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Amino Acid Copolymer

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Jack L. Strominger – One of the best experts on this subject based on the ideXlab platform.

  • Proliferation, cytokine secretion, and immunosuppressive activity of YFAK-specific regulatory T cells. (THER3P.885)
    Journal of Immunology, 2014
    Co-Authors: Jack L. Strominger
    Abstract:

    Autoimmune diseases occur when there is misregulation within the immune system. Regulatory T cells (Tregs) are critical for the regulation of this immune response, however, little is known about their own regulation. The induction and activation of Tregs have been shown to alleviate symptoms of autoimmune disease such as human multiple sclerosis (MS). Our lab has identified Tregs that are activated by the random Amino Acid Copolymer YFAK. These YFAK-specific Tregs can reduce the symptoms of experimental autoimmune enceencephalomyelitis (EAE), the animal model of MS, more effectively than YEAK (Copaxone), a drug currently used in MS therapy. We have generated both YFAK-specific T cell lines as well as retrogenic mice expressing YFAK-specific T cell receptors (TCR) in order to study the regulation and activation of these beneficial Tregs. We find that these YFAK-specific Tregs will proliferate upon stimulation with glucococorticoid-induced TNF receptor ligand (GITRL). In addition, these Tregs can be activated to produce high levels of anti-inflammatory cytokines, and are immunosuppressive against conventional T cells. We plan to further characterize these YFAK-specific Tregs, as well as to utilize the TCR retrogenic mice in in vivo functional experiments. These studies will help to further explore the use of YFAK-specific Tregs in the prevention of autoimmune diseases such as multiple sclerosis.

  • Inhibition of experimental autoimmune uveitis by Amino Acid Copolymers.
    Journal of neuroimmunology, 2009
    Co-Authors: Hongen Yin, Jack L. Strominger, Barbara P Vistica, Chi-chao Chan, Igal Gery
    Abstract:

    Glatiramer acetate (GA), a synthetic random Amino Acid Copolymer, poly(Y, E, A, K)n, is widely used for treatment of multiple sclerosis. It inhibits experimental autoimmune enceencephalomyelitis (EAE) in mice by competition with the antigen and by induction of regulatory T cells. A novel Copolymer, poly (F, Y, A, K)n , designated FYAK, was more effective than GA in its immunomodulatory activity in EAE. Here, FYAK and GA were compared in the amelioration of another disease model in mice, experimental autoimmune uveoretinitis (EAU). When tested by co-immunization with an uveitogenic antigen, FYAK was superior to GA in its capacity to inhibit EAU induction, as well as immune processes related to this condition. Further, regulatory T-cell lines specific to FYAK were more immunosuppressive than GA-specific lines in the EAU model. The superiority of FYAK-specific lines was accompanied by higher production of Th2 cytokines. These data thus demonstrate that FYAK, a novel Copolymer, is superior to GA in its capacity to inhibit immunopathogenic processes in a non-central nervous system tissue.

  • T cell receptors in an IL-10-secreting Amino Acid Copolymer-specific regulatory T cell line that mediates bystander immunosuppression.
    Proceedings of the National Academy of Sciences of the United States of America, 2009
    Co-Authors: Hong Zhang, Joel N. H. Stern, Jack L. Strominger
    Abstract:

    The T cell receptors from the regulatory IL-10-secreting T cell line induced by the random Amino Acid Copolymers poly(F,Y,A,K,)n in SJL mice (H-2s) have been characterized, cloned, sequenced and expressed both in 293T cells and in 2 different TCR α−/β− T cell hybridomas. The usage of TCR α and β V regions in the cell line was oligoclonal. Four TCR α/β pairs cloned from single cells of the T cell line were inserted into a retrovirus vector linked by an oligonucleotide encoding the 2A peptide that spontaneously cleaves in vivo. After cotransfection of this vector with a CD3 vector into the 293T cells, the TCR were surface expressed. Moreover, after transduction into the 2 T cell hybridomas, all 4 were functional as evidenced by their response to stimulation by poly(F,Y,A,K)n. All 4 pairs were Vα3.2(3.5)/Vβ14, a prominent clonotype found in the poly(F,Y,A,K)n-specific T cell line. These V regions are identical to those recently found in a regulatory T ceT cell line that secretes both IL-4 and IL-10 induced in B10.PL mice with a different MHC hapotype (H-2u) by a small peptide obtained from an autoimmune TCR of that strain. These data lead to a hypothesis regarding the origin of the epigenetic modifications that lead to selective cytokine secretion in T cells.

