jay; Keskin, Derin B.; Sheu, Eric G.; Fridkis-Hareli, Masha; Nishimura, Hiroyuki; Brosnan, Celia F.; Santambrogio, Laura; Kuchroo, Vijay K.; Strominger, Jack L.

doi:10.1073/pnas.0403832101

Cited by 43 publications

(49 citation statements)

References 54 publications

(41 reference statements)

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“…5). These effects essentially reproduce those previously found by using random amino acid copolymers (29,30).…”

Section: Discussionsupporting

confidence: 79%

“…Three such copolymers have been described (29,30). Cop1 is made in solution by polymerization of N-carboxy amino acid anhydrides, whereas FYAK and VWAK were made by the more recent solid phase chemistry.…”

Section: Discussionmentioning

confidence: 99%

“…Proliferative responses were measured as described in refs. 17 (17,29,30), peptide synthesis (13), isolation of empty HLA-DR2 (12,13), inhibition by peptide 15-mers of MBP 85-99 binding to HLA-DR2 (DRA͞DRB1*1501) (13,17), sorting of tg and endogenous (non-tg) T cells from humanized mice by flow cytometry (30), cytokine measurement by ELISA (30), and detection of PLP 139-151-reactive CD4 ϩ T cells by using I-A s ͞PLP 139-151 tetramers (31,32). (11,17).…”

Section: Methodsmentioning

confidence: 99%

“…Cop1 binds to several human HLA-DR molecules, including HLA-DR2, and blocks modestly the presentation of MBP 85-99 (27,28). The effectiveness of amino acid copolymers with in vitro and in vivo assays was greatly improved by modifications that enhanced their binding to HLA-DR2 (29,30). We hypothesized that by similarly improving the binding of synthetic peptide mimetics (13,29,30), their effectiveness might also be greatly enhanced.…”

mentioning

confidence: 99%

“…The effectiveness of amino acid copolymers with in vitro and in vivo assays was greatly improved by modifications that enhanced their binding to HLA-DR2 (29,30). We hypothesized that by similarly improving the binding of synthetic peptide mimetics (13,29,30), their effectiveness might also be greatly enhanced. Thus, T cell recognition of MBP 85-99 might be more effectively inhibited and͞or additional immunosuppressive functions of the copolymers might be enhanced by the peptide mimetics.…”

mentioning

confidence: 99%

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Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis

Stern

Illés

Reddy

et al. 2005

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

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Myelin basic protein (MBP) is a major candidate autoantigen in multiple sclerosis (MS).Cop1 ͉ HLA-DR ͉ multiple sclerosis ͉ T cells M ultiple sclerosis (MS), an autoimmune inflammatory disease of the CNS, is associated with the HLA-DR2 haplotype (DRA*0101, DRB1*1501, DQA1*0102, DQB1*0602) (1-3). Myelin basic protein (MBP) is one of the major candidate autoantigens in the pathogenesis of MS. Particularly, T cell reactivity to the immunodominant MBP 85-99 epitope is found in subjects carrying human leukocyte antigen (HLA)-DR2, a genetic marker for susceptibility to MS. HLA-DR2-restricted MBP-specific T cells are clonally expanded and activated in MS patients (4-9). Furthermore, HLA-DR2͞MBP 85-99 complexes have been detected in the CNS plaques of these patients (10). Critical residues for binding to HLA-DR2 and for T cell antigen receptor (TCR) recognition of the MBP 85-99 epitope have been defined (11,12).Several therapeutic approaches to MS have been attempted by using cytokines, copolymers, dimers of class II major histocompatibility complex-peptide complexes, peptide antigens that induce anergy, vaccination with TCR, and an altered peptide ligand (13)(14)(15)(16)(17)(18)(19). Many of these studies aimed to interfere with the MBP 85-99-specific T cell recognition and͞or to deviate the T cell response from the Th1 to the Th2 phenotype. Copolymer 1 [Cop1, Copaxone, Glatiramer Acetate, poly(Y, E, A, K)n], the only approved drug known to reduce MBP-specific T cell responses, reduces the relapse rate by Ϸ30% in relapsingremitting forms of MS (20-26). Cop1 binds to several human HLA-DR molecules, including HLA-DR2, and blocks modestly the presentation of MBP 85-99 (27, 28). The effectiveness of amino acid copolymers with in vitro and in vivo assays was greatly improved by modifications that enhanced their binding to HLA-DR2 (29, 30). We hypothesized that by similarly improving the binding of synthetic peptide mimetics (13, 29, 30), their effectiveness might also be greatly enhanced. Thus, T cell recognition of MBP 85-99 might be more effectively inhibited and͞or additional immunosuppressive functions of the copolymers might be enhanced by the peptide mimetics. In this paper we report generation of three peptide inhibitors based on the binding motif of MBP 85-99 to HLA-DR2 with improved functions in inhibiting T cell responses and experimental autoimmune encephalomyelitis (EAE). These 15-mers (J2, J3, and J5) competed with MBP 85-99 for binding to HLA-DR2, inhibited IL-2 secretion by MBP 85-99-specific T cell clones and induced production of Th2 cytokines by splenocytes. Additionally they did not crossreact with MBP 85-99-or PLP 139-151-specific T cells. They also suppressed EAE in two different murine disease models in a manner equivalent to that achieved by using the modified random amino acid copolymers. Materials and MethodsGeneration of Peptide-Specific Short-Term T Cell Lines and Proliferative Responses to Peptides. Mice were immunized with proteolipid protein (PLP) 139-151 or peptide 15-mers (100 g per mouse) em...

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“…5). These effects essentially reproduce those previously found by using random amino acid copolymers (29,30).…”

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis

Stern

Illés

Reddy

et al. 2005

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

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Multiple Sclerosis

Huryn

2010

Burger's Medicinal Chemistry and Drug Discovery

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Multiple sclerosis ( MS ) is a severe, debilitating disease that affects more than a million individuals worldwide. Unfortunately, most aspects of this disease are poorly understood, thereby making drug discovery efforts particularly challenging. Historically, therapeutics for MS have relied on broad immunosuppression, and therefore these agents cause significant limiting side effects. Many of these older drugs were developed first as cancer therapeutics, and their ability to prevent the proliferation of immune cells was exploited in treating MS patients. Other current frontline therapies include immunosuppressants and immunomodulators that originally found use in inflammatory or other automimmune disorders. Current efforts are focusing on a more subtle approach at immunomodulation that target specific aspects of the immune response or putative MS autoantigens. This chapter provides an overview of currently approved therapies, including small‐molecule and protein‐based therapeutics as well as a more detailed review of promising new approaches, particularly those with a medicinal chemistry component.

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