The Effect of Glutamate on Neurite Outgrowth in Fiddler Crab (Uca
Sa.38. The Effect of Immune Cells on Neurite Outgrowth
1
mice immunized with PLP 139—151, poorly expressed in the thymus, developed anaphylactic reactions after re-exposure to these peptide. Antigen-specific T-cells proliferation was similar in both groups of immunization, but IL10 production was increased in T-cells reactive to PLP 178—191, expressed in the thymus, compared to T-cells reactive to PLP 139— 151. Furthermore, compared to mice immunized with PLP 139—151, mice immunized with PLP 178—191 produced lower levels of specific antibodies of all IgG isotype, and a complete abrogation of peptide-specific IgG3 response. These data suggest that thymic expression of self peptides might result in the peripheral expansion of regulatory cells that can prevent anaphylaxis through an IL-10 dependent mechanism. doi:10.1016/j.clim.2006.04.268 Sa.37. Control of Autoimmune Diseases By Epitope Specific Immunotherapy. Rosario Billetta, 1 Mayuko Omori, 1 Allan Kaspar, 1 Negar Ghahramani, 1 Daniel Brigham, 1 Carol Meschter, 2 Paola Lanza, 1 Salvatore Albani. 31 Androclus Therapeutics, Inc., San Diego, CA; 2 Research, Comparative Biosciences, Inc., Sunnyvale, CA; 3 UCSD Medical Center, UCSD, San Diego, CA. Previous approaches to modulate adaptive immunity for autoimmune disease therapies largely focused on putative triggers of the disease, as determined by animal models of the disease. These approaches rely on the direct transla- tion to human therapy of the model trigger antigens used in induction of the animal model. However, little is known in human autoimmune disease of the actual trigger(s) that induce disease or if such triggers can modulate the disease. We have identified a mechanism which modulates inflammation that is independent of the triggering antigen in autoimmune disease. This mechanism is based on the recognition by T-cells of epitopes derived from heat shock proteins (HSP). By default, this recognition is pro-inflam- matory but can be modulated by naturally occurring regulatory mechanisms that are impaired in autoimmunity. Our approach aims to restore such regulatory mechanisms by tolerizing to the pro-inflammatory HSP antigens. EAE is a model autoimmune disease that is induced by immuni- zation with MBP. Tolerization to MBP can protect animals from this model disease. Our data show that in MBP- immunized rats, EAE development is suppressed clinically and histologically by mucosal administration of a particu- lar HSP-derived peptide. We find that the regulatory mechanism activated involves a change in cytokine expression from inflammatory (IFN-g and TNF-a) to a regulatory profile (IL-4 and IL-10). Additionally, we observe an upregulation of foxP3 expressing CD4+CD25+ T-cells, indicating an increase in a regulatory pathway. These data suggest the existence of regulatory circuits in the immune system that can be activated by antigens unrelated to the induction of autoimmune disease. The existence of such heretofore unidentified regulatory path- ways suggests new approaches to treating autoimmunity independent of the specific pro-inflammatory pathway involved in disease induction. doi:10.1016/j.clim.2006.04.269 Sa.38. The Effect of Immune Cells on Neurite Outgrowth. Melissa Wright, Alyson Fournier, Amit Bar-Or. Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, QC, Canada. Multiple Sclerosis (MS) involves demyelination and axonal damage, believed to be mediated by infiltration of activated immune cells. Sustained neurological disability is believed to be due to failure of axons to regenerate. Little is known about the potential impact of immune cells on axonal regeneration. We demonstrate that activated and non- activated total peripheral blood mononuclear cells (PBMCs) have a significant inhibitory effect on neurite outgrowth. Purified CD3+ T lymphocytes significantly inhibit neurite outgrowth only when stimulated. In contrast, purified CD19+ B-cells were not able to inhibit neurite outgrowth, even after three day stimulation with PMA/ionomycin. Interest- ingly, B-cells exposed in culture to the PBMC pool for several days acquired the ability to inhibit neurite outgrowth. Neurons exhibited no evidence of cell death, indicating that the effect on outgrowth is not a side effect of cell death. We have found a clear inhibitory effect of immune cells on neurite outgrowth in various paradigms. Our findings provide insights into injury mechanisms relevant to CNS inflammatory conditions and may point to new therapeutic strategies to promote axonal regeneration in MS. doi:10.1016/j.clim.2006.04.270 Sa.39. Characterization and Clinical Response of a T-Cell Vaccination for Multiple Sclerosis. Brian Newsom, Glenn Winnier, Donna Rill, Mitzi Montgomery, Jim Williams. PharmaFrontiers Corp., The Woodlands, TX. Multiple Sclerosis (MS), an inflammatory, demyelinating disorder of the human central nervous system (CNS) is the leading cause of nontraumatic neurological disability in young adults. The pathogenesis of MS involves antigen specific T-cells directed against the protective myelin sheath of the neural network leading to a blocking of the transmis- sion of nerve impulses. Over time exacerbations of the disease occur, leading to debilitating symptoms and eventu- ally total disability. Current MS treatments have been shown to slightly reduce the number of exacerbations, however, they have serious side effects. We have developed a novel technology that utilizes an autologous T-cell vaccine known as Tovaxin TM . Tovaxin TM is composed of Myelin Reactive T-cell (MRTC) lines against the major proteins of the myelin sheath, MBP, PLP and MOG. We have developed a screening process to identify reactive T-cells from a patient, expand them in culture, irradiate them to render them non-replicating, and Abstracts S118
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Transcript of Sa.38. The Effect of Immune Cells on Neurite Outgrowth
mice immunized with PLP 139—151, poorly expressed in thethymus, developed anaphylactic reactions after re-exposureto these peptide. Antigen-specific T-cells proliferation wassimilar in both groups of immunization, but IL10 productionwas increased in T-cells reactive to PLP 178—191, expressedin the thymus, compared to T-cells reactive to PLP 139—151. Furthermore, compared to mice immunized with PLP139—151, mice immunized with PLP 178—191 producedlower levels of specific antibodies of all IgG isotype, and acomplete abrogation of peptide-specific IgG3 response.These data suggest that thymic expression of self peptidesmight result in the peripheral expansion of regulatory cellsthat can prevent anaphylaxis through an IL-10 dependentmechanism.
