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H mice with etsablished chronic relapsing experimental allergic encephalomyelitis (CREAE) is reversible
Journal of Neuroimmunology ELSEVIER
Journal of Neuroimmunology 52 (1994) 111-115
Memorial meeting for Professor Alan Davison July 14th 1994, St. Thomas' Hospital, UMDS, London, UK To celebrate the considerable contribution that Professor Alan Davison, Professor of Neurochemistry at the Institute of Neurology, London, made in the fields of Neurochemistry and Multiple Sclerosis research, a symposium in his memory will be held at St Thomas' Hospital, London, on the 14th July 1994. The topics to be covered include experimental models of multiple sclerosis, immunotherapies of experimental allergic encephalomyelitis, neuroendocrine-immune interactions and physiological aspects of glial cells and axons in demyelination. For further details of this meeting please contact: Dr. Sandra Amor, Immunology Department, Rayne Institute, St. Thomas' Hospital, UMDS, London SE1 7EH. Tel: (071) 928 9292 ext. 2592 Dr. Arthur Butt, Physiology Department, St. Thomas' Hospital, UMDS, London SE1 7EH. Tel: (071) 928 9292 ext. 3822
This meeting is dedicated to the life and work of Professor Alan Davison who during his scientific career was renowned for encouraging and supporting younger scientific researchers in the field of neurochemistry and neuroimmunology particularly multiple sclerosis. Accordingly we have organised this meeting to provide the opportunity for research scientists to discuss their work. This should be a stimulating forum and will generate greater interaction between younger workers.
A role for complement in demyelination: A review of evidence from cells, experimental animals and patients B. Paul Morgan
Department of Medical Biochemistry, UWCM, Cardiff CF4 4XN, UK An involvement of complement in demyelination was first suggested by experiments carried out in the mid-60s which demonstrated a heat-labile component of MS patient serum and cerebrospinal fluid which caused myelin loss from cerebral explants. This in vitro demyelinating activity of complement was further explored in the early 1980s when it was shown that formation of the lytic membrane attack complex was required. Evidence for an involvement of complement in demyelination in vivo was provided by several studies in the 1970s which showed that animals lacking a functional complement system, either due to deficiency 0165-5728/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0 1 6 5 - 5 7 2 8 ( 9 4 ) 0 0 0 4 5 - P
or pharmacological depletion, were refractory to the induction of experimental demyelination. With the recognition of the central role of T cells in demyelination, interest in the part played by complement waned. However, recent years have seen a resurgence of interest in the role of complement in demyelination and also in neurodegeneration. In this brief presentation I will summarise current knowledge and discuss potential therapeutic strategies targeting complement activation in the nervous system.
Identification of encephalitogenic determinants of PLP, MBP and MOG for Biozzi A B / H mice S. Amor a, J.K. O'Neill b, N. Groome c, M.M. Morris a, J.L. Turk b, D. Baker b
a Immunology Department, Rayne Institute, UMDS, St Thomas' Hospital, London, UK, b Department of
112
Pathology, The Royal College of Surgeons of England, London, UK, c Multiple Sclerosis Society Peptide Laboratory, School of Biological and Molecular Sciences, Oxford Brookes University, Oxford, UK Experimental allergic encephalomyelitis (EAE), an autoimmune disease of the CNS mediated by MHC class II restricted CD4 + T lymphocytes, may be induced in mice with spinal cord homogenate (SCH) or the major myelin constituents. Biozzi A B / H (H-2 dql) mice express H-2A n°d, which is homologous to the HLA.DQBI*0302 allele associated with susceptibility to insulin-dependent diabetes and multiple sclerosis in a subset of patients. A B / H mice exhibit a reproducible form of relapsing EAE after induction with SCH. Although the encephalitogenic antigens are restricted to the white matter, there is little information concerning the antigens involved. Using native myelin basic protein (MBP) and proteolipid protein (PLP) or synthetic 15- or 16mer peptides based on the whole MBP, PLP and myelin oligodendrocyte glycoprotein molecules we have identified the encephalitogenic determinants of these myelin components for the induction of EAE in the Biozzi A B / H mouse. These share a common peptide motif which may be important in MHC:T cell interactions in animals which bear this haplotype.
