Publications
Glatiramer acetate: mechanisms of action in multiple sclerosis.
Int Rev Neurobiol.
Ziemssen T, Schrempf W.
Multiple Sclerosis Center Dresden, Neurological University Clinic Dresden University of Technology, Dresden 01307, Germany.
Glatiramer acetate (GA), formerly known as copolymer 1, is a mixture of synthetic polypeptides composed of four amino acids resembling the myelin basic protein (MSP). GA has been shown to be highly effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Therefore, it was tested in several clinical studies and so approved for the immunomodulatory treatment of relapsing-type MS. In contrast to other immunomodulatory MS therapies, GA has a distinct mechanism of action: GA demonstrates an initial strong promiscuous binding to major histocompatibility complex molecules and consequent competition with various (myelin) antigens for their presentation to T cells. In addition, antigen-based therapy generating a GA-specific immune response seems to be the prerequisite for GA therapy. GA treatment induces an in vivo change of the frequency, cytokine secretion pattern and the effector function of GA-specific CD4+ and CD8+ T cells, probably by affecting the properties of antigen-presenting cells such as monocytes and dendritic cells. As demonstrated extensively in animal experiments, GA-specific, mostly, T helper 2 cells migrate to the brain and lead to in situ bystander suppression of the inflammatory process in the brain. Furthermore, GA-specific cells in the brain express neurotrophic factors like the brain-derived neurotrophic factor (BDNF) in addition to anti-inflammatory T helper 2-like cytokines. This might help tip the balance in favor of more beneficial influences because there is a complex interplay between detrimental and beneficial factors and mediators in the inflammatory milieu of MS lesions.
Multiple Sclerosis Center Dresden, Neurological University Clinic Dresden University of Technology, Dresden 01307, Germany.
Glatiramer acetate (GA), formerly known as copolymer 1, is a mixture of synthetic polypeptides composed of four amino acids resembling the myelin basic protein (MSP). GA has been shown to be highly effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Therefore, it was tested in several clinical studies and so approved for the immunomodulatory treatment of relapsing-type MS. In contrast to other immunomodulatory MS therapies, GA has a distinct mechanism of action: GA demonstrates an initial strong promiscuous binding to major histocompatibility complex molecules and consequent competition with various (myelin) antigens for their presentation to T cells. In addition, antigen-based therapy generating a GA-specific immune response seems to be the prerequisite for GA therapy. GA treatment induces an in vivo change of the frequency, cytokine secretion pattern and the effector function of GA-specific CD4+ and CD8+ T cells, probably by affecting the properties of antigen-presenting cells such as monocytes and dendritic cells. As demonstrated extensively in animal experiments, GA-specific, mostly, T helper 2 cells migrate to the brain and lead to in situ bystander suppression of the inflammatory process in the brain. Furthermore, GA-specific cells in the brain express neurotrophic factors like the brain-derived neurotrophic factor (BDNF) in addition to anti-inflammatory T helper 2-like cytokines. This might help tip the balance in favor of more beneficial influences because there is a complex interplay between detrimental and beneficial factors and mediators in the inflammatory milieu of MS lesions.
TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1.
Nat Med.
Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, Gery I, Lee YS, Egwuagu CE.
Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
T-helper type 17 cells (T(H)17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T(H)17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-gamma. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-alpha in retinal cells, suggesting a mechanism by which T(H)17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-gamma and inhibited proliferation of T(H)17. These findings suggest that T(H)1 cells may mitigate uveitis by antagonizing the T(H)17 phenotype through the IFN-gamma-mediated induction of IL-27 in target tissue. The finding that IL-2 promotes T(H)17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of T(H)17 by IFN-gamma and/or IL-27 could be used for the treatment of chronic inflammation.
Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
T-helper type 17 cells (T(H)17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T(H)17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-gamma. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-alpha in retinal cells, suggesting a mechanism by which T(H)17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-gamma and inhibited proliferation of T(H)17. These findings suggest that T(H)1 cells may mitigate uveitis by antagonizing the T(H)17 phenotype through the IFN-gamma-mediated induction of IL-27 in target tissue. The finding that IL-2 promotes T(H)17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of T(H)17 by IFN-gamma and/or IL-27 could be used for the treatment of chronic inflammation.
Production of brain-derived neurotrophic factor by mononuclear cells of patients with multiple sclerosis treated with glatiramer acetate, interferon-beta 1a, and high doses of immunoglobulins.
Mult Scler.
Sarchielli P, Zaffaroni M, Floridi A, Greco L, Candeliere A, Mattioni A, Tenaglia S, Di Filippo M, Calabresi P.
