Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein

Sakai, Koichiro; Zamvil, Scott S.; Mitchell, Dennis J.; Lim, Min Chin; Jonathan, B Rothbard; Steinman, Lawrence

doi:10.1016/0165-5728(88)90032-x

Cited by 143 publications

(60 citation statements)

References 24 publications

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“…Determinant Spreading during EAE. At days 7, 28, 56, and 84 after immunization of (SWR • SJL) F1 mice with p 139-151, spleen cells were tested for proliferative responses to the 265 overlapping PLP pin peptides, to MBP 87-99, an immunodominant encephalitogenic determinant for both SJL/J (15,16) and SWtL/J (17) mice, and to myelin oligodendrocyte glycoprotein (MOG) 92-106, an immunodominant encephalitogen for SjL/j mice (18). Mononuclear cells were separated from single-cell suspensions by centrifugation on Lympholyte-M (Accurate Chemical & Science Corp., Westbury, NY) for 20 rain at 2,500 rpm.…”

Section: Methodsmentioning

confidence: 99%

A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease.

Johnson

Tuohy

1996

The Journal of Experimental Medicine

256

185

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SummaryThe development of autoimmune disease is accompanied by the acquired recognition of new self-determinants, a process commonly referred to as determinant spreading. In this study, we addressed the question of whether determinant spreading is pathogenic for progression of chronic-relapsing experimental autoimmune encephalomyelitis (EAE), a disease with many similarities to multiple sclerosis (MS). Our approach involved a systematic epitope mapping of responses to myelin proteolipid protein (PLP) as well as assaying responses to known encephalitogenic determinants of myelin basic protein (MBP 87-99) and myelin oligodendrocyte g|yco-protein (MOG 92-106) at various times after induction of EAE in (SWRXSJL)F1 mice immunized with PLP 139-151. We found that the order in which new determinants are recognized during the course of disease follows a predictable sequential pattem. At monthly intervals after immunization with p139-151, responses to PLP 249-273, MBP 87-99, and PLP 173-198 were sequentially accumulated in all mice examined. Three lines of evidence showed that determinant spreading is pathogenic for disease progression: (a) spreading determinants mediate passive transfer of acute EAE in naive (S'W~• 1 recipients; (b) an invariant relationship exists between the development of relapse/progression and the spreading of recognition to new immunodominant encephalitogenic determinants; and (c) after EAE onset, the induction ofpeptidespecific tolerance to spreading but not to nonspreading encephalitogenic determinants prevents subsequent progression of EAE. Thus, the predictability of acquired self-determinant recognition provides a basis for sequential determinant-specific therapeutic intervention after onset of the autoimmune disease process.

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Section: Methodsmentioning

confidence: 99%

A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease.

Johnson

Tuohy

1996

The Journal of Experimental Medicine

256

185

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“…30 In the current study, we demonstrate that a second pathogenic epitope, MBP 89-101, is also effective in treating ongoing EAE disease in SJL/J mice. 31 Additionally, we have enhanced our delivery system to address practical and safety concerns which may arise in moving to a clinical setting. By changing the leader sequence, we have been able to increase antigen secretion, thereby reducing the number of cells required for treatment.…”

Section: Discussionmentioning

confidence: 99%

“…30 With the goal of translation to the clinic, we now report the results of experiments in SJL/J mice designed to optimize this therapy for the treatment of MS. We show that our strategy is efficacious using a second epitope antigen, MBP 89-101. 31 This is of critical importance, since T cells responding to this epitope have been detected in many MS patients. 21,[32][33][34][35] To address clinical practicality and safety concerns, we have sequestered the transduced cells within a chamber that is implanted subcutaneously (s.c.).…”

Section: Introductionmentioning

confidence: 99%

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

Louie

Weiner

et al. 2005

Gene Ther

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With the ultimate goal of developing a novel treatment for multiple sclerosis (MS), we have developed a cell-based gene therapy protocol for the treatment of murine experimental autoimmune encephalomyelitis (EAE), a powerful animal model for MS. We have determined that transduced fibroblasts secreting encephalogenic epitopes, when injected into mice with EAE, cause a striking abrogation of disease. Both myelin basic protein (MBP) and proteolipid protein mini-gene constructs expressed in syngeneic fibroblast cells were capable of ameliorating ongoing EAE induced by MBP protein. These experiments are crucial since they suggest that not all encephalogenic epitopes need be secreted for the control of disease. We also demonstrate the success of this protocol when transduced syngeneic, and most importantly, allogeneic cells are sequestered within an implantable chamber. Furthermore, we find that through modifying antigen expression by changing the signal sequence of the mini-gene construct, we were able to significantly reduce the dose of cells required for treatment. These improvements to the minigene delivery system are critical for the eventual translation of our protocol to the clinic.

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“…18 Modulating the immune response to this region on myelin basic protein has been the subject of attempts at immune therapy in MS, with both altered peptides ligands and native protein. This region of MBP has homology to similar peptides that are found in various microbes (Table 1), [22][23][24] In theory tolerizing to this epitope could lead to tolerization against the corresponding microbe, but fortunately the adaptive immune re- sponse to microbes may be far more diverse than it is to self-antigens.…”

Section: The Antigenic Targets Of T Cells and Antibodies In Msmentioning

confidence: 99%

“…14 The major immunodominant T and B cell epitope for myelin basic protein lies between residues 82 and 99. 22,23 Intravenous administration of injection of myelin basic protein peptide 82-98, containing the immunodominant region VVHFFKNIVT, in a phase 1 trial lead to tolerance, with the absence of antibodies to myelin basic protein in the spinal fluid for up to 4 months. Tolerance was more enduring after a second injection.…”

Section: Trials With Native Myelin Proteins and Native Myelin Peptidesmentioning

confidence: 99%

Antigen-Specific Therapy of Multiple Sclerosis: The Long-Sought Magic Bullet

Steinman

2007

Neurotherapeutics

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Summary:The adaptive immune response in multiple sclerosis (MS) targets various myelin proteins and even some inducible heat shock proteins. A few attempts have been made to tolerize relapsing-remitting patients with MS to either fulllength myelin basic protein or to a key peptide epitope between residues 83-99. These trials have demonstrated that this approach may potentially provide benefit to patients with relapsing-remitting MS. However, manipulation of responses to myelin proteins can have deleterious effects. The immune response to myelin components is positioned at a key tipping point in the pathophysiology of the disease. Clarification of the key target antigens in MS, and better understanding of practical methods to attain tolerance to a wide variety of myelin and neuronal molecules will provide the basis for the ultimately successful antigen specific therapy.

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Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein

Cited by 143 publications

References 24 publications

A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease.

A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease.

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

Antigen-Specific Therapy of Multiple Sclerosis: The Long-Sought Magic Bullet

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