Mark A. Jensen

Interferon β decreases T cell activation and interferon γ production in multiple sclerosis

Abstract Interferons (IFN) are biological molecules with anti-viral, anti-proliferative and immunomodulatory actions. There is evidence that IFN-γ increases the frequency of exacerbations of multiple sclerosis (MS) whereas IFN-β may reduce their frequency. Here we present evidence that IFN-β significantly decreases concanavalin A (Con A)-induced proliferation of peripheral blood mononuclear cells (PBMC) of MS patients and healthy individuals. Similar results were obtained when PBMS were activated through the T cell receptor (TcR) by anti-CD3 monoclonal antibody or independently of it by phorbol ester and Ca 2+ ionophore. These effects of IFN-β were also noted when IFN-γ and IFN-β were added together. Furthermore, IFN-β decreased proliferation when added to cells that were already pre-activated. Activated CD4 + and CD8 + T cells were downregulated to approximately the same extent. Analysis of cytokine production showed that IFN-γ production by Con A activated PBMC was increased in MS when compared to controls. IFN-β significantly decreased IFN-γ production in MS patients and control individuals. Con A activated cultures treated with IFN-β showed decreased IL2R expression and accumulation of IL2. These results show that IFN-β decreases T cell activation and IFN-γ production in vitro, effects that may be beneficial in MS.

Interfer beta augments supperssor cell function in multiple sclerosis

Suppressor cell function has been previously reported to be decreased in patients with progressive multiple sclerosis (MS). The abnormality could not be corrected in vitro and was present even after patients were treated with immunosuppressive agents. We now report that interferon beta augments suppressor function in vitro in progressive MS. Nonspecific suppressor cell function as measured in a concanavalin A (Con A) suppressor assay was reduced in 24 MS patients (mean percent suppression, 19.6 ± 2.2) when compared to 19 normal subjects (mean percent suppression, 35.0 ± 3.3). The data are highly significant (p < 0.001). When recombinant human interferon beta (103 units/ml) was added to lymphocyte cultures with Con A, Suppressor activity improved from 19.6 ± 2.2 to 37.8 ± 2.6 in MS (p < 0.001) and from 35.0 ± 3.3 to 46.2 ± 3.5 (p < 0.025) in control subjects. This study shows that recombinant interferon beta improves suppressor function in humans, an effect that is particularly significant in progressive MS.

Interferon-gamma-secreting cells in multiple sclerosis patients treated with interferon beta-1b

Fifteen percent of multiple sclerosis patients about to be treated with interferon beta-1b exhibited elevated numbers of circulating interferon-gamma-secreting cells, defined as a value that exceeded the mean value for healthy controls by more than two standard deviations. Sixty percent of patients receiving the drug exhibited elevated interferon-gamma-secreting cell numbers during their first 2 months of treatment. Values normalized after 3 months. Prednisone treatment during the first month on the drug prevented the interferon-gamma-secreting cell surge. NEUROLOGY 1995;45: 2173-2177

Interferon γ- and interleukin-4-secreting cells in multiple sclerosis

Interleukin 4 (IL-4)- and interferon γ (IFNγ)-secreting peripheral blood cells were enumerated by immunospot assay in 13 multiple sclerosis (MS) patients during exacerbations, in 24 patients with progressive multiple sclerosis (CPMS), and in 20 controls. Cells that spontaneously secreted IFNγ were significantly higher in MS patients experiencing an attack (P<0.001) than in controls or in CPMS (P<0.04). IL-4-secreting cell numbers were elevated significantly and to a comparable extent in both MS groups compared to controls. Our finding of increased numbers of IFNγ-secreting cells is in keeping with prior work showing increased IFNγ levels in the circulation prior to and durinng MS attacks and increased release of IFNγ to the supernatant in bulk cultured blood cells from MS patients. What role an increase in IL-4-secreting cells might play in MS is unclear, but it could relate to immune system regulation. Following in vitro exposure to MBP, IFNγ-secreting cell number rose above levels observed in the absence of stimulation in controls and in both MS groups with the rise in acutely exacerbating MS patients being significantly greater than in controls. Our results provide further evidence for reactivity to MBP in MS, the significance of which in terms of pathogenesis remains clouded.

Prostaglandins and inhibitors of arachidonate metabolism suppress experimental allergic encephalomyelitis

Experimental allergic encephalomyelitis (EAE) is an autoimmune inflammatory disease of the central nervous system (CNS). It is an animal model of post-infectious encephalomyelitis and multiple sclerosis (MS). Acute EAE is mediated by macrophages and by T helper 1 (Th1) lymphocytes directed against brain antigens. Inflammation in EAE could potentially be modified by prostaglandins (PG) secreted by blood monocytes (Mo) and brain glial cells. PGE elevates cAMP, which inhibits Mo function and selectively blocks secretion of cytokines by Th1 cells. In the present study, we found that a long-acting PGE1 analogue (LAPGE) inhibited clinical and histological EAE. Indomethacin (INDO) also suppressed active EAE. The combination of INDO plus LAPGE inhibited disease further, possibly by allowing LAPGE to function unopposed by immunostimulatory PG. EAE was suppressed when these agents were administered from the time of immunization or from the onset of clinical disease. The combination of INDO plus LAPGE also inhibited delayed-type hypersensitivity (DTH) reactions to myelin basic protein (MBP), and diminished in vitro lymphocyte responses to mitogens and MBP. PGE analogues and modifiers of arachidonate metabolism block autoimmune responses to brain antigens in vitro and in vivo, and may ameliorate inflammatory and autoimmune diseases of the brain and other organs.

