Olaf Stüve

The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are approved for cholesterol reduction, may also be beneficial in the treatment of inflammatory diseases. Atorvastatin (Lipitor) was tested in chronic and relapsing experimental autoimmune encephalomyelitis, a CD4+ Th1-mediated central nervous system (CNS) demyelinating disease model of multiple sclerosis. Here we show that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming growth factor (TGF)-β. Conversely, STAT4 phosphorylation was inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon (IFN)-γ and tumour necrosis factor (TNF)-α) was suppressed. Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from EAE induction. Atorvastatin reduced CNS infiltration and major histocompatibility complex (MHC) class II expression. Treatment of microglia inhibited IFN-γ-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-γ-inducible expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product of HMG-CoA reductase, reversed atorvastatins effects on antigen-presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T cells suppressed antigen-specific T-cell activation. Thus, atorvastatin has pleiotropic immunomodulatory effects involving both APC and T-cell compartments. Statins may be beneficial for multiple sclerosis and other Th1-mediated autoimmune diseases.

Interferon beta in the treatment of multiple sclerosis Mechanisms of action

Interferon beta (IFN-β) has been shown in several clinical trials to have efficacy in MS. Its mechanism of action, however, remains unclear. In this review, several biological activities of IFN-β are highlighted, including its inhibitory effects on proliferation of leukocytes and antigen presentation. Furthermore, IFN-β may modulate the profile of cytokine production toward that of the anti-inflammatory phenotype, and this appears to occur in the systemic circulation and within the CNS. Finally, IFN-β can reduce T-cell migration by inhibiting the activity of T-cell matrix metalloproteinases. These activities are likely to act in concert to account for the mechanism of IFN-β in MS.

Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor

Article abstract Four of 10 patients who were enrolled on protocols of high-dose immunosuppression with peripheral blood stem cell rescue for MS experienced neurologic worsening while receiving recombinant human granulocyte colony-stimulating factor. There was improvement when methylprednisolone was given to three of the patients, but one patient died of respiratory failure. The mechanism of the neurologic worsening is uncertain.

Statins as potential therapeutic agents in neuroinflammatory disorders.

PURPOSE OF REVIEWnMultiple sclerosis is a central nervous system inflammatory demyelinating disease that is thought to have an autoimmune pathogenesis. Recent results indicate that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are the most commonly used oral cholesterol-lowering drugs, have immunomodulatory properties. In this article we will review those findings that indicate that statins may be beneficial in the treatment of multiple sclerosis, neurodegenerative disease, and ischemic stroke.nnnRECENT FINDINGSnIt was reported that statin treatment could either inhibit or reverse chronic and relapsing experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Several immunomodulatory properties of statins may account for their beneficial clinical effect: Statins decreased the migration of leukocytes into the central nervous system, inhibited MHC class II and costimulatory signals required for activation of proinflammatory T cells, induced a T(H)2 phenotype in T cells, and decreased the expression of inflammatory mediators in the central nervous system, including nitric oxide and tumor necrosis factor alpha. It was also demonstrated that statin use significantly reduced beta-amyloid secretion in the cerebrospinal fluid of experimental animals. Clinically, there is emerging evidence that statins have beneficial effects in patients with multiple sclerosis, Alzheimers disease, and ischemic stroke.nnnSUMMARYnIn-vitro studies have indicated that statins may have anti-inflammatory properties. Results from in-vivo animal models suggest that statins may be beneficial in treatment of different central nervous system conditions. Larger scale, randomized, double-blind trials are needed to validate the role of statins as a treatment of inflammatory central nervous system diseases.

Requirement for endocytic antigen processing and influence of invariant chain and H-2M deficiencies in CNS autoimmunity

The role of processing in antigen (Ag) presentation and T cell activation in experimental allergic encephalomyelitis (EAE) was evaluated in wild-type mice, mice that selectively express either Ii p31 or p41, and mice completely deficient in Ii or H-2M. We demonstrate that processing of myelin oligodendrocyte glycoprotein (MOG) is required for presentation of the dominant encephalitogenic MOG epitope, p35-55. Ii p31- and p41-expressing mice developed EAE with similar incidence to wild-type mice, although p41 mice had a more severe course. Ag-presenting cells (APCs) from Ii- or H-2M-deficient mice could present p35-55, but not MOG, demonstrating that these APCs could not process native MOG. Ii- and H-2M-deficient mice were not susceptible to EAE by immunization with p35-55 or MOG or by adoptive transfer of encephalitogenic T cells. However, CD4+ T cells from p35-55-immunized H-2M-deficient mice proliferated, secreted IFN-gamma, and transferred EAE to wild-type, but not H-2M-deficient, mice. Thus, EAE resistance in H-2M-deficient mice is not due to an inability of APCs to present p35-55, or an intrinsic defect in the encephalitogenic T cell repertoire, but reflects a defect in APC function. Our results indicate that processing is required for initial Ag presentation and CNS T cell activation and suggest that autopathogenic peptides of CNS autoantigen may not be readily available for presentation without processing.

PATHOGENESIS, DIAGNOSIS, AND TREATMENT OF ACUTE DISSEMINATED ENCEPHALOMYELITIS

Acute disseminated encephalomyelitis is considered a monophasic, inflammatory demyelinating disorder of the central nervous system. A temporal relationship usually exists between the onset of neurologic symptoms and an infection or a vaccination. A viral exanthem facilitates the diagnosis. Some heterogeneity exists with regard to etiology and clinical course of this disease. Immunosuppression is considered the treatment of choice.

