Experimental Autoimmune Model Research Articles

Role of T lymphocytes in the development of rheumatoid arthritis. Implications for treatment.

T cells play a role in the initiation and perpetuation of tissue inflammation that can lead to tissue destruction. With the discovery of a number of T helper subsets and their potential plasticity during disease it became clear that the T cell behaviour in autoimmune diseases is much more complex than the first Th1/Th2 concept. From experimental autoimmune arthritis models it became clear that the IL-23/IL-17 immune pathway is critical in the development of autoimmune arthritis and IL-17A has been recognized to be a key cytokine involved in initiation and perpetuation of chronic destructive arthritis. Functional studies using T cells and stromal cells from patients with RA revealed improvement of anti-TNF effects when combined with agents neutralizing IL-17A or agents suppressing Th17 cytokines production. Clinic trials will be needed to test whether these data from experimental settings can be translated to human arthritis. Different approaches are available or under investigation to target: (1) pathogenic T cell activity by inhibiting RORc or STAT3 or the costimulator pathway by CTLA4-Ig; (2) Th17 cytokine production by anti-IL-17A, anti-IL-22, or combination of anti-IL-17A/anti-TNF approaches; (3) Th17 polarization by neutralizing IL-23 using an anti-IL-23 specific antibody, IL-12/IL-23 by an anti-p40 antibody, or the IL-6 signaling pathway; (4) Th17 migration by interfering the CCR6-CCL20 interaction. The challenge is to bring the best to the clinic to further improve current therapy for patients with RA and to reach stable remission or even prevent the development of this disabling disease.

Investigation of the impact of intravenous injection of mesenchymal stem cells from mouse bone marrow on muscle weakness and immunological parameters in experimental autoimmune myasthenia gravis model

Myasthenia gravis (MG) is a T cell dependent and antibody mediated autoimmune disease. Around 85% of the patients show AChR antibodies, 5% have muscle specific tyrosine kinase (MuSK) antibodies, whereas the remaining patients are seronegative. Although experimental autoimmune myasthenia gravis (EAMG) model has provided important information on MG pathogenesis, treatment strategies are still somewhat limited. In recent years, mesenchymal stem cells from human umbilical cord or blood marrow have been successfully tried in AChR related EAMG model, reducing muscle weakness and AChR reactive lymphocytes.

Regulatory B cells are enriched within the IgM memory and transitional subsets in healthy donors but are deficient in chronic GVHD

AbstractA subset of regulatory B cells (Bregs) in mice negatively regulate T-cell immune responses through the secretion of regulatory cytokines such as IL-10 and direct cell-cell contact and have been linked to experimental models of autoimmunity, inflammation, and cancer. However, the regulatory function of Bregs in human disease is much less clear. Here we demonstrate that B cells with immunoregulatory properties are enriched within both the CD19+IgM+CD27+ memory and CD19+CD24hiCD38hi transitional B-cell subsets in healthy human donors. Both subsets suppressed the proliferation and interferon-γ production of CD3/CD28-stimulated autologous CD4+ T cells in a dose-dependent manner, and both relied on IL-10 secretion as well as cell-cell contact, likely mediated through CD80 and CD86, to support their full suppressive function. Moreover, after allogeneic stem cell transplantation, Bregs from patients with chronic graft-versus-host disease (cGVHD) were less frequent and less likely to produce IL-10 than were Bregs from healthy donors and patients without cGVHD. These findings suggest that Bregs may be involved in the pathogenesis of cGVHD and support future investigation of regulatory B cell–based therapy in the treatment of this disease.