Mechanisms of action of interferon-β in multiple sclerosis

Interferon-β-lb (IFN-β-lb, Betaseron) at a dose of 8 million units (8MU) given subcutaneously (s.c.) every other day to patients with the relapsing-remitting form of multiple sclerosis (MS) lessens the overall frequency of MS attacks by 35%, the frequency of major attacks by 50%, and the number of MS-related hospitalizations by 40% [1, 2], Benefit persists for at least 5 years, the last assessable time point in the pivotal clinical trial that led to approval of the agent for the treatment of MS [3] by the United States Food and Drug Administration. The agent drastically curtails accumulating disease burden, as assessed by annual magnetic resonance imaging (MRI) scans, again over at least 5 years [4]. Disease activity as measured by serial MRI scans performed at 6-week intervals, is also markedly reduced by IFN-β-lb treatment [4]. IFN-β-lb is currently approved for the treatment of ambulatory MS patients in the United States and Australia; approval in Europe is expected imminently. Trials to determine whether it is effective in progressive MS are underway currently.

A reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis Implications for treatment of inflammatory brain disease

Glucocorticoid (GCC) therapy usually inhibits inflammatory diseases, but certain regimens can trigger relapses. Clinical use of steroids is not uniform and in some instances may be dangerous. In the present study, GCCs modified the course of experimental allergic encephalomyelitis (EAE) in Lewis rats, a model of inflammatory CNS disease. Continuous treatment with dexamethasone (DEX) completely blocked EAE. RU 486, a GCC antagonist, counteracted the effects of endogenous GCCs and worsened EAE. Sudden withdrawal of DEX also caused severe clinical and histologic exacerbations at a time when paired saline-treated animals had completely recovered. In rats that had complete clinical recovery from EAE, and would not have relapsed without this acute steroid deficit, a short pulse of DEX was followed by severe exacerbations. In contrast, a slow steroid taper prevented exacerbations. Abrupt discontinuation of GCCs provokes inflammatory brain disease.

Central nervous system cytokine mRNA expression following Theiler's murine encephalomyelitis virus infection.

DA strain of Theilers murine encephalomyelitis virus (TMEV) produces a biphasic disease with an initial self-limited acute gray matter polioencephalomyelitis in all strains of mice followed by, in the case of certain susceptible strains of mice, a chronic inflammatory demyelination of the spinal cord with a persistent virus infection. A pathogenic role for T-helper 1 (Th1) cells during the demyelinating phase of disease has been proposed. We characterized the cytokine mRNA expression in the brain and spinal cord of susceptible and resistant strains of mice during the early encephalomyelitic disease and the late demyelination, using a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay. At the time of the encephalomyelitis, both resistant and susceptible mice expressed proinflammatory cytokine mRNAs followed by T-cell derived mRNAs; susceptible mice expressed more IL-12 p40 mRNA than resistant mice. During this early disease, there was no significant difference in Th1 cytokine mRNA expression in the brain and spinal cord among the four strains and relatively little Th2 type cytokine upregulation above levels seen in mock-infected controls. During the late demyelinating disease, susceptible but not resistant mice had evidence of viral genome and a continuous expression of Th1 type cytokine mRNAs. The expression of Th2 cytokine mRNAs varied among the different strains and did not correlate with susceptibility or resistance. The results indicate the complexity of cytokine mRNA expression following TMEV infection and the dependence of the expression on disease pathology, the time following infection and the genetics of the host.

Soft tissue coverage of the elbow: a reconstructive algorithm.

Soft tissue defects can occur for various reasons, but they are primarily due to trauma, tumor, and infection. Coverage choices may include primary closure, skin grafting, local cutaneous flaps, fasciocutaneous transposition flaps, island fascial or fasciocutaneous flaps, muscle or myocutaneous pedicled flaps, and microvascular free-tissue transfer. Despite the multitude of options for coverage, the authors have found four flaps to provide reliable coverage for most elbow deficits within their practice; these flaps are the latissimus dorsi flap, the radial forearm flap, the anconeus flap, and the free anterior lateral thigh flap. This article provides an overview of treatment options for elbow coverage, with specific emphasis on the use of these four specific flaps.

Targeting of Myelin Protein Zero in a Spontaneous Autoimmune Polyneuropathy

Elimination of the costimulatory molecule B7-2 prevents autoimmune diabetes in NOD mice, but leads to the development of a spontaneous autoimmune polyneuropathy (SAP), which resembles the human disease chronic inflammatory demyelinating polyneuropathy (CIDP). In this study, we examined the immunopathogenic mechanisms in this model, including identification of SAP Ags. We found that B7-2-deficient NOD mice exhibit changes in cytokine and chemokine gene expression in spleens over time. There was an increase in IL-17 and a decrease in IL-10 transcript levels at 4 mo (preclinical phase), whereas IFN-γ expression peaked at 8 mo (clinical phase). There was also an increase in transcript levels of Th1 cytokines, CXCL10, and RANTES in sciatic nerves of mice that developed SAP. Splenocytes from SAP mice exhibited proliferative and Th1 cytokine responses to myelin P0 (180–199), but not to other P0 peptides or P2 (53–78). Adoptive transfer of P0-reactive T cells generated from SAP mice induced neuropathy in four of six NOD.SCID mice. Data from i.v. tolerance studies indicate that myelin P0 is one of the autoantigens targeted by T cells in SAP in this model. The expression of P0 by peri-islet Schwann cells provides a potential mechanism linking islet autoimmunity and inflammatory neuropathy.