doi:10.1016/j.clim.2006.04.268
Sa.37. Control of Autoimmune Diseases By EpitopeSpecific Immunotherapy.Rosario Billetta,1 Mayuko Omori,1 Allan Kaspar,1
Negar Ghahramani,1 Daniel Brigham,1 Carol Meschter,2
Paola Lanza,1 Salvatore Albani.3 1Androclus Therapeutics,Inc., San Diego, CA; 2Research, Comparative Biosciences,Inc., Sunnyvale, CA; 3UCSD Medical Center, UCSD, SanDiego, CA.
Previous approaches to modulate adaptive immunity forautoimmune disease therapies largely focused on putativetriggers of the disease, as determined by animal models ofthe disease. These approaches rely on the direct transla-tion to human therapy of the model trigger antigens usedin induction of the animal model. However, little is knownin human autoimmune disease of the actual trigger(s) thatinduce disease or if such triggers can modulate thedisease. We have identified a mechanism which modulatesinflammation that is independent of the triggering antigenin autoimmune disease. This mechanism is based on therecognition by T-cells of epitopes derived from heat shockproteins (HSP). By default, this recognition is pro-inflam-matory but can be modulated by naturally occurringregulatory mechanisms that are impaired in autoimmunity.Our approach aims to restore such regulatory mechanismsby tolerizing to the pro-inflammatory HSP antigens. EAE isa model autoimmune disease that is induced by immuni-zation with MBP. Tolerization to MBP can protect animalsfrom this model disease. Our data show that in MBP-immunized rats, EAE development is suppressed clinicallyand histologically by mucosal administration of a particu-lar HSP-derived peptide. We find that the regulatorymechanism activated involves a change in cytokineexpression from inflammatory (IFN-g and TNF-a) to aregulatory profile (IL-4 and IL-10). Additionally, weobserve an upregulation of foxP3 expressing CD4+CD25+T-cells, indicating an increase in a regulatory pathway.These data suggest the existence of regulatory circuits inthe immune system that can be activated by antigensunrelated to the induction of autoimmune disease. Theexistence of such heretofore unidentified regulatory path-ways suggests new approaches to treating autoimmunity
independent of the specific pro-inflammatory pathwayinvolved in disease induction.
doi:10.1016/j.clim.2006.04.269
Sa.38. The Effect of Immune Cells on NeuriteOutgrowth.Melissa Wright, Alyson Fournier, Amit Bar-Or. Neurology andNeurosurgery, Montreal Neurological Institute, Montreal,QC, Canada.
Multiple Sclerosis (MS) involves demyelination and axonaldamage, believed to be mediated by infiltration of activatedimmune cells. Sustained neurological disability is believedto be due to failure of axons to regenerate. Little is knownabout the potential impact of immune cells on axonalregeneration. We demonstrate that activated and non-activated total peripheral blood mononuclear cells (PBMCs)have a significant inhibitory effect on neurite outgrowth.Purified CD3+ T lymphocytes significantly inhibit neuriteoutgrowth only when stimulated. In contrast, purified CD19+B-cells were not able to inhibit neurite outgrowth, evenafter three day stimulation with PMA/ionomycin. Interest-ingly, B-cells exposed in culture to the PBMC pool for severaldays acquired the ability to inhibit neurite outgrowth.Neurons exhibited no evidence of cell death, indicating thatthe effect on outgrowth is not a side effect of cell death. Wehave found a clear inhibitory effect of immune cells onneurite outgrowth in various paradigms. Our findingsprovide insights into injury mechanisms relevant to CNSinflammatory conditions and may point to new therapeuticstrategies to promote axonal regeneration in MS.
doi:10.1016/j.clim.2006.04.270
Sa.39. Characterization and Clinical Response of aT-Cell Vaccination for Multiple Sclerosis.Brian Newsom, Glenn Winnier, Donna Rill,Mitzi Montgomery, Jim Williams. PharmaFrontiers Corp.,The Woodlands, TX.
Multiple Sclerosis (MS), an inflammatory, demyelinatingdisorder of the human central nervous system (CNS) is theleading cause of nontraumatic neurological disability inyoung adults. The pathogenesis of MS involves antigenspecific T-cells directed against the protective myelin sheathof the neural network leading to a blocking of the transmis-sion of nerve impulses. Over time exacerbations of thedisease occur, leading to debilitating symptoms and eventu-ally total disability. Current MS treatments have been shownto slightly reduce the number of exacerbations, however,they have serious side effects. We have developed a noveltechnology that utilizes an autologous T-cell vaccine knownas TovaxinTM. TovaxinTM is composed of Myelin Reactive T-cell(MRTC) lines against the major proteins of the myelin sheath,MBP, PLP and MOG. We have developed a screening process toidentify reactive T-cells from a patient, expand them inculture, irradiate them to render them non-replicating, and
AbstractsS118
