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Natalizumab analogon therapy in a B cell-dependent experimental autoimmune encephalomyelitis model of multiple sclerosis
220
Abstracts
229 Natalizumab analogon therapy in a B cell-dependent experimental autoimmune encephalomyelitis model of multiple sclerosis Darius Häusler, Stefan Nessler, Niels Kruse, Wolfgang Brück, Imke Metz Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany Multiple sclerosis (MS) is considered to be a T cell-mediated demyelinating disease. However, there is increasing evidence for the involvement of B cells and plasma cells in MS pathogenesis: for instance, B cells and plasma cells are present in MS lesions and a subgroup of early active lesions are characterized by immunoglobulin and complement depositions. Natalizumab is a humanized monoclonal antibody approved for the treatment of relapsingremitting MS. It hinders the transmigration of immune cells into the CNS by blocking the interaction between the alpha-4 chain (CD49d) of integrins and their ligands. Thus far, treatment with the natalizumab analogon PS/2 immunoglobulin G (IgG) has been investigated in T cell-mediated animal models of MS. In the present study we aimed at analyzing the effects of PS/2 IgG in a mouse model of MS with T- and B cell cooperation (OSE mice). Transgenic mice with B- and T cell receptors which recognize the myelin oligodendrocyte glycoprotein (MOG) spontaneously develop experimental autoimmune encephalomyelitis (EAE). When the first clinical symptoms were observed, mice were treated either twice or 15 times with 75 μg of PS/2 IgG every other day. In an alternative regimen, treatment was also performed after the peak of disease or with PS/2 F(ab’)2 fragments. The injection of PS/2 increased leukocyte numbers in the blood and resulted in a partial internalization of CD49d in T- and B cells. This treatment improved the clinical outcome and decreased spinal cord demyelination and immune cell infiltrations if given early in the disease. The therapeutic effects of PS/2 antibody injections were independent of the Fc fragment of the antibody, since F(ab’)2 injections were also beneficial. In conclusion, treatment with PS/2 IgG led to increased blood leukocyte numbers, very similar to the effects observed in humans after treatment with natalizumab. In OSE mice the natalizumab analogon treatment is effective if given early in disease development. doi:10.1016/j.jneuroim.2014.08.589
419 Effect of intravenous immunoglobulins on natural killer cells Maximilian K. Heiningera, Gerd Meyer Zu Horsteb, Steffen Cordesc, Mark Stettnera, Anne K. Mausberga, Bernd C. Kieseiera
in particular in chronic inflammatory demyelinating polyneuropathy (CIDP). However the exact mechanism of action still remains unknown. Using flow cytometry based assays we analysed the effects of IVIg on isolated peripheral blood lymphocytes, NK cell activity and cytotoxicity, as well as on cell surface marker expression. By measuring degranulation and intracellular cytokine staining after stimulation with target cells, we found that IVIg reduces both cytotoxic and regulatory potential of NK cells in a dose dependent manner. Incubation with IVIg also alters expression levels of functional NK receptors, such as CD161 or NKG2A. IVIg-treatment has an approximate 70% efficiency in patients with CIDP. The lack of a predictive marker for IVIg-responsiveness avoids the preservation of not responding patients from a treatment period of up to several months before discrimination into responders and nonresponders is possible. With high treatment costs and potential undesirable side effects a biomarker for treatment response would be of high patient and economic interest. Further experiments are warranted to prove if differences in the NK cell status of patients with CIDP represent a potential surrogate marker in predicting the outcome of IVIg-treatment. doi:10.1016/j.jneuroim.2014.08.590
164 The DNA methylation inhibitor decitabine completely blocks autoimmune mediated CNS demyelination Kristof Thewissen, Jerome Hendriks, Piet Stinissen, Helena Slaets, Niels Hellings Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium This study aimed to examine whether epigenetic modulation is able to significantly affect the development of autoimmune disease. We demonstrate that the DNA methylation inhibitor decitabine (DAC) completely blocks the develop of clinical symptoms in a preclinical model of multiple sclerosis (MS), namely experimental autoimmune encephalomyelitis (EAE). Resistance to EAE was associated with a complete absence of demyelinating lesions and infiltrating macrophages and T cells. Further analyses of the immune response in primary and secondary lymphoid organs demonstrated that DAC blocks priming of myelin-specific Th17 cells and significantly enhances the percentage of CD4+ Foxp3+ regulatory T cells. These observations indicate that DAC restores immune tolerance to self thereby leading to disease resistance. RT-PCR further confirmed this, as genes involved in driving pathogenic T cell differentiation and migration towards inflammatory sites are suppressed in DAC treated animals. We conclude that DAC is a powerful new therapeutic approach to consider for treatment of (auto)immune diseases with proven involvement of Th17 and/or Treg cells. doi:10.1016/j.jneuroim.2014.08.591
a
Department of Neurology, Heinrich-Heine-University, Duesseldorf, Germany; bCenter for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, United States; cDepartment of Hematology Oncology & Tumorimmunology, Charite, Berlin, Germany Natural Killer (NK) cells are part of the innate immune system with regulatory and effector functions playing an important role in early reactions in anti-viral and anti-tumour defences. NK cells are known for their regulatory potential to modulate immune reactions under autoimmune conditions. Different studies suggest that treatment with intravenous immunoglobulins (IVIg) has an immunomodulatory effect on NK cells. IVIg is a first-line treatment for various autoimmune diseases
596 Therapeutic antiviral T cells noncytopathically clear persistently infected microglia following conversion into antigen presenting cells Jasmin Herz, Dorian Mcgavern National Institutes of Health, National Institutes of Neurological Disorder and Stroke (NINDS), Bethesda, United States