54: Helminth-induced innate type-2 cytokines protect against autoimmunity

Helminth parasites typically establish chronic infections in the mammalian host which can persist for decades. Helminths evade protective host immune responses by promoting innate and adaptive anti-inflammatory networks which can also suppress immune responses to unrelated antigens. Indeed, it has been shown parasitic infection of humans is associated with a lower incidence of allergy and autoimmune disease in rural areas of the developing world. Experimental models of autoimmunity have revealed that helminth-induced protection against disease can be mediated by the action of either Treg or Th2 cells [1] . Here we examined the immunoregulatory effects of the excretory-secretory (ES) products of the helminth parasite, Fasciola hepatica, in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Administration of ES delayed the onset and attenuated the clinical severity of EAE which was associated with a decreased production of auto antigen-specific IFN- γ and IL-17. Unexpectedly, IL-10, TGF- β , or regulatory T cells did not play a role in the ES-induced attenuation of disease. Moreover, ES-elicited T cells did not suppress EAE and protection from disease was also retained in IL-4-deficient mice, suggesting that Th2 cells do not play a role in ES-induced amelioration of EAE. However adoptive transfer of macrophages or eosinophils, from ES-treated mice transferred protection. Furthermore, IL-5, a cytokine which mediates eosinophilia in vivo, was required for ES-induced protection against EAE. We are currently investigating the role of the epithelial cell-derived ‘alarmin’ cytokine, IL-33, in mediating the regulatory effects of ES. We have determined that IL-33 acts on mast cells to promote the alternative activation of macrophages with regulatory capacity while also promoting eosinophilia in vivo. These findings provide new insights into how helminths target innate immune cells in order to modulate the immune response thereby inhibiting the Th1 and Th17 responses that mediate inflammatory disease.

Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model.

The cause of chronic pelvic pain in interstitial cystitis/painful bladder syndrome (IC/PBS) remains unclear; autoimmunity is a possible etiology. We have recently shown that injection of a single immunogenic peptide of uroplakin 3A (UPK3A 65-84) induces experimental autoimmune cystitis (EAC) in female BALB/cJ mice that is unique among experimental models in accurately reflecting both the urinary symptoms and pelvic pain of IC/PBS. The aim of this project was to identify the roles of mast cells and mast cell chemoattractant/activator monocyte chemoattractant protein-1 [chemokine (C-C motif) ligand 2 (CCL2)] in the allodynia in this model. We immunized 6- to 8-wk-old female BALB/cJ mice with UPK3A 65-84 peptide and, 5-40 days later, observed increased responses to stimulation of the suprapubic abdominal and hindpaw surfaces with von Frey monofilaments compared with mice injected with adjuvant alone. Suprapubic and hindpaw tactile allodynia responses by EAC mice were blocked by instillation of lidocaine into the bladder but not by lidocaine in the uterus, confirming the bladder as the source of the hypersensitivity. Markedly increased numbers of activated mast cells and expression of CCL2 were found in the bladder after immunization with UPK3A 65-84. Hypersensitive responses were inhibited by mast cell stabilizer cromolyn sodium and antagonists of histamine receptors 1 and 2. Furthermore, BALB/cJ mice with deletion of the Ccl2 or chemokine (C-C motif) receptor 2 gene exhibited markedly reduced allodynia and accumulation of mast cells after UPK3A 65-84 immunization. These results show that UPK3A 65-84 immunization causes chronic visceral allodynia and suggest that it is mediated by CCL2-driven mast cell accumulation in the bladder.

Abstract 447: Ac-SDKP Suppresses TNFα-induced ICAM-1 Expression In Endothelial Cells Via Inhibition Of IκB Kinase And NF-κB Activation

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that Ac-SDKP decreased transcription factor NF-κB activation in angiotensin II-induced hypertension and also reduced intercellular adhesion molecule-1 (ICAM-1) expression in an experimental autoimmune myocarditis and hypertension animal model. However, the mechanisms by which Ac-SDKP down-regulated ICAM-1 expression are unclear. TNFα is a proinflammatory cytokine that induces ICAM-1 expression on different cell types. We hypothesized that Ac-SDKP suppresses TNFα-induced ICAM-1 via inhibition of IκB kinase (IKK) and subsequently by blockade of NF-κB activation. Human coronary artery endothelial cells were treated with Ac-SDKP or vehicle and then stimulated with TNFα (0.5 ng/ml). ICAM-1 protein expression and phosphorylation of IKK (p-IKK), inhibitory κB (p-IκB), p38 (p-p38) and ERK (p-ERK) were measured by Western Blot. Activation of NF-κB was determined by electrophoretic mobility shift assay (EMSA). ICAM-1 expression was virtually undetectable under basal conditions, but greatly increased by TNFα. Ac-SDKP dose-dependently suppressed TNFα-induced ICAM-1 expression (set at a value of 1.0 arbitrary units, AU) to 0.67±0.13 (p<0.05), 0.51±0.12 (p<0.01) and 0.39±0.09 AU (p<0.01) at 0.1 nM, 1 nM and 10 nM, respectively. In addition, Ac-SDKP (10 nM) inhibited TNFα-induced p-IKK from 1.0 to 0.71±0.02 AU (p<0.01). Ac-SDKP also inhibited TNFα-induced IKKβ expression from 1.0 to 0.64±0.12 AU (p<0.05), without affecting IKKα expression. Furthermore, Ac-SDKP inhibited TNFα-induced p-IκB from 1.0 to 0.54±0.03 AU (p<0.01). EMSA results showed that Ac-SDKP inhibited TNFα-mediated activation of NF-κB, which was 0.63±0.04-fold of TNFα-treated cells. However, Ac-SDKP had no effect on TNFα-induced p-p38 and p-ERK. Thus, we conclude that Ac-SDKP inhibits TNFα-induced IKK and subsequent degradation of IκB, thereby preventing NF-κB activation and ICAM-1 expression. These inhibitory effects are independent of p38 and ERK.

