Contributions
Abstract: 142
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Neutrophils are thought to reflect innate effector cells of Th17 mediated inflammatory responses and are considered to contribute to tissue damage in a subset of central nervous system (CNS) specific autoimmune diseases like neuromyelitis optica. Their role during multiple sclerosis (MS), however, is unclear. In a first step, we used Ly6G reporter mice to investigate the role of neutrophils during the murine MS model of experimental autoimmune encephalomyelitis (EAE). Ly6G+ neutrophils appeared in the cerebrospinal fluid (CSF) and CNS throughout the whole course of EAE. At the peak of EAE, neutrophils purified from the CSF and the CNS altered their phenotype, expressed high levels of NOS2 and Arginase and were capable of suppressing proliferation of both T and B cells in vitro. Further cytologic and flow cytometric analysis of neutrophils were reminiscent of myeloid derived suppressor cells (MDSC), which have been described in the context of tumor biology and have been shown to suppress adaptive immune responses. Antibody-mediated depletion of Ly6G+ neutrophils after disease onset exacerbated EAE disease course and provoked CNS infiltration of GM-CSF producing pro-inflammatory B cells. In turn, recruitment of Ly6G+ neutrophils by G-CSF therapy attenuated the disease course and reduced B cell mediated tissue inflammation. EAE in mice with conditional ablation of Stat3 in neutrophils phenocopied the disease course of neutrophil depleted mice and led to enhanced CNS infiltration of pro-inflammatory B cells. In a second step, we investigated granulocytic MDSCs in MS patients. Examination of MS patients revealed higher frequencies of LOX-1+ granulocytic MDSCs in the peripheral blood mononuclear cell (PBMC) compartment as compared to healthy controls. Interestingly, patients suffering from acute relapse had significantly lower MDSC frequencies than patients in remission. Higher MDSC frequencies in the peripheral blood were also associated (by trend) with lower B cell frequencies in the CSF. In conclusion, our data suggest that a specialized MDSC subset of neutrophils exert immune regulatory functions by controlling the abundance of inflammatory B cells in a Stat3 dependent manner during murine EAE and could also be involved in the regulation of human autoimmune inflammation in the CNS.
Disclosure:
Funding: Dr. Knier, Dr. Hemmer and Dr. Korn are supported by the Bundesminsterium für Bildung und Forschung (Kompetenznetz Multiple Sklerose KKNMS). Dr. Knier received intramural funding from the Technical University of Munich. Dr. Aly is supported by a clinical scientist program provided by the Deutsche Forschungsgemeinschaft DFG (Synergy). Dr. Hemmer receives funding from the DFG (TR 128). Dr. Korn is supported by the DFG (SFB 1054 and TR 128) and by the European Research Council ERC (CoG 647215).
Disclosures:
B. Knier: has nothing to disclose.
M. Hiltensperger: has nothing to disclose.
C Sie: has nothing to disclose.
L. Aly: has nothing to disclose.
G. Garg: has nothing to disclose.
U. Koedel: has nothing to disclose.
M. Gunzer: has nothing to disclose.
B. Hemmer: has served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC member for AllergyCare; he or his institution have received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals and Hoffmann-La-Roche; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon β.
T. Korn: has nothing to disclose.
Abstract: 142
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Neutrophils are thought to reflect innate effector cells of Th17 mediated inflammatory responses and are considered to contribute to tissue damage in a subset of central nervous system (CNS) specific autoimmune diseases like neuromyelitis optica. Their role during multiple sclerosis (MS), however, is unclear. In a first step, we used Ly6G reporter mice to investigate the role of neutrophils during the murine MS model of experimental autoimmune encephalomyelitis (EAE). Ly6G+ neutrophils appeared in the cerebrospinal fluid (CSF) and CNS throughout the whole course of EAE. At the peak of EAE, neutrophils purified from the CSF and the CNS altered their phenotype, expressed high levels of NOS2 and Arginase and were capable of suppressing proliferation of both T and B cells in vitro. Further cytologic and flow cytometric analysis of neutrophils were reminiscent of myeloid derived suppressor cells (MDSC), which have been described in the context of tumor biology and have been shown to suppress adaptive immune responses. Antibody-mediated depletion of Ly6G+ neutrophils after disease onset exacerbated EAE disease course and provoked CNS infiltration of GM-CSF producing pro-inflammatory B cells. In turn, recruitment of Ly6G+ neutrophils by G-CSF therapy attenuated the disease course and reduced B cell mediated tissue inflammation. EAE in mice with conditional ablation of Stat3 in neutrophils phenocopied the disease course of neutrophil depleted mice and led to enhanced CNS infiltration of pro-inflammatory B cells. In a second step, we investigated granulocytic MDSCs in MS patients. Examination of MS patients revealed higher frequencies of LOX-1+ granulocytic MDSCs in the peripheral blood mononuclear cell (PBMC) compartment as compared to healthy controls. Interestingly, patients suffering from acute relapse had significantly lower MDSC frequencies than patients in remission. Higher MDSC frequencies in the peripheral blood were also associated (by trend) with lower B cell frequencies in the CSF. In conclusion, our data suggest that a specialized MDSC subset of neutrophils exert immune regulatory functions by controlling the abundance of inflammatory B cells in a Stat3 dependent manner during murine EAE and could also be involved in the regulation of human autoimmune inflammation in the CNS.
Disclosure:
Funding: Dr. Knier, Dr. Hemmer and Dr. Korn are supported by the Bundesminsterium für Bildung und Forschung (Kompetenznetz Multiple Sklerose KKNMS). Dr. Knier received intramural funding from the Technical University of Munich. Dr. Aly is supported by a clinical scientist program provided by the Deutsche Forschungsgemeinschaft DFG (Synergy). Dr. Hemmer receives funding from the DFG (TR 128). Dr. Korn is supported by the DFG (SFB 1054 and TR 128) and by the European Research Council ERC (CoG 647215).
Disclosures:
B. Knier: has nothing to disclose.
M. Hiltensperger: has nothing to disclose.
C Sie: has nothing to disclose.
L. Aly: has nothing to disclose.
G. Garg: has nothing to disclose.
U. Koedel: has nothing to disclose.
M. Gunzer: has nothing to disclose.
B. Hemmer: has served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC member for AllergyCare; he or his institution have received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals and Hoffmann-La-Roche; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon β.
T. Korn: has nothing to disclose.