Multiple sclerosis: Comparison of copolymer-1- reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells

275

181

Our group recently demonstrated that autoimmune T cells directed against central nervous system-associated myelin antigens protect neurons from secondary degeneration. We further showed that the synthetic peptide copolymer 1 (Cop-1), known to suppress experimental autoimmune encephalomyelitis, can be safely substituted for the natural myelin antigen in both passive and active immunization for neuroprotection of the injured optic nerve. Here we attempted to determine whether similar immunizations are protective from retinal ganglion cell loss resulting from a direct biochemical insult caused, for example, by glutamate (a major mediator of degeneration in acute and chronic optic nerve insults) and in a rat model of ocular hypertension. Passive immunization with T cells reactive to myelin basic protein or active immunization with myelin oligodendrocyte glycoprotein-derived peptide, although neuroprotective after optic nerve injury, was ineffective against glutamate toxicity in mice and rats. In contrast, the number of surviving retinal ganglion cells per square millimeter in glutamate-injected retinas was significantly larger in mice immunized 10 days previously with Cop-1 emulsified in complete Freund's adjuvant than in mice injected with PBS in the same adjuvant (2,133 ؎ 270 and 1,329 ؎ 121, respectively, mean ؎ SEM; P < 0.02). A similar pattern was observed when mice were immunized on the day of glutamate injection (1,777 ؎ 101 compared with 1,414 ؎ 36; P < 0.05), but not when they were immunized 48 h later. These findings suggest that protection from glutamate toxicity requires reinforcement of the immune system by antigens that are different from those associated with myelin. The use of Cop-1 apparently circumvents this antigen specificity barrier. In the rat ocular hypertension model, which simulates glaucoma, immunization with Cop-1 significantly reduced the retinal ganglion cell loss from 27.8% ؎ 6.8% to 4.3% ؎ 1.6%, without affecting the intraocular pressure. This study may point the way to a therapy for glaucoma, a neurodegenerative disease of the optic nerve often associated with increased intraocular pressure, as well as for acute and chronic degenerative disorders in which glutamate is a prominent participant.

Section: Discussionmentioning

confidence: 99%

Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: Implications for glaucoma

Schori

Kipnis

Yoles

et al. 2001

275

181

“…Currently, glatiramer acetate (GA), a random polymer of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine, is the only approved therapy for MS that is purported to act in a semiantigen-specific manner (24). GA is thought to induce T cells that produce T helper 2 cytokines, such as IL-4, IL-5, IL-10, and IL-13, which suppress inflammatory cells (25,26). GA treatment requires daily s.c. injections and is beneficial to only a minority of relapsing-remitting MS patients (27), and 10% of patients experience a transient systemic postinjection reaction characterized by flushing, chest tightness, palpitations, dyspnea, and anxiety (28).…”

Section: Discussionmentioning

confidence: 99%

Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis

Smith

Eagar

Strominger

et al. 2005

100

The ability of different forms of myelin peptides to induce tolerance for the treatment of preestablished murine experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, was evaluated. i.v. administration of myelin peptidepulsed, ethylene carbodiimide-fixed syngeneic splenocytes, but not soluble myelin peptide monomers or oligomers, proved exceedingly effective at treating preestablished EAE, resulting in amelioration of disease progression. In addition to the lack of therapeutic efficacy of soluble peptide and peptide oligomer, administering them i.v. after the onset of clinical symptoms in many but not all peptide-induced EAE models led to a rapid-onset anaphylactic reaction characterized by respiratory distress, erythema, decreased body temperature, unresponsiveness, and, often, death. By using anti-IgE antibody treatments and mice with targeted mutations of the Fc␥RIII ␣-chain or the common ␥-chain of Fc RI and Fc␥RI͞III, we demonstrate that IgE crosslinking of Fc RI appears to be necessary and sufficient for myelin peptide-induced anaphylaxis. The implications of these findings to myelin peptide͞ protein tolerance strategies for the treatment of multiple sclerosis are discussed.myelin ͉ tolerance M ultiple sclerosis (MS) is a CNS-demyelinating disease characterized by the perivascular infiltration of inflammatory mononuclear cells (1). Although the etiology of MS is unknown, evidence from human patients (2-4) and an animal model of MS, experimental autoimmune encephalomyelitis (EAE) (5-7), supports a major pathogenic role for autoreactive myelin-specific CD4 ϩ T cells, which are a logical target for clinical therapies. Two protocols that have shown promise in inducing antigen-specific immune tolerance for the prevention and͞or treatment of EAE are the i.v. injection of soluble protein, peptide, or peptide oligomers (8-10) and the i.v. injection of myelin proteins or peptides chemically coupled to syngeneic splenocytes [antigen-coupled splenocytes (Ag-SP)] (11). We performed a side-by-side comparison of these two tolerance protocols in preventing EAE induction and ameliorating ongoing EAE. We found that i.v. injection of soluble peptide monomer was not particularly effective when administered at any time point tested, and a soluble peptide oligomer was only fully effective when administered after immunization (day ϩ7) but before the onset of clinical symptoms of EAE. In contrast, i.v. administration of Ag-SP proved effective at preventing the onset of clinical symptoms and treating preestablished disease. In addition, an unexpected result of the administration of soluble peptide and peptide oligomer after the onset of clinical symptoms in many, but not all, peptide-induced EAE models was a rapid-onset anaphylactic reaction characterized by respiratory distress, erythema, decreased body temperature, unresponsiveness, and often death. This result is especially alarming given the proposed use of peptide-based tolerance therapies for the treatment of autoimmune diseases.Anaphylaxis i...

“…Yet, the disease induced by PLP and MOG can be suppressed by GA as well as by GA-induced cells, probably by ''bystander mechanisms'' (11). A shift from a Th1-biased cytokine profile toward a Th2-biased profile was also observed in GA-treated MS patients (12)(13)(14), indicating that such GAspecific cells are involved in the therapeutic effect brought about by GA in MS. However, until recently, GA-induced Th2 regulatory cells were demonstrated only in the periphery (spleens and lymph nodes of experimental animals or peripheral blood mononuclear cells in human) and not in the organ in which the pathological processes of EAE and MS occur.…”

mentioning

confidence: 91%

Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications

Arnon

Aharoni

2004

173

131

Glatiramer acetate (GA, Copaxone, Copolymer 1) is an approved drug for the treatment of multiple sclerosis and is highly effective in the suppression of experimental autoimmune encephalomyelitis in various species. The mode of action of GA is by initial strong promiscuous binding to MHC molecules and consequent competition with various myelin antigens for their presentation to T cells. A further aspect of its action is potent induction of specific suppressor cells of the T helper 2 (Th2) type that migrate to the brain and lead to in situ bystander suppression. Furthermore, the GA-specific cells in the brain express the antiinflammatory cytokines IL-10 and transforming growth factor ␤, in addition to brain-derived neurotrophic factor, whereas they do not express IFN-␥. Based on this immunomodulatory mode of action, we explored the potential of GA for two other applications: prevention of graft rejection and amelioration of inflammatory bowel diseases. GA was effective in amelioration of graft rejection in two systems by prolongation of skin graft survival and inhibition of functional deterioration of thyroid grafts, across minor and major histocompatibility barriers. In all transplantation systems GA treatment inhibited the detrimental secretion of Th1 inflammatory cytokines and induced beneficial Th2͞3 antiinflammatory response. GA was effective also in combination with low-dose immunosuppressive drugs. Inflammatory bowel diseases are characterized by detrimental imbalanced proinflammatory immune reactivity in the gut. GA significantly suppressed the various manifestations of trinitrobenzene sulfonic acid-induced colitis, including mortality, weight loss, and macroscopic and microscopic colonic damage. GA suppressed local lymphocyte proliferations and tumor necrosis factor ␣ detrimental secretion but induced transforming growth factor ␤, thus confirming the involvement of Th1 to Th2 shift in GA mode of action.