Hyporesponsiveness induced by antigen coupled splenocytes, CD3 or CD4-specific antibodies in Biozzi A B / H mice with established chronic relapsing experimental allergic encephalomyelitis (CREAE) is reversible Janet K. O'Neill a, John L. Turk b, David Baker a,b
a Department of Clinical Ophthalmology, Institute of Ophthalmology, London, EC1V 9EL, UK, b Department of Pathology, Royal College of Surgeons of England, London, WC2A 3PN, UK The clinical progression of actively induced CREAE in Biozzi A B / H mice can be inhibited by pre-treatment with specific antigen, including spinal cord homogenate coupled splenocytes, or immunosuppressive agents. Established CREAE can also be controlled by the administration of depleting or non-depleting/ blocking CD4-specific antibodies (mAbs). However, cessation of treatment with CD4-specific mAbs results in clinical disease which may be accelerated following antigen rechallenge in Freund's complete or incomplete adjuvant, where the latter is tolerogenic in naive animals. The development of CREAE after antigen rechallenge can only be inhibited while the CD4 mAb is exerting immunosuppressive effects. Unresponsive-
ness induced by CD3-specific mAb or antigen coupled splenocytes on day 9 post-inoculation or at the onset of clinical signs can be reversed by antigenic rechallenge within 2 weeks of treatment, suggesting that tolerance has not been induced. The data indicate that following priming, relapses can be induced by endogenous or exogenous signals, if they are received once the veil of immunosuppression has been removed.
Induction of nonresponsiveness by antigen administration via mucosal surfaces in a mouse model of experimental allergic encephalomyelitis B. Metzler, D.C. Wraith
Cambridge University Department of Pathology, Immunology Division, Tennis Court Road, Cambridge CB2 lOP, UK This study explores antigen administration via mucosal surfaces as a potential means of inducing antigen-specific nonresponsiveness in experimental autoimmune encephalomyelitis (EAE). In the H-2 u mouse model of EAE, oral administration of the major encephalitogenic peptide ( A c l - 9 or Ac1-11) or whole mouse myelin over a wide range of doses failed to induce oral tolerance to EAE. In contrast, a single intranasal dose of this peptide inhibited EAE when administered prior to disease induction. Furthermore, there was a positive correlation between the degree of protection from EAE and peptide affinity for class II MHC. Inhalation of A c l - 9 also protected against EAE induced with whole spinal cord homogenate rather than only peptide-induced disease. Importantly, protection from EAE by peptide inhalation was also successful after disease induction in some but not all experiments. Under these conditions, the timing of peptide administration appeared to be crucial.
Anti-class II MHC antibodies prevent and treat EAE without antigen presenting cell depletion Richard M. Smith, David C. Wraith
Cambridge University Department of Pathology, Division of Immunology, Tennis Court Road, Cambridge CB2 1QP, UK Antibodies binding the class II MHC molecule have been shown to be effective at preventing disease in many models of autoimmunity. However, the demonstration that such antibodies can cause marked and longlasting depletion of class II positive cells not only provided a trivial explanation of their action, but also questioned their safety in human disease. We have
Journal of Neuroimmunology 52 (1994) 111-115
Memorial meeting for Professor Alan Davison July 14th 1994, St. Thomas' Hospital, UMDS, London, UK To celebrate the considerable contribution that Professor Alan Davison, Professor of Neurochemistry at the Institute of Neurology, London, made in the fields of Neurochemistry and Multiple Sclerosis research, a symposium in his memory will be held at St Thomas' Hospital, London, on the 14th July 1994. The topics to be covered include experimental models of multiple sclerosis, immunotherapies of experimental allergic encephalomyelitis, neuroendocrine-immune interactions and physiological aspects of glial cells and axons in demyelination. For further details of this meeting please contact: Dr. Sandra Amor, Immunology Department, Rayne Institute, St. Thomas' Hospital, UMDS, London SE1 7EH. Tel: (071) 928 9292 ext. 2592 Dr. Arthur Butt, Physiology Department, St. Thomas' Hospital, UMDS, London SE1 7EH. Tel: (071) 928 9292 ext. 3822
This meeting is dedicated to the life and work of Professor Alan Davison who during his scientific career was renowned for encouraging and supporting younger scientific researchers in the field of neurochemistry and neuroimmunology particularly multiple sclerosis. Accordingly we have organised this meeting to provide the opportunity for research scientists to discuss their work. This should be a stimulating forum and will generate greater interaction between younger workers.
A role for complement in demyelination: A review of evidence from cells, experimental animals and patients B. Paul Morgan
Department of Medical Biochemistry, UWCM, Cardiff CF4 4XN, UK An involvement of complement in demyelination was first suggested by experiments carried out in the mid-60s which demonstrated a heat-labile component of MS patient serum and cerebrospinal fluid which caused myelin loss from cerebral explants. This in vitro demyelinating activity of complement was further explored in the early 1980s when it was shown that formation of the lytic membrane attack complex was required. Evidence for an involvement of complement in demyelination in vivo was provided by several studies in the 1970s which showed that animals lacking a functional complement system, either due to deficiency 0165-5728/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0 1 6 5 - 5 7 2 8 ( 9 4 ) 0 0 0 4 5 - P
or pharmacological depletion, were refractory to the induction of experimental demyelination. With the recognition of the central role of T cells in demyelination, interest in the part played by complement waned. However, recent years have seen a resurgence of interest in the role of complement in demyelination and also in neurodegeneration. In this brief presentation I will summarise current knowledge and discuss potential therapeutic strategies targeting complement activation in the nervous system.