Michael Sela – One of the best experts on this subject based on the ideXlab platform.

  • Binding Motifs of Copolymer 1 to Multiple Sclerosis- and Rheumatoid Arthritis-Associated HLA-DR Molecules
    Journal of immunology (Baltimore Md. : 1950), 1999
    Co-Authors: Masha Fridkis-hareli, Michael Sela, John M. Neveu, Renee A. Robinson, William S. Lane, Laurent Gauthier, Kai W. Wucherpfennig, Jack L. Strominger
    Abstract:

    Copolymer 1 (Cop 1, poly (Y, E, A, K)) is a random synthetic Amino Acid Copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS). Cop 1 binds promiscuously, with high affinity and in a peptide-specific manner to purified MS-associated HLA-DR2 (DRB1*1501) and rheumatoid arthritis-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules. In the present work at least 95% of added Cop 1 could be bound to recombinant “empty” HLA-DR1 and -DR4, and 80% could be bound to HLA-DR2 proteins. Amino Acid composition, HPLC profiles, and sequencing patterns of Cop 1 eluted by Acid extraction from HLA-DR molecules were similar to those of the unseparated Cop 1. Protruding N-terminal ends of Cop 1 bound to HLA-DR1, -DR2, or -DR4 molecules were then treated with Aminopeptidase I, followed by elution, HPLC, and pool sequencing. In contrast to untreated or unbound Cop 1, this material exhibited distinct motifs at some positions with increases in levels of E at the first and second cycles, of K at the second and third cycles, and of Y (presumably at P1 of the bound peptide) at the third to fifth cycles, regardless of the HLA-DR molecule employed. No preference was seen at the following cycles that were mainly A. These first pooled HLA-DR binding epitopes provide clues to the components of Cop 1 that are biologically active in suppressing MS and possibly rheumatoid arthritis.

  • Copolymer 1 acts against the immunodominant epitope 82–100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Rina Aharoni, Ruth Arnon, Dvora Teitelbaum, Michael Sela
    Abstract:

    The synthetic random Amino Acid Copolymer Copolymer 1 (Cop 1, Copaxone, glatiramer acetate) suppresses experimental autoimmune enceencephalomyelitis, slows the progression of disability, and reduces relapse rate in multiple sclerosis (MS). Cop 1 binds to various class II major histocompatibility complex (MHC) molecules and inhibits the T cell responses to several myelin antigens. In this study we attempted to find out whether, in addition to MHC blocking, Cop 1, which is immunologically cross-reactive with myelin basic protprotein (MBP), inhibits the response to this autoantigen by T cellcell receptor (TCR) antagonism. Two experimental systems, “prepulse assay” and “split APC assay,” were used to discriminate between competition for MHC molecules and TCR antagonism. The results in both systems using T cell lines/clones from mouse and human origin indicated that Cop 1 is a TCR antagonist of the 82–100 epitope of MBP. In contrast to the broad specificity of the MHC blocking induced by Cop 1, its TCR antagonistic activity was restricted to the 82–100 determinant of MBP and could not be demonstrated for proteolipid protein peptide or even for other MBP epitopes. Yet, it was shown for all the MBP 82–100-specific T cell lines/clones tested that were derived from mice as well as from an MS patient. The ability of Cop 1 to act as altered peptide and induce TCR antagonistic effect on the MBP p82–100 immunodominant determinant response elucidates further the mechanism of Cop 1 therapeutic activity in experimental autoimmune enceencephalomyelitis and MS.