The role of the MHC class II transactivator in class II expression and antigen presentation by astrocytes and in susceptibility to central nervous system autoimmune disease

The role of the MHC class II transactivator (CIITA) in Ag presentation by astrocytes and susceptibility to experimental autoimmune encephalomyelitis (EAE) was examined using CIITA-deficient mice and newly created transgenic mice that used the glial fibrillary acidic protein promoter to target CIITA expression in astrocytes. CIITA was required for class II expression on astrocytes. Like class II-deficient mice, CIITA-deficient mice were resistant to EAE by immunization with CNS autoantigen, although T cells from immunized CIITA-deficient, but not class II-deficient, mice proliferated and secreted Th1 cytokines. CIITA-deficient splenic APC presented encephalitogenic peptide to purified wild-type encephalitogenic CD4+ T cells, indicating that CIITA-independent mechanisms can be used for class II-restricted Ag presentation in lymphoid tissue. CIITA-deficient mice were also resistant to EAE by adoptive transfer of encephalitogenic class II-restricted CD4+ Th1 cells, indicating that CIITA-dependent class II expression was required for CNS Ag presentation. Despite constitutive CIITA-driven class II expression on astrocytes in vivo, glial fibrillary acidic protein-CIITA transgenic mice were no more susceptible to EAE than controls. CIITA-transfected astrocytes presented peptide Ag, but in contrast to IFN-γ-activated astrocytes, they could not process and present native Ag. CIITA-transfected astrocytes did not express cathepsin S without IFN-γ activation, indicating that CIITA does not regulate other elements that may be required for Ag processing by astrocytes. Although our results demonstrate that CIITA-directed class II expression is required for EAE induction, CIITA-directed class II expression by astrocytes does not appear to increase EAE susceptibility. These results do not support the role of astrocytes as APC for class II-restricted Ag presentation during the induction phase of EAE.

Migratory behavior of lymphocytes isolated from multiple sclerosis patients: Effects of interferon β-1b therapy

Previous reports by our group and by others have shown that in vitro treatment of T cells derived from healthy, normal subjects with interferon β‐1b (IFN‐β1b) reduces metalloproteinase (metalloproteinase type 9 [MMP‐9]) activity with a consequent reduction in lymphocyte migration. In this study, we used a Boyden chamber assay to assess the migratory capacity of T cells derived from multiple sclerosis patients who either did or did not receive IFN‐β1b. Lymphocytes derived from patients treated for less than 2 years with IFN‐β migrated at a low rate that was indistinguishable from that of cells isolated from healthy donors. However, longer term treatment with IFN (>3.5 years) was associated with a reversion of the migration to a high level that did not differ statistically from that of cells isolated from untreated multiple sclerosis patients. For both high‐migratory groups, migration could be reduced to control levels after the exogenous addition of TIMP‐1, a relatively specific inhibitor of the MMP‐9, implicating this protease in the process of T‐cell migration. Our findings suggest that one of the mechanisms by which IFN‐β exerts its action is by reducing MMP‐9 activity and thus the entry of inflammatory cells into the nervous system and, as such, MMPs may constitute potential therapeutic targets in inflammatory diseases such as multiple sclerosis.

Cutting Edge: Oral Type I IFN-τ Promotes a Th2 Bias and Enhances Suppression of Autoimmune Encephalomyelitis by Oral Glatiramer Acetate

IFN-τ, a novel type I IFN that possesses immunomodulatory properties, lacks toxicity normally associated with other type I IFNs. We examined the effects of oral IFN-τ alone and in combination with oral glatiramer acetate in experimental allergic encephalomyelitis (EAE). By comparison of oral administration of IFN-α, -β, and -τ to myelin basic protein-specific TCR-transgenic mice, we demonstrate these type I IFNs promote secretion of the Th2 cytokine IL-10 with similar efficiency. Whereas IFN-α and -β induced IFN-γ secretion, a Th1 cytokine, IFN-τ did not. Oral IFN-τ alone suppressed EAE. When suboptimal doses were administered orally in combination to wild-type mice, IFN-τ and glatiramer acetate had a synergistic beneficial effect in suppression of EAE. This combination was associated with TGF-β secretion and enhanced IL-10 production. Thus, IFN-τ is a potential candidate for use as a single agent or in combination therapy for multiple sclerosis.

Malignant glioma cells use MHC class II transactivator (CIITA) promoters III and IV to direct IFN‐γ‐inducible CIITA expression and can function as nonprofessional antigen presenting cells in endocytic processing and CD4+ T‐cell activation

Malignant gliomas (MGs), lethal human central nervous system (CNS) neoplasms, contain tumor infiltrating lymphocytes (TIL). Although MHC class II molecules are frequently detected on MG cells, suggesting that they may be capable of antigen (Ag) presentation to CD4+ T cells, deficiencies in CD4+ T‐cell activation are associated with these nonimmunogenic tumors. We evaluated regulation of the MHC class II transactivator (CIITA), the key intermediate that controls class II expression, in MG cells and tested whether MG cells could process native Ag. After interferon‐γ (IFN‐γ) stimulation, MG cells upregulated CIITA and class II molecules. IFN‐γ‐inducible CIITA expression in MG cells, as well as primary human astrocytes, was directed by two CIITA promoters, pIV, the promoter for IFN‐γ‐inducible CIITA expression in nonprofessional antigen‐presenting cells (APC), and pIII, the promoter that directs constitutive CIITA expression in B cells. Both pIII and pIV directed CIITA transcription in vivo in MGs and ex vivo in IFN‐γ‐activated primary MG cultures. We also demonstrate for the first time that MG cells can process native Ag for presentation to CD4+ MHC class II‐restricted Th1 cells, indicating that MG cells can serve as nonprofessional APC. CIITA may be a key target to modulate MHC class II expression, which could augment immunogenicity, Ag presentation, and CD4+ T‐cell activation in MG therapy. GLIA 36:391–405, 2001.