IL-12-and IL-23 in health and disease

Interleukin (IL)-12 and IL-23 play important roles in the development of experimental autoimmune disease models and numerous afflictions affecting humans. Preclinical data over the last 20 years combined with successful clinical trials has identified a clear relationship between IL-12, IL-23 and the generation of pathogenic T helper cells capable of orchestrating tissue inflammation. Observations made in the clinic have shown that IL-12p40, a common subunit shared by IL-12 and IL-23, is critical to pathologies associated with psoriasis, inflammatory bowel disease (IBD) and tumor growth. These advancements have set in motion the development of a number of potential therapeutics aimed at manipulating IL-12/23 signaling pathways in both mice and humans. This review will discuss a brief history of the understanding and expansion of the IL-12 cytokine family, some difficulties associated with preclinical data interpretation and finally the medicinal interventions that have been developed to combat IL-12/23-driven autoimmune disorders.

Characteristics of Mouse Adipose Tissue-Derived Stem Cells and Therapeutic Comparisons between Syngeneic and Allogeneic Adipose Tissue-Derived Stem Cell Transplantation in Experimental Autoimmune Thyroiditis

Previously, we found that the intravenous administration of human adipose tissue-derived mesenchymal stem cells was a promising therapeutic option for autoimmune thyroiditis even when the cells were transplanted into a xenogeneic model without an immunosuppressant. Therefore, we explored the comparison between the therapeutic effects of syngeneic and allogeneic adipose tissue-derived stem cells on an experimental autoimmune thyroiditis mouse model. Experimental autoimmune thyroiditis was induced in C57BL/6 mice by immunization with porcine thyroglobulin. Adipose tissue-derived stem cells derived from C57BL/6 mice (syngeneic) or BALB/c mice (allogeneic) or saline as a vehicle control were administered intravenously four times weekly. Blood and tissue samples were collected 1 week after the last transplantation. Adipose tissue-derived stem cells from mice were able to differentiate into multiple lineages in vitro; however, mouse adipose tissue-derived stem cells did not have immunophenotypes identical to those from humans. Syngeneic and allogeneic administrations of adipose tissue-derived stem cells reduced thyroglobulin autoantibodies and the inflammatory immune response, protected against lymphocyte infiltration into the thyroid, and restored the Th1/Th2 balance without any adverse effects. However, different humoral immune responses were observed for infused cells from different stem cell sources. The strongest humoral immune response was induced by xenogeneic transplantation, followed by allogeneic and syngeneic administration, in that order. The stem cells were mostly found in the spleen, not the thyroid. This migration might be because the stem cells primarily function in systemic immune modulation, due to being given prior to disease induction. In this study, we confirmed that there were equal effects of adipose tissue-derived stem cells in treating autoimmune thyroiditis between syngeneic and allogeneic transplantations.

PET imaging of disease progression and treatment effects in the experimental autoimmune encephalomyelitis rat model.