Neurologic Clinic, Department of Medical and Surgical Specialties and Public Health, University of Perugia, Perugia 06158, Italy. neuro.pg@tiscalinet.it
Sixty, relapsing remitting (RR) multiple sclerosis (MS) patients, who underwent treatment with glatiramer acetate (GA), interferon (IFN)-beta 1a, and immunoglobulins (Igs) (20 per treatment group), were assessed for levels of brain-derived neurotrophic factor (BDNF) in the supernatants of unstimulated and stimulated peripheral blood mononuclear cells (PBMCs) in the first year of treatment. Phytohemagglutinin (PHA), anti-OKT3 antibody, myelin basic protein (MPB) and GA were used as stimuli. Cytokine responses by ELISPOT and lymphoproliferative responses were also assessed. The GA-treated MS patient group showed a progressive increase in BDNF levels, from baseline to month three; thereafter, the levels remained stable and significantly greater compared with baseline and controls (ANOVA=P<0.001). IFN-beta 1a had no effect on BDNF production, whereas Igs induced a slight decrease (ANOVA=P<0.04). ELISPOT analysis revealed a significant decrease of IFN-gamma, an increase of interleukin (IL)-4 and IL-5 in GA-treated MS patients, and an increase of IL-10 in patients treated with IFN-beta 1a and GA. No significant correlation was found between BDNF secretion in the supernatants of PBMCs and cytokine response, lesional load, and measures of atrophy. Increased BDNF production related to GA treatment can have implications for understanding the mechanism of action of this immunomodulatory agent, in light of evidence suggesting its effects in promoting neuroprotective immunity in MS patients; however, a clinically measurable effect, especially in terms of an impact on actual disease progression, remains to be established.
Neurologic Clinic, Department of Medical and Surgical Specialties and Public Health, University of Perugia, Perugia 06158, Italy. neuro.pg@tiscalinet.it
Sixty, relapsing remitting (RR) multiple sclerosis (MS) patients, who underwent treatment with glatiramer acetate (GA), interferon (IFN)-beta 1a, and immunoglobulins (Igs) (20 per treatment group), were assessed for levels of brain-derived neurotrophic factor (BDNF) in the supernatants of unstimulated and stimulated peripheral blood mononuclear cells (PBMCs) in the first year of treatment. Phytohemagglutinin (PHA), anti-OKT3 antibody, myelin basic protein (MPB) and GA were used as stimuli. Cytokine responses by ELISPOT and lymphoproliferative responses were also assessed. The GA-treated MS patient group showed a progressive increase in BDNF levels, from baseline to month three; thereafter, the levels remained stable and significantly greater compared with baseline and controls (ANOVA=P<0.001). IFN-beta 1a had no effect on BDNF production, whereas Igs induced a slight decrease (ANOVA=P<0.04). ELISPOT analysis revealed a significant decrease of IFN-gamma, an increase of interleukin (IL)-4 and IL-5 in GA-treated MS patients, and an increase of IL-10 in patients treated with IFN-beta 1a and GA. No significant correlation was found between BDNF secretion in the supernatants of PBMCs and cytokine response, lesional load, and measures of atrophy. Increased BDNF production related to GA treatment can have implications for understanding the mechanism of action of this immunomodulatory agent, in light of evidence suggesting its effects in promoting neuroprotective immunity in MS patients; however, a clinically measurable effect, especially in terms of an impact on actual disease progression, remains to be established.
Randomized, double-blind, dose-comparison study of glatiramer acetate in relapsing-remitting MS.
Nat Clin Pract Neurol
Cohen JA, Rovaris M, Goodman AD, Ladkani D, Wynn D, Filippi M; 9006 Study Group.
Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. cohenj@ccf.org
OBJECTIVE: To evaluate the safety, tolerability, and efficacy of glatiramer acetate (GA) 40 mg daily vs the approved 20-mg formulation in relapsing-remitting multiple sclerosis. METHODS: Eligibility criteria included clinically definite multiple sclerosis, Expanded Disability Status Scale score 0 to 5.0, no previous use of GA, at least one relapse in the previous year, and 1 to 15 gadolinium-enhancing (GdE) lesions on a screening MRI. MRI was repeated at months 3, 7, 8, and 9, and neurologic examinations were performed at baseline and months 3, 6, and 9. RESULTS: Of 229 subjects screened, 90 were randomly assigned to GA 20 mg (n = 44) or 40 mg (n = 46). The groups were well matched at baseline for demographic, clinical, and MRI characteristics. The primary efficacy endpoint, total number of GdE lesions at months 7, 8, and 9, showed a trend favoring the 40-mg group (38% relative reduction, p = 0.0898). A difference between the two dose groups emerged as early as month 3 (52% reduction; p = 0.0051). There was a trend favoring the 40-mg group for relapse rate with benefit on proportion of relapse-free subjects (p = 0.0183) and time to first relapse (p = 0.0367). GA 40 mg was well tolerated, with an overall safety profile similar to that of 20 mg. Some features of injection site reactions and immediate postinjection reactions were more common and severe with the higher dose. CONCLUSIONS: Glatiramer acetate (GA) 40 mg was safe and well tolerated. The overall efficacy results suggested that a 40-mg dose of GA may be more effective than the currently approved 20-mg daily dose in reducing MRI activity and clinical relapses.
Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. cohenj@ccf.org
OBJECTIVE: To evaluate the safety, tolerability, and efficacy of glatiramer acetate (GA) 40 mg daily vs the approved 20-mg formulation in relapsing-remitting multiple sclerosis. METHODS: Eligibility criteria included clinically definite multiple sclerosis, Expanded Disability Status Scale score 0 to 5.0, no previous use of GA, at least one relapse in the previous year, and 1 to 15 gadolinium-enhancing (GdE) lesions on a screening MRI. MRI was repeated at months 3, 7, 8, and 9, and neurologic examinations were performed at baseline and months 3, 6, and 9. RESULTS: Of 229 subjects screened, 90 were randomly assigned to GA 20 mg (n = 44) or 40 mg (n = 46). The groups were well matched at baseline for demographic, clinical, and MRI characteristics. The primary efficacy endpoint, total number of GdE lesions at months 7, 8, and 9, showed a trend favoring the 40-mg group (38% relative reduction, p = 0.0898). A difference between the two dose groups emerged as early as month 3 (52% reduction; p = 0.0051). There was a trend favoring the 40-mg group for relapse rate with benefit on proportion of relapse-free subjects (p = 0.0183) and time to first relapse (p = 0.0367). GA 40 mg was well tolerated, with an overall safety profile similar to that of 20 mg. Some features of injection site reactions and immediate postinjection reactions were more common and severe with the higher dose. CONCLUSIONS: Glatiramer acetate (GA) 40 mg was safe and well tolerated. The overall efficacy results suggested that a 40-mg dose of GA may be more effective than the currently approved 20-mg daily dose in reducing MRI activity and clinical relapses.
Immunomodulatory therapeutic effect of glatiramer acetate on several murine models of inflammatory bowel disease.
J Pharmacol Exp Ther.
Aharoni R, Kayhan B, Brenner O, Domev H, Labunskay G, Arnon R.
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel 76100.
Inflammatory bowel disease (IBD) is characterized by detrimental immune reactivity in the gut and imbalance between proinflammatory and anti-inflammatory reactivity. In an attempt to down-regulate colitis, we investigated the effect of the immunomodulator glatiramer acetate (GA, Copaxone, copolymer 1) on two murine models of IBD, chemically induced and spontaneous. Acute experimental colitis of different levels of severity was induced in C57BL/6 mice by dextran sulfate sodium (DSS) administered orally at different concentrations and frequencies. It was manifested in weight loss, intestinal bleeding, and diarrhea, as well as by macroscopic and microscopic colon damage. GA treatment led to amelioration of all of these pathological manifestations, resulting in improved long-term survival. Moreover, even when colitis was induced by three cycles of DSS in this highly susceptible mouse strain, as well as in BALB/c mice that exhibit a chronic disease pattern, a substantial reduction in disease activity and mortality was obtained. GA treatment induced a beneficial effect also in a spontaneous model of colitis developed in the C3H/HeJBir IL-10-deficient mice. The detrimental proinflammatory response manifested by proliferation, tumor necrosis factor-alpha, and interferon-gamma expression was modulated by GA, whereas the regulatory anti-inflammatory transforming growth factor-beta and IL-10 cytokines response was elevated. This was demonstrated on the level of protein secretion in splenocytes and local mesenteric lymphocytes in response to syngeneic colon extract and in the overall response to anti-CD3, as well as on the level of mRNA expression in the colon.
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel 76100.
Inflammatory bowel disease (IBD) is characterized by detrimental immune reactivity in the gut and imbalance between proinflammatory and anti-inflammatory reactivity. In an attempt to down-regulate colitis, we investigated the effect of the immunomodulator glatiramer acetate (GA, Copaxone, copolymer 1) on two murine models of IBD, chemically induced and spontaneous. Acute experimental colitis of different levels of severity was induced in C57BL/6 mice by dextran sulfate sodium (DSS) administered orally at different concentrations and frequencies. It was manifested in weight loss, intestinal bleeding, and diarrhea, as well as by macroscopic and microscopic colon damage. GA treatment led to amelioration of all of these pathological manifestations, resulting in improved long-term survival. Moreover, even when colitis was induced by three cycles of DSS in this highly susceptible mouse strain, as well as in BALB/c mice that exhibit a chronic disease pattern, a substantial reduction in disease activity and mortality was obtained. GA treatment induced a beneficial effect also in a spontaneous model of colitis developed in the C3H/HeJBir IL-10-deficient mice. The detrimental proinflammatory response manifested by proliferation, tumor necrosis factor-alpha, and interferon-gamma expression was modulated by GA, whereas the regulatory anti-inflammatory transforming growth factor-beta and IL-10 cytokines response was elevated. This was demonstrated on the level of protein secretion in splenocytes and local mesenteric lymphocytes in response to syngeneic colon extract and in the overall response to anti-CD3, as well as on the level of mRNA expression in the colon.