  • Binding of random Copolymers of three Amino Acids to class II MHC molecules
    International immunology, 1999
    Co-Authors: Masha Fridkis-hareli, Michael Sela, Ruth Arnon, Rina Aharoni, Dvora Teitelbaum, Jack L. Strominger
    Abstract:

    Copolymer 1 [Cop 1, poly(Y,E,A,K)] is a random synthetic Amino Acid Copolymer of L-tyrotyrosine, L-glutamic Acid, L-alanine and L-lysilysine, effective both in suppression of experimental allergic enceencephalomyelitis and in the treatment of relapsing forms of multiple sclerosis. Cop 1 binds promiscuously and very efficiently to purified human HLA-DR molecules within the peptide-binding groove. In the present study the binding of Copolymers composed of three of the four Amino Acids found in poly(Y,E,A,K) to purified class II MHC molecules was examined. Poly(Y,A,K) and poly(Y,E,A,K) bound to purified human HLA-DR1 or -DR4 molecules with affinity higher than poly(Y,E,A), poly(E,A,K) or poly(Y,E,K), whereas poly(Y,E,A,K) and poly(E,A,K) were the better binders of HLA-DR2 molecules. On the other hand, poly(Y,E,A) and poly(Y,A,K) inhibited the binding of biotinylated poly(Y,E,A,K) to these molecules 10-fold more efficiently than poly(Y,E,K). Finally, poly(Y,E,A), poly(Y,A,K) and poly(E,A,K) were cross-reactive with poly(Y,E,A,K) using YEAK-specific T cell lines and clones of mouse or human origin.

Ruth Arnon – One of the best experts on this subject based on the ideXlab platform.

  • Glatiramer Acetate: from Bench to Bed and Back.
    The Israel Medical Association journal : IMAJ, 2019
    Co-Authors: Ruth Arnon, Rina Aharoni
    Abstract:

    Abstract The Amino Acid Copolymer glatiramer acetate (GA; Copaxone®, Copolymer1, Cop 1) is an approved drug for the treatment of relapsing-remitting multiple sclerosis (MS). Its efficacy in reducing the frequency of exacerbations and its high safety profile establish it as a first-line therapy for MS. Evidence from the animal model experimental autoimmune enceencephalomyelitis and from MS patients indicates that GA affects various levels of the immune response, inducing deviation from the proinflammatory to the antiinflammatory pathways. This includes the induction of Th2/3 and T regulatory cells and downregulation of both Th1 and Th17 cells. The immune cells induced by GA reach the central nervous system (CNS) and secrete in situ antiinflammatory cytokines, alleviating the pathological processes. In addition to its immunomodulatory activities GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis, indicating that repair process in the CNS can be upregulated by therapy.

  • Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy.
    Multiple sclerosis (Houndmills Basingstoke England), 2003
    Co-Authors: Dvora Teitelbaum, M Sela, Rina Aharoni, T Brenner, Oded Abramsky, Ruth Arnon
    Abstract:

    Glatiramer acetate (GA) previously known as Copolymer 1 (Cop 1), a synthetic Amino Acid Copolymer, suppresses experimental autoimmune enceencephalomyelitis (EAE) and shows a beneficial effect in relapsing-remitting type of multiple sclerosis (MS). GA acts as a specific immunomodulator by binding to MHC Class II molecules, inducing specific T suppressor (Ts) cells and interfering with T cell responses to myelin antigens. MS patients treated with GA developed GA reactive antibodies, which peaked at three months and decreased at six months. In order to find out whether anti-GA antibodies may neutralize the therapeutic effect of GA, we tested both polyclonal (mouse and human) and monoclonal GA specific antibodies for their ability to interfere with the biological activity of GA in several assay systems. None of the antibodies interfered with GA activities either in vitro (binding to MHC molecules and T cell stimulation) or in vivo (blocking of EAE). Furthermore, 53 samples of sera obtained from 34 MS patients that participated in the open label trial in Israel, and all developed GA specific antibodies, were tested for their ability to inhibit the proliferation response of GA specific Ts cell clone and to interfere with GA competitive inhibition of the response to peptide 84-102 of myelin basic protprotein (MBP). None of the sera inhibited and some even enhanced the in vitro activities of GA. Furthermore, representative MS sera with high titer of GA reactive antibodies did not neutralize the biological activities of GA and did not inhibit Th2 cytokine secretion by human GA specific clone. These results are consistent with the findings that the therapeutic effect of GA is not affected by GA reactive antibodies and is sustained upon long term treatment.