The experimental autoimmune encephalomyelitis model is a model of multiple sclerosis that closely mimics the disease characteristics in humans. The main hallmarks of multiple sclerosis are neuroinflammation (microglia activation, monocyte invasion, and T-cell infiltration) and demyelination. PET imaging may be a useful noninvasive technique for monitoring disease progression and drug treatment efficacy in vivo. Experimental autoimmune encephalomyelitis was induced by myelin-oligodendrocyte glycoprotein immunization in female Dark Agouti rats. Experimental autoimmune encephalomyelitis rats were imaged at baseline and at days 6, 11, 15, and 19 after immunization to monitor monocyte and microglia activation ((11)C-PK11195) and demyelination ((11)C-MeDAS) during normal disease progression and during treatment with dexamethasone. (11)C-PK11195 PET detected activation of microglia and monocytes in the brain stem and spinal cord during disease progression. The uptake of (11)C-PK11195 was elevated in dexamethasone-treated animals that had shown mild clinical symptoms that had resolved at the time of imaging. Demyelination was not detected by (11)C-MeDAS PET, probably because of the small size of the lesions (average, 0.13 mm). PET imaging of neuroinflammation can be used to monitor disease progression and the consequences of treatment in the experimental autoimmune encephalomyelitis rat model. PET imaging was more sensitive than clinical symptoms for detecting inflammatory changes in the central nervous system.

Interleukin-6 blockade in ocular inflammatory diseases

Interleukin-6 (IL-6) is a key cytokine featuring redundancy and pleiotropic activity. It plays a central role in host defence against environmental stress such as infection and injury. Dysregulated, persistent interleukin (IL)-6 production has been implicated in the development of various autoimmune, chronic inflammatory diseases and even cancers. Significant elevation of IL-6 has been found in ocular fluids derived from refractory/chronic uveitis patients. In experimental autoimmune uveitis models with IL-6 knock-out mice, IL-6 has shown to be essential for inducing inflammation. IL-6 blockade can suppress acute T helper type 17 (Th17) responses via its differentiation and, importantly, can ameliorate chronic inflammation. Tocilizumab, a recombinant humanized anti-IL-6 receptor antibody, has been shown to be effective in several autoimmune diseases, including uveitis. Herein, we discuss the basic biology of IL-6 and its role in development of autoimmune conditions, focusing particularly on non-infectious uveitis. It also provides an overview of efficacy and safety of tocilizumab therapy for ocular inflammatory diseases.

Raloxifene suppresses experimental autoimmune encephalomyelitis and NF-κB-dependent CCL20 expression in reactive astrocytes.

Recent clinical data have led to the consideration of sexual steroids as new potential therapeutic tools for multiple sclerosis. Selective estrogen receptor modulators can exhibit neuroprotective effects like estrogen, with fewer systemic estrogen side effects than estrogen, offering a more promising therapeutic modality for multiple sclerosis. The important role of astrocytes in a proinflammatory effect mediated by CCL20 signaling on inflammatory cells has been documented. Their potential contribution to selective estrogen receptor modulator-mediated protection is still unknown. Using a mouse model of chronic neuroinflammation, we report that raloxifene, a selective estrogen receptor modulator, alleviated experimental autoimmune encephalomyelitis–an animal model of multiple sclerosis–and decreased astrocytic production of CCL20. Enzyme-linked immunosorbent assay, immunohistochemistry imaging and transwell migration assays revealed that reactive astrocytes express CCL20, which promotes Th17 cell migration. In cultured rodent astrocytes, raloxifene inhibited IL-1β-induced CCL20 expression and chemotaxis ability for Th17 migration, whereas the estrogen receptor antagonist ICI 182,780 blocked this effect. Western blotting further indicated that raloxifene suppresses IL-1β-induced NF-κB activation (phosphorylation of p65) and translocation but does not affect phosphorylation of IκB. In conclusion, these data demonstrate that raloxifene provides robust neuroprotection against experimental autoimmune encephalomyelitis, partially via an inhibitory action on CCL20 expression and NF-κB pathways in reactive astrocytes. Our results contribute to a better understanding of the critical roles of raloxifene in treating experimental autoimmune encephalomyelitis and uncover reactive astrocytes as a new target for the inhibitory action of estrogen receptors on chemokine CCL20 expression.

Mechanisms of autoimmunity in human diseases

Autoimmune diseases such as rheumatoid arthritis (RA) pose an increasing, worldwide economic and health burden. Significantly, no cure exists for the majority of autoimmune diseases and consequently treatment is largely aimed at controlling disease symptoms. Therefore, there exists a critical need to develop new approaches that directly address the cause of disease, leading to disease remission and ultimately cure. The organs, cells and molecules involved in the breach of self-tolerance have been partially defined in experimental models of autoimmunity. However, the broad applicability of this dogma in clinical disease is only partially understood. This gap between analyses of established disease and investigating early disease pathogenesis argues for the need for complementary studies in mice and humans. Through a combination of clinical and experimental systems, novel autoantigens and neoepitopes involved in RA have been revealed. These have clear utility in predisease diagnosis and offer the possibility of antigen-specific immunotherapy. Ongoing experimental and clinical studies, for example using dendritic cell transfer, will facilitate a clearer understanding of the molecules, cells and organs that should be targeted to reinstate immunological tolerance. Antigen-specific immunotherapy therefore offers disease intervention without broad immunosuppression, and most importantly increases the likelihood of achieving true disease remission and cure.

Relevance of Nck–CD3ε Interaction for T Cell Activation In Vivo

On TCR ligation, the adaptor Nck is recruited through its src homology 3.1 domain to a proline-rich sequence (PRS) in CD3ε. We have studied the relevance of this interaction for T cell activation in vitro and in vivo by targeting the interaction sites in both partners. The first approach consisted of studying a knockin (KI) mouse line (KI-PRS) bearing a conservative mutation in the PRS that makes the TCR incompetent to recruit Nck. This deficiency prevents T cell activation by Ag in vitro and inhibited very early TCR signaling events including the tyrosine phosphorylation of CD3ζ. Most important, KI-PRS mice are partly protected against the development of neurological symptoms in an experimental autoimmune encephalitis model, and show a deficient antitumoral response after vaccination. The second approach consisted of using a high-affinity peptide that specifically binds the src homology 3.1 domain and prevents the interaction of Nck with CD3ε. This peptide inhibits T cell proliferation in vitro and in vivo. These data suggest that Nck recruitment to the TCR is fundamental to mount an efficient T cell response in vivo, and that the Nck-CD3ε interaction may represent a target for pharmacological modulation of the immune response.

Iodine Intake Increases IP-10 Expression in the Serum and Thyroids of Rats with Experimental Autoimmune Thyroiditis

Here, we sought to establish an experimental autoimmune thyroiditis rat model induced by bovine thyroglobulin (bTg) injection and to investigate pathological changes and variations in serum interferon-γ-inducible protein of 10 kDa (IP-10) in thyroid tissue following iodine treatment. Four-week-old female Lewis rats (n = 135) were randomly divided into normal (NC), thyroglobulin (TG), HI, HI+TG, HII, and HII+TG groups; rats in the NC and TG groups drank only distilled water (iodine concentration: 10 μg/L), rats in the HI and HI+TG groups were given water containing 25.7 mg/L iodine, and rats in the HII and HII+TG groups were given water containing 423.3 mg/L iodine. Rats in the TG, HI+TG, and HII+TG groups were immunized with 0.1 mL bTg (8 mg/mL) in incomplete Freund's adjuvant once every 2 weeks for 6 weeks. Compared with the NC group, the TG, HI+TG, and HII+TG groups exhibited higher iodine intake and increased thyroid weights with increasing iodine doses (P < 0.05). The high iodine intake in the TG group was associated with increased CD4+ T cells and serum IP-10. Thus, high iodine consumption aggravated the inflammatory reaction in the thyroid and mild high iodine consumption increased serum IP-10 levels after induction with bTg.

PReS-FINAL-2153: Intestinal gamma/delta- T cells are upregulated in children with active uveitis

Conclusion Our finding suggests, that intestinal immune activation involving the increase of g/δ lymphocytes contributes to the pathogenesis of uveitis in children with JIA. Although both the factors inducing the intestinal mucosal immune activation in JIA and the mechanism linking intestinal activation and uveitis remain speculative, we suspect that pathological entry of the gut originating lymphocytes into the iris is possible because intensive distribution of the adhesion molecules on the endothelium of the vessels in the iris in patients with uveitis. Our finding encourages to study the potential role of gastrointestinal factors in the pathogenesis of uveitis associated with JIA. Our finding together with reports of experimental autoimmune uveitis models support the hypothesis of gut mucosa, gut lymphocyte homing receptors in the uvea, and the role of gut originating lymphocytes in the development of uveitis.

Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis

Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.