Abstracts
229 Natalizumab analogon therapy in a B cell-dependent experimental autoimmune encephalomyelitis model of multiple sclerosis Darius Häusler, Stefan Nessler, Niels Kruse, Wolfgang Brück, Imke Metz Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany Multiple sclerosis (MS) is considered to be a T cell-mediated demyelinating disease. However, there is increasing evidence for the involvement of B cells and plasma cells in MS pathogenesis: for instance, B cells and plasma cells are present in MS lesions and a subgroup of early active lesions are characterized by immunoglobulin and complement depositions. Natalizumab is a humanized monoclonal antibody approved for the treatment of relapsingremitting MS. It hinders the transmigration of immune cells into the CNS by blocking the interaction between the alpha-4 chain (CD49d) of integrins and their ligands. Thus far, treatment with the natalizumab analogon PS/2 immunoglobulin G (IgG) has been investigated in T cell-mediated animal models of MS. In the present study we aimed at analyzing the effects of PS/2 IgG in a mouse model of MS with T- and B cell cooperation (OSE mice). Transgenic mice with B- and T cell receptors which recognize the myelin oligodendrocyte glycoprotein (MOG) spontaneously develop experimental autoimmune encephalomyelitis (EAE). When the first clinical symptoms were observed, mice were treated either twice or 15 times with 75 μg of PS/2 IgG every other day. In an alternative regimen, treatment was also performed after the peak of disease or with PS/2 F(ab’)2 fragments. The injection of PS/2 increased leukocyte numbers in the blood and resulted in a partial internalization of CD49d in T- and B cells. This treatment improved the clinical outcome and decreased spinal cord demyelination and immune cell infiltrations if given early in the disease. The therapeutic effects of PS/2 antibody injections were independent of the Fc fragment of the antibody, since F(ab’)2 injections were also beneficial. In conclusion, treatment with PS/2 IgG led to increased blood leukocyte numbers, very similar to the effects observed in humans after treatment with natalizumab. In OSE mice the natalizumab analogon treatment is effective if given early in disease development. doi:10.1016/j.jneuroim.2014.08.589
419 Effect of intravenous immunoglobulins on natural killer cells Maximilian K. Heiningera, Gerd Meyer Zu Horsteb, Steffen Cordesc, Mark Stettnera, Anne K. Mausberga, Bernd C. Kieseiera
in particular in chronic inflammatory demyelinating polyneuropathy (CIDP). However the exact mechanism of action still remains unknown. Using flow cytometry based assays we analysed the effects of IVIg on isolated peripheral blood lymphocytes, NK cell activity and cytotoxicity, as well as on cell surface marker expression. By measuring degranulation and intracellular cytokine staining after stimulation with target cells, we found that IVIg reduces both cytotoxic and regulatory potential of NK cells in a dose dependent manner. Incubation with IVIg also alters expression levels of functional NK receptors, such as CD161 or NKG2A. IVIg-treatment has an approximate 70% efficiency in patients with CIDP. The lack of a predictive marker for IVIg-responsiveness avoids the preservation of not responding patients from a treatment period of up to several months before discrimination into responders and nonresponders is possible. With high treatment costs and potential undesirable side effects a biomarker for treatment response would be of high patient and economic interest. Further experiments are warranted to prove if differences in the NK cell status of patients with CIDP represent a potential surrogate marker in predicting the outcome of IVIg-treatment. doi:10.1016/j.jneuroim.2014.08.590
164 The DNA methylation inhibitor decitabine completely blocks autoimmune mediated CNS demyelination Kristof Thewissen, Jerome Hendriks, Piet Stinissen, Helena Slaets, Niels Hellings Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium This study aimed to examine whether epigenetic modulation is able to significantly affect the development of autoimmune disease. We demonstrate that the DNA methylation inhibitor decitabine (DAC) completely blocks the develop of clinical symptoms in a preclinical model of multiple sclerosis (MS), namely experimental autoimmune encephalomyelitis (EAE). Resistance to EAE was associated with a complete absence of demyelinating lesions and infiltrating macrophages and T cells. Further analyses of the immune response in primary and secondary lymphoid organs demonstrated that DAC blocks priming of myelin-specific Th17 cells and significantly enhances the percentage of CD4+ Foxp3+ regulatory T cells. These observations indicate that DAC restores immune tolerance to self thereby leading to disease resistance. RT-PCR further confirmed this, as genes involved in driving pathogenic T cell differentiation and migration towards inflammatory sites are suppressed in DAC treated animals. We conclude that DAC is a powerful new therapeutic approach to consider for treatment of (auto)immune diseases with proven involvement of Th17 and/or Treg cells. doi:10.1016/j.jneuroim.2014.08.591
a
Department of Neurology, Heinrich-Heine-University, Duesseldorf, Germany; bCenter for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, United States; cDepartment of Hematology Oncology & Tumorimmunology, Charite, Berlin, Germany Natural Killer (NK) cells are part of the innate immune system with regulatory and effector functions playing an important role in early reactions in anti-viral and anti-tumour defences. NK cells are known for their regulatory potential to modulate immune reactions under autoimmune conditions. Different studies suggest that treatment with intravenous immunoglobulins (IVIg) has an immunomodulatory effect on NK cells. IVIg is a first-line treatment for various autoimmune diseases
596 Therapeutic antiviral T cells noncytopathically clear persistently infected microglia following conversion into antigen presenting cells Jasmin Herz, Dorian Mcgavern National Institutes of Health, National Institutes of Neurological Disorder and Stroke (NINDS), Bethesda, United States