  • Copolymer 1 acts against the immunodominant epitope 82–100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Rina Aharoni, Ruth Arnon, Dvora Teitelbaum, Michael Sela
    Abstract:

    The synthetic random Amino Acid Copolymer Copolymer 1 (Cop 1, Copaxone, glatiramer acetate) suppresses experimental autoimmune encephalomyelitis, slows the progression of disability, and reduces relapse rate in multiple sclerosis (MS). Cop 1 binds to various class II major histocompatibility complex (MHC) molecules and inhibits the T cell responses to several myelin antigens. In this study we attempted to find out whether, in addition to MHC blocking, Cop 1, which is immunologically cross-reactive with myelin basic protein (MBP), inhibits the response to this autoantigen by T cell receptor (TCR) antagonism. Two experimental systems, “prepulse assay” and “split APC assay,” were used to discriminate between competition for MHC molecules and TCR antagonism. The results in both systems using T cell lines/clones from mouse and human origin indicated that Cop 1 is a TCR antagonist of the 82–100 epitope of MBP. In contrast to the broad specificity of the MHC blocking induced by Cop 1, its TCR antagonistic activity was restricted to the 82–100 determinant of MBP and could not be demonstrated for proteolipid protein peptide or even for other MBP epitopes. Yet, it was shown for all the MBP 82–100-specific T cell lines/clones tested that were derived from mice as well as from an MS patient. The ability of Cop 1 to act as altered peptide and induce TCR antagonistic effect on the MBP p82–100 immunodominant determinant response elucidates further the mechanism of Cop 1 therapeutic activity in experimental autoimmune encephalomyelitis and MS.

Yonggang Yan – One of the best experts on this subject based on the ideXlab platform.

  • experimental study on repair of large segmental bone defects of goat femur by nano calcium deficient hydroxyapatite multi Amino Acid Copolymer membrane tubes
    Journal of Biomaterials Applications, 2021
    Co-Authors: Yan Xiong, Hong Duan, Bin Zhang, Cheng Ren, Yonggang Yan
    Abstract:

    ObjectiveThe purpose of this study was to observe feasibility of nano calcium-deficient hydroxyapatite-multi (Amino Acid) Copolymer (n-CDHA-MAC) membrane tubes in repairing goat femurs’ large defec…

  • © 2013 Duan et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
    , 2016
    Co-Authors: Hong Duan, Yonggang Yan, Yan Xiong, Bin Zhang, Cheng Ren, Hong-sheng Yang, Li Min, Wenli Zhang, Fuxing Pei
    Abstract:

    which permits unrestricted noncommercial use, provided the original work is properly cited. International Journal of Nanomedicine 2013:8 2801–2807 International Journal of Nanomedicine Effects of mechanical loading on the degradability and mechanical properties of the nanocalcium-deficient hydroxyapatite–multi(Amino Acid) Copolymer composite membrane tube for guided bone regeneratio

  • Degradability and cytocompatibility of tricalcium phosphate/poly(Amino Acid) composite as bone tissue implants in orthopaedic surgery
    Journal of biomaterials science. Polymer edition, 2014
    Co-Authors: Songchao Tao, Yonggang Yan, Xiaoman Luo, Lili Yang, Jie Wei
    Abstract:

    In this study, a tricalcium phosphate (TCP) and poly (Amino Acid) Copolymer (PAA) biocomposite were fabricated for bone repair and characterized. The results show that the compressive strength of the TCP/PAA composites increased with an increase in the TCP content at TCP contents less than 40 w%. The weight loss of the composite after soaking in phosphate buffered saline for 12 weeks significantly increased with an increase in the TCP content, revealing its good degradability. In addition, the composite maintained adequate mechanical strength during the degradation period because it underwent a surface erosion process. In vitro MG63 cell culture experiments showed that the composite is non-cytotoxic and thus allows cells to adhere, proliferate and differentiate. Osteoid formation was evidenced on the composite surfaces 12 weeks after its implantation into the femoral bone of dogs. Furthermore, the composite combined directly with the host bone tissue without fibrous capsule tissue, and no inflammatory responses were found, showing the good biocompatibility of the composite. It is expected that the composite may be used for the development of bone implants for orthopaedic surgery.

Masha Fridkis-hareli – One of the best experts on this subject based on the ideXlab platform.

