Interferons Types 1 & 2

Cytokines are PleioTropic molecules showing a wide variety of biologic functions on various cells and tissues, and several different Cytokines exert similar and overlapping functions on certain cells.

Interferons (IFNs), among the first Cytokines identified, play a crucial role in human disease. The IFN Cytokine family consists of Type 1 IFNs-alpha & beta (IFN- and IFN-ß) and Type 2 IFN- (IFN-).

In the first decades of IFN research, Type 1 IFNs were considered primarily as Viral Inhibitors, whereas Type 2 IFN, also termed "Immune IFN", was generally considered to be uniquely involved in Immune Reactions. This view has changed considerably in the last years.

The importance of Type 1 IFNs in Inflammation, ImmunoRegulation and T-Cell responses has been identified and has changed dramatically our interpretation of the biological relevance of Type 1 and 2 IFNs.

Recent data suggest that IFN- is a multifