The Experts below are selected from a list of 249 Experts worldwide ranked by ideXlab platform
Jack L. Strominger - One of the best experts on this subject based on the ideXlab platform.
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Proliferation, cytokine secretion, and immunosuppressive activity of YFAK-specific regulatory T cells. (THER3P.885)
Journal of Immunology, 2014Co-Authors: Jack L. StromingerAbstract: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 encephalomyelitis (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.
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Inhibition of experimental autoimmune uveitis by Amino Acid Copolymers.
Journal of neuroimmunology, 2009Co-Authors: Hongen Yin, Jack L. Strominger, Barbara P Vistica, Chi-chao Chan, Igal GeryAbstract: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 encephalomyelitis (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.
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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, 2009Co-Authors: Hong Zhang, Joel N. H. Stern, Jack L. StromingerAbstract: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 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.
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Amino Acid Copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Joel N. H. Stern, Derin B. Keskin, Hong Zhang, Zenichiro Kato, Jack L. StromingerAbstract: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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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, 2005Co-Authors: Joel N. H. Stern, Masha Fridkis-hareli, Derin B. Keskin, Zsolt Illes, Jayagopala Reddy, Vijay K. Kuchroo, Jack L. StromingerAbstract:Myelin basic protein (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 encephalomyelitis (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.
Michael Sela - One of the best experts on this subject based on the ideXlab platform.
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Binding Motifs of Copolymer 1 to Multiple Sclerosis- and Rheumatoid Arthritis-Associated HLA-DR Molecules
Journal of immunology (Baltimore Md. : 1950), 1999Co-Authors: Masha Fridkis-hareli, Michael Sela, John M. Neveu, Renee A. Robinson, William S. Lane, Laurent Gauthier, Kai W. Wucherpfennig, Jack L. StromingerAbstract: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.
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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, 1999Co-Authors: Rina Aharoni, Ruth Arnon, Dvora Teitelbaum, Michael SelaAbstract: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.
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The concept of specific immune treatment against autoimmune diseases.
International reviews of immunology, 1999Co-Authors: Michael SelaAbstract:Copolymer 1 (Cop 1, Copaxone) is a synthetic Amino Acid Copolymer effective in suppression of experimental allergic encephalomyelitis (EAE). The suppressive effect of Cop 1 in EAE is not restricted to a certain species, disease type or encephalitogen used for EAE induction. In phases II and III clinical trials Cop 1 was found to slow progression of disability and reduce the relapse rate in exacerbating-remitting multiple sclerosis (MS) patients. To extend this concept we have more recently shown that a similar approach is possible in the case of myasthenia gravis. We used two myasthenogenic T cell epitopes of the human acetylcholine receptor alpha-subunit and demonstrated that they are capable of triggering peripheral blood lymphocytes of the majority (>80%) of myasthenic patients tested. Both single Amino Acid analogs, and a dual analog composed of the tandemly arranged two single Amino Acid analogs were able to inhibit in vitro proliferative responses of T cell lines, and in vivo priming of lymph node cells. The dual analog inhibited experimental autoimmune myasthenia gravis even when the mice were treated fourteen days after the injection of the pathogenic T cell line.
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Binding of random Copolymers of three Amino Acids to class II MHC molecules
International immunology, 1999Co-Authors: Masha Fridkis-hareli, Michael Sela, Ruth Arnon, Rina Aharoni, Dvora Teitelbaum, Jack L. StromingerAbstract:Copolymer 1 [Cop 1, poly(Y,E,A,K)] is a random synthetic Amino Acid Copolymer of L-tyrosine, L-glutamic Acid, L-alanine and L-lysine, effective both in suppression of experimental allergic encephalomyelitis 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.
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Specific vaccines against autoimmune diseases.
Comptes rendus de l'Academie des sciences. Serie III Sciences de la vie, 1999Co-Authors: Michael SelaAbstract:Copolymer 1 (Cop 1, Copaxone) is a synthetic Amino Acid Copolymer effective in suppression of experimental allergic encephalomyelitis (EAE). The suppressive effect of Cop 1 in EAE is not restricted to a certain species, disease type or encephalitogen used for EAE induction. In phase II and III clinical trials, Cop 1 was found to slow the progression of disability and reduce the relapse rate in exacerbating-remitting multiple sclerosis (MS) patients. In vivo and in vitro studies suggest that the mechanism for Cop 1 activity in EAE and MS involves, as an initial step, the binding of Cop 1 to MHC class II molecules. This binding results in competition with myelin antigens for T-cell activation, both at the MHC and T-cell receptor levels and in induction of specific suppressor cells of the Th2 type. As an antigen-specific intervention, Cop 1 has the advantage of reduced probability for long-term damage to the immune system, and is thus a safe and effective novel therapeutic approach to MS. It also serves to illustrate the new concept of a drug/vaccine specific for a single autoimmune disease. Indeed, we have used a similar approach for myasthenia gravis. Myasthenia gravis (MG) and its experimental animal model, experimental autoimmune MG (EAMG), are immune disorders characterized by circulating antibodies and lymphocyte autoreactivity to nicotinic acetylcholine receptor (AChR). We utilized peptides representing different sequences of the human acetylcholine receptor alpha-subunit to study the role of T cells in the initiation, development and immunomodulation of myasthenia gravis. Here we summarize our studies over the last decade on T cells specific to 'myasthenogenic' epitopes of the alpha-subunit of the human acetylcholine receptor and their relevance for myasthenia gravis.
Ruth Arnon - One of the best experts on this subject based on the ideXlab platform.
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Glatiramer Acetate: from Bench to Bed and Back.
The Israel Medical Association journal : IMAJ, 2019Co-Authors: Ruth Arnon, Rina AharoniAbstract: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 encephalomyelitis 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.
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Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy.
Multiple sclerosis (Houndmills Basingstoke England), 2003Co-Authors: Dvora Teitelbaum, M Sela, Rina Aharoni, T Brenner, Oded Abramsky, Ruth ArnonAbstract:Glatiramer acetate (GA) previously known as Copolymer 1 (Cop 1), a synthetic Amino Acid Copolymer, suppresses experimental autoimmune encephalomyelitis (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 protein (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.
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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, 1999Co-Authors: Rina Aharoni, Ruth Arnon, Dvora Teitelbaum, Michael SelaAbstract: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.
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Binding of random Copolymers of three Amino Acids to class II MHC molecules
International immunology, 1999Co-Authors: Masha Fridkis-hareli, Michael Sela, Ruth Arnon, Rina Aharoni, Dvora Teitelbaum, Jack L. StromingerAbstract:Copolymer 1 [Cop 1, poly(Y,E,A,K)] is a random synthetic Amino Acid Copolymer of L-tyrosine, L-glutamic Acid, L-alanine and L-lysine, effective both in suppression of experimental allergic encephalomyelitis 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.
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Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Rina Aharoni, Michael Sela, Dvora Teitelbaum, Ruth ArnonAbstract:The synthetic Amino Acid Copolymer Copolymer 1 (Cop 1) suppresses experimental autoimmune encephalomyelitis (EAE) and is beneficial in multiple sclerosis. To further understand Cop 1 suppressive activity, we studied the cytokine secretion profile of various Cop 1-induced T cell lines and clones. Unlike T cell lines induced by myelin basic protein (MBP), which secreted either T cell helper type 1 (Th1) or both Th1 and Th2 cytokines, the T cell lines/clones induced by Cop 1 showed a progressively polarized development toward the Th2 pathway, until they completely lost the ability to secrete Th1 cytokines. Our findings indicate that the polarization of the Cop 1-induced lines did not result from the immunization vehicle or the in vitro growing conditions, but rather from the tendency of Cop 1 to preferentially induce a Th2 response. The response of all of the Cop 1 specific lines/clones, which were originated in the (SJL/J×BALB/c)F1 hybrids, was restricted to the BALB/c parental haplotype. Even though the Cop 1-induced T cells had not been exposed to the autoantigen MBP, they crossreacted with MBP by secretion of interleukin (IL)-4, IL-6, and IL-10. Administration of these T cells in vivo resulted in suppression of EAE induced by whole mouse spinal cord homogenate, in which several autoantigens may be involved. Secretion of anti-inflammatory cytokines by Cop 1-induced suppressor cells, in response to either Cop 1 or MBP, may explain the therapeutic effect of Cop 1 in EAE and in multiple sclerosis.
Yonggang Yan - One of the best experts on this subject based on the ideXlab platform.
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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, 2021Co-Authors: Yan Xiong, Hong Duan, Bin Zhang, Cheng Ren, Yonggang YanAbstract: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...
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© 2013 Duan et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
2016Co-Authors: Hong Duan, Yonggang Yan, Yan Xiong, Bin Zhang, Cheng Ren, Hong-sheng Yang, Li Min, Wenli Zhang, Fuxing PeiAbstract: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
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Degradability and cytocompatibility of tricalcium phosphate/poly(Amino Acid) composite as bone tissue implants in orthopaedic surgery
Journal of biomaterials science. Polymer edition, 2014Co-Authors: Songchao Tao, Yonggang Yan, Xiaoman Luo, Lili Yang, Jie WeiAbstract: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.
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Preparation and properties of BSA-loaded microspheres based on multi-(Amino Acid) Copolymer for protein delivery.
International journal of nanomedicine, 2014Co-Authors: Xingtao Chen, Yonggang Yan, Jue Zhang, Songchao Tang, Su Jiacan, Jie WeiAbstract:A multi-(Amino Acid) Copolymer (MAC) based on ω-Aminocaproic Acid, γ-Aminobutyric Acid, L-alanine, L-lysine, L-glutamate, and hydroxyproline was synthetized, and MAC microspheres encapsulating bovine serum albumin (BSA) were prepared by a double-emulsion solvent extraction method. The experimental results show that various preparation parameters including surfactant ratio of Tween 80 to Span 80, surfactant concentration, benzyl alcohol in the external water phase, and polymer concentration had obvious effects on the particle size, morphology, and encapsulation efficiency of the BSA-loaded microspheres. The sizes of BSA-loaded microspheres ranged from 60.2 μm to 79.7 μm, showing different degrees of porous structure. The encapsulation efficiency of BSA-loaded microspheres also ranged from 38.8% to 50.8%. BSA release from microspheres showed the classic biphasic profile, which was governed by diffusion and polymer erosion. The initial burst release of BSA from microspheres at the first week followed by constant slow release for the next 7 weeks were observed. BSA-loaded microspheres could degrade gradually in phosphate buffered saline buffer with pH value maintained at around 7.1 during 8 weeks incubation, suggesting that microsphere degradation did not cause a dramatic pH drop in phosphate buffered saline buffer because no Acidic degradation products were released from the microspheres. Therefore, the MAC microspheres might have great potential as carriers for protein delivery.
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Composite scaffolds of nano calcium deficient hydroxyapatite/multi-(Amino Acid) Copolymer for bone tissue regeneration
Journal of materials science. Materials in medicine, 2014Co-Authors: Lili Yang, Xieping Dong, Yonggang YanAbstract:In this study, nano calcium deficient hydroxyapatite (n-DA)/multi-(Amino Acid) Copolymer composite scaffolds were prepared by injection molding foaming method using calcium sulphate dihydrate as a foaming agent. The composite scaffolds showed well interconnected macropores with the pore size of ranging from 100 to 600 μm, porosity of 81 % and compressive strength of 12 MPa, and the compressive strength obviously affected by the porosity. The composite scaffolds could be slowly degraded in phosphate buffered solution (PBS), which lost its initial weight of 61 w % after immersion into PBS for 12 weeks, and the porosity significantly affected the degradability of the scaffolds. Moreover, it was found that the composite scaffolds could promote the MG-63 cells growth and proliferation, and enhance its alkaline phosphatase activity. The implantation of the scaffolds into the femoral bone of rabbits confirmed that the composite scaffolds were biocompatibitive, degradable, and osteoconductive in vivo.
Masha Fridkis-hareli - One of the best experts on this subject based on the ideXlab platform.
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Design of peptide immunotherapies for MHC Class-II-associated autoimmune disorders.
Clinical & developmental immunology, 2013Co-Authors: Masha Fridkis-hareliAbstract: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 protein (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.
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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, 2005Co-Authors: Joel N. H. Stern, Masha Fridkis-hareli, Derin B. Keskin, Zsolt Illes, Jayagopala Reddy, Vijay K. Kuchroo, Jack L. StromingerAbstract:Myelin basic protein (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 encephalomyelitis (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.
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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, 2001Co-Authors: Masha Fridkis-hareli, Lars Fugger, Joel N. H. Stern, Jack L. StromingerAbstract: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 protein (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.
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Synthetic peptides that inhibit binding of the collagen type II 261-273 epitope to rheumatoid arthritis-associated HLA-DR1 and -DR4 molecules and collagen-specific T-cell responses.
Human immunology, 2000Co-Authors: Masha Fridkis-hareli, Lars Fugger, Edward F. Rosloniec, Jack L. StromingerAbstract: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). Another Copolymer [poly (Y, A, K)] was also identified that binds to rheumatoid arthritis (RA)-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules and inhibits the response of HLA-DR1- and -DR4-restricted T cell clones to an immunodominant epitope of collagen type II (CII) 261-273 (a candidate autoantigen in RA). In the present study various peptides have been synthesized based on binding "motifs" of Cop 1 for HLA-DR1 and -DR4 molecules. Those peptides with K at P-1 or K at P8 were particularly effective as inhibitors of binding of CII 261-273, of Cop 1 and of the influenza virus hemagglutinin peptide 306-318 to these class II proteins. Moreover, several of them were also potent inhibitors of the CII 261-273-reactive T cell clones. These findings suggest that small peptides or their more stable derivatives may be able to substitute for Copolymers in the treatment of RA, and by implication of MS.
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Binding Motifs of Copolymer 1 to Multiple Sclerosis- and Rheumatoid Arthritis-Associated HLA-DR Molecules
Journal of immunology (Baltimore Md. : 1950), 1999Co-Authors: Masha Fridkis-hareli, Michael Sela, John M. Neveu, Renee A. Robinson, William S. Lane, Laurent Gauthier, Kai W. Wucherpfennig, Jack L. StromingerAbstract: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.