  • Design of peptide immunotherapies for MHC Class-II-associated autoimmune disorders.
    Clinical & developmental immunology, 2013
    Co-Authors: Masha Fridkis-hareli
    Abstract:

    Autoimmune disorders, that occur when autoreactive immune cells are induced to activate their responses against self-tissues, affect one percent of the world population and represent one of the top 10 leading causes of death. The major histocompatibility complex (MHC) is a principal susceptibility locus for many human autoimmune diseases, in which self-tissue antigens providing targets for pathogenic lymphocytes are bound to HLA molecules encoded by disease-associated alleles. In spite of the attempts to design strategies for inhibition of antigen presentation targeting the MHC-peptide/TCR complex via generation of blocking antibodies, altered peptide ligands (APL), or inhibitors of costimulatory molecules, potent therapies with minimal side effects have yet to be developed. Copaxone (glatiramer acetate, GA) is a random synthetic Amino Acid Copolymer that reduces the relapse rate by about 30% in relapsing-remitting multiple sclerosis (MS) patients. Based on the elucidated binding motifs of Copaxone and of the anchor residues of the immunogenic myelin basic protprotein (MBP) peptide to HLA-DR molecules, novel Copolymers have been designed and proved to be more effective in suppressing MS-like disease in mice. In this report, we describe the rationale for design of second-generation synthetic random Copolymers as candidate drugs for a number of MHC class-II-associated autoimmune disorders.

  • Peptide 15-mers of defined sequence that substitute for random Amino Acid Copolymers in amelioration of experimental autoimmune encephalomyelitis
    Proceedings of the National Academy of Sciences of the United States of America, 2005
    Co-Authors: Joel N. H. Stern, Masha Fridkis-hareli, Derin B. Keskin, Zsolt Illes, Jayagopala Reddy, Vijay K. Kuchroo, Jack L. Strominger
    Abstract:

    Myelin basic protprotein (MBP) is a major candidate autoantigen in multiple sclerosis (MS). Its immunodominant epitope, MBP 85-99, forms a complex with human leukocyte antigen (HLA)-DR2 with which multiple sclerosis is genetically associated. Copolymer 1 (Copaxone), a random Amino Acid Copolymer [poly (Y,E,A,K)n] as well as two modified synthetic Copolymers [poly (F,Y,A,K)n and poly (V,W,A,K)n] also form complexes with HLA-DR2 (DRA/DRB1*1501) and compete with MBP 85-99 for binding. Moreover, two high-affinity synthetic peptide 15-mers that could inhibit binding even more effectively were previously designed. Here, we show that further-modified peptide 15-mers inhibited even more strongly (in order J5 > J3 > J2) both the binding of MBP 85-99 to HLA-DR2 and IL-2 production by two MBP 85-99-specific HLA-DR2-restricted T cells. J5, J3, and J2 also suppressed both MBP 85-99-induced experimental autoimmune enceencephalomyelitis (EAE) in humanized mice and proteolipid protein 139-151-induced EAE in SJL/J mice. Moreover, none of these previously uncharacterized peptide inhibitors crossreacted with MBP 85-99- or proteolipid protein 139-151-specific T cells. In both cases, spleen and lymph node cultures stimulated with these peptides produced large amounts of Th2 cytokines (IL-4 and IL-10), and adoptive transfer of established T cell lines suppressed disease induction. These peptide 15-mers provide specific, nonrandom sequences that appear to be at least as effective as random Copolymers in suppressing EAE in several models.

  • Synthetic peptides that inhibit binding of the myelin basic protein 85-99 epitope to multiple sclerosis-associated HLA-DR2 molecules and MBP-specific T-cell responses
    Human Immunology, 2001
    Co-Authors: Masha Fridkis-hareli, Joel N. H. Stern, Lars Fugger, Jack L. Strominger
    Abstract:

    Abstract Copolymer 1 (Cop 1, poly [Y, E, A, K]) is a random synthetic Amino Acid Copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS), a disease that is linked to HLA-DR2 (DRB1∗1501). In the present study various peptides, synthesized according to the binding motifs for both the immunodominant epitope of myelin basic protprotein (MBP) 85-99, a candidate autoantigen in MS, and Cop 1, differentially inhibited binding of these antigens to disease-associated HLA-DR2 (DRB1∗1501) molecules. In particular, two peptides with residue K at position P-1, as referred to MBP 85-99, inhibited effectively the binding of both biotinylated MBP 85-99 and Cop 1 to HLA-DR2 molecules as well as IL-2 production by two MBP-specific HLA-DR2-restricted T-cell clones. These findings suggest the possible utility of these compounds or their more stable derivatives in treatment of MS.