Intravenous immunoglobulin preparation attenuates neurological signs in rat experimental autoimmune neuritis with the suppression of macrophage inflammatory protein -1α expression

To clarify the mechanism of action of an intravenous immunoglobulin (IVIG) preparation in chronic inflammatory demyelinating polyneuropathy, the effects of IVIG were investigated using an experimental autoimmune neuropathy model in the rat. IVIG significantly suppressed the progression of neurologic signs and sciatic nerve conduction velocity with the inhibition of inflammatory cell infiltration, mainly of macrophages, to the peripheral nerves. A significant suppressive effect on the expression of macrophage inflammatory protein 1-α (MIP-1α) was simultaneously observed in the nerves. These results suggest that IVIG is effective for inflammatory demyelinating polyneuropathy by inhibiting the chemotactic factor of macrophages.

FTY720 protects neuronal cells from damage induced by human prion protein by inactivating the JNK pathway

Prion diseases affect the central nervous system (CNS) in humans and animals, and are associated with the conversion of the cellular prion protein (PrPC) to the misfolded isoform (PrPSc). FTY720, an immune modulator and synthetic analogue of sphingosine-1-phosphate (S1P), activates S1P receptors and has been shown to be effective in experimental models of transplantation and autoimmunity, including multiple sclerosis. Whereas the immune modulatory functions of FTY720 have been extensively investigated, the other functions of FTY720 are not yet well understood. In this study, we investigated the effects of FTY720 phosphate (FTY720-p) on prion protein-mediated neuronal cell death, as well as its effects on intracellular apoptotic pathways. Treatment with FTY720-p protected neuronal cells from synthetic human prion protein peptide [PrP(106‑126)]-mediated damage and prevented mitochondrial dysfunction by inhibiting the activation of c-jun N-terminal kinase. Moreover, FTY720-p prevented the PrP(106‑126)-induced reduction in mitochondrial potential, the translocation of Bax to the mitochondria and the release of cytochromec. To the best of our knowledge, this study is the first to demonstrate the effects of FTY720 on prion protein-mediated neurotoxicity and to suggest that FTY720 has therapeutic potential in prion diseases.

Stress in Multiple Sclerosis: Review of New Developments and Future Directions

In the experimental autoimmune encephalitis model of multiple sclerosis, the effects of stress on disease severity depend on multiple factors, including the animal's genetics and the type of stressor. The studies in humans relating stress to the risk of developing multiple sclerosis have found discordant results. The studies looking at the association of stress with relapses show a fairly consistent association, where higher stress is associated with a higher risk of relapse. Higher stress levels also appear to increase the risk of development of gadolinium-enhancing lesions. A recent randomized trial shows that reducing stress using stress management therapy (SMT), a cognitive-behavioral therapy approach, results in a statistically significant reduction in new magnetic resonance imaging lesions. The magnitude of this effect is large and comparable to the effects of existent disease-modifying therapies, but no data exist yet proving that SMT reduces relapses or clinical progression; the effect of SMT appears to be short-lived. Additional work is needed to improve the duration of this effect and make this therapy more widely accessible.

Uroplakin Peptide-Specific Autoimmunity Initiates Interstitial Cystitis/Painful Bladder Syndrome in Mice

The pathophysiology of interstitial cystitis/painful bladder syndrome (IC/PBS) is enigmatic. Autoimmunity and impaired urothelium might lead the underlying pathology. A major shortcoming in IC/PBS research has been the lack of an appropriate animal model. In this study, we show that the bladder specific uroplakin 3A-derived immunogenic peptide UPK3A 65–84, which contains the binding motif for IAd MHC class II molecules expressed in BALB/c mice, is capable of inducing experimental autoimmune cystitis in female mice of that strain. A highly antigen-specific recall proliferative response of lymph node cells to UPK3A 65–84 was observed, characterized by selectively activated CD4+ T cells with a proinflammatory Th1-like phenotype, including enhanced production of interferon γ and interleukin-2. T cell infiltration of the bladder and bladder-specific increased gene expression of inflammatory cytokines were observed. Either active immunization with UPK3A 65–84 or adoptive transfer of peptide-activated CD4+ T cells induced all of the predominant IC/PBS phenotypic characteristics, including increased micturition frequency, decreased urine output per micturition, and increased pelvic pain responses to stimulation with von Frey filaments. Our study demonstrates the creation of a more specific experimental autoimmune cystitis model that is the first inducible model for IC/PBS that manifests all of the major symptoms of this debilitating condition.