Identification of encephalitogenic determinants of PLP, MBP and MOG for Biozzi A B / H mice S. Amor a, J.K. O'Neill b, N. Groome c, M.M. Morris a, J.L. Turk b, D. Baker b
a Immunology Department, Rayne Institute, UMDS, St Thomas' Hospital, London, UK, b Department of
112
Pathology, The Royal College of Surgeons of England, London, UK, c Multiple Sclerosis Society Peptide Laboratory, School of Biological and Molecular Sciences, Oxford Brookes University, Oxford, UK Experimental allergic encephalomyelitis (EAE), an autoimmune disease of the CNS mediated by MHC class II restricted CD4 + T lymphocytes, may be induced in mice with spinal cord homogenate (SCH) or the major myelin constituents. Biozzi A B / H (H-2 dql) mice express H-2A n°d, which is homologous to the HLA.DQBI*0302 allele associated with susceptibility to insulin-dependent diabetes and multiple sclerosis in a subset of patients. A B / H mice exhibit a reproducible form of relapsing EAE after induction with SCH. Although the encephalitogenic antigens are restricted to the white matter, there is little information concerning the antigens involved. Using native myelin basic protein (MBP) and proteolipid protein (PLP) or synthetic 15- or 16mer peptides based on the whole MBP, PLP and myelin oligodendrocyte glycoprotein molecules we have identified the encephalitogenic determinants of these myelin components for the induction of EAE in the Biozzi A B / H mouse. These share a common peptide motif which may be important in MHC:T cell interactions in animals which bear this haplotype.
Hyporesponsiveness induced by antigen coupled splenocytes, CD3 or CD4-specific antibodies in Biozzi A B / H mice with established chronic relapsing experimental allergic encephalomyelitis (CREAE) is reversible Janet K. O'Neill a, John L. Turk b, David Baker a,b
a Department of Clinical Ophthalmology, Institute of Ophthalmology, London, EC1V 9EL, UK, b Department of Pathology, Royal College of Surgeons of England, London, WC2A 3PN, UK The clinical progression of actively induced CREAE in Biozzi A B / H mice can be inhibited by pre-treatment with specific antigen, including spinal cord homogenate coupled splenocytes, or immunosuppressive agents. Established CREAE can also be controlled by the administration of depleting or non-depleting/ blocking CD4-specific antibodies (mAbs). However, cessation of treatment with CD4-specific mAbs results in clinical disease which may be accelerated following antigen rechallenge in Freund's complete or incomplete adjuvant, where the latter is tolerogenic in naive animals. The development of CREAE after antigen rechallenge can only be inhibited while the CD4 mAb is exerting immunosuppressive effects. Unresponsive-
ness induced by CD3-specific mAb or antigen coupled splenocytes on day 9 post-inoculation or at the onset of clinical signs can be reversed by antigenic rechallenge within 2 weeks of treatment, suggesting that tolerance has not been induced. The data indicate that following priming, relapses can be induced by endogenous or exogenous signals, if they are received once the veil of immunosuppression has been removed.
Induction of nonresponsiveness by antigen administration via mucosal surfaces in a mouse model of experimental allergic encephalomyelitis B. Metzler, D.C. Wraith
Cambridge University Department of Pathology, Immunology Division, Tennis Court Road, Cambridge CB2 lOP, UK This study explores antigen administration via mucosal surfaces as a potential means of inducing antigen-specific nonresponsiveness in experimental autoimmune encephalomyelitis (EAE). In the H-2 u mouse model of EAE, oral administration of the major encephalitogenic peptide ( A c l - 9 or Ac1-11) or whole mouse myelin over a wide range of doses failed to induce oral tolerance to EAE. In contrast, a single intranasal dose of this peptide inhibited EAE when administered prior to disease induction. Furthermore, there was a positive correlation between the degree of protection from EAE and peptide affinity for class II MHC. Inhalation of A c l - 9 also protected against EAE induced with whole spinal cord homogenate rather than only peptide-induced disease. Importantly, protection from EAE by peptide inhalation was also successful after disease induction in some but not all experiments. Under these conditions, the timing of peptide administration appeared to be crucial.
Anti-class II MHC antibodies prevent and treat EAE without antigen presenting cell depletion Richard M. Smith, David C. Wraith
Cambridge University Department of Pathology, Division of Immunology, Tennis Court Road, Cambridge CB2 1QP, UK Antibodies binding the class II MHC molecule have been shown to be effective at preventing disease in many models of autoimmunity. However, the demonstration that such antibodies can cause marked and longlasting depletion of class II positive cells not only provided a trivial explanation of their action, but also questioned their safety in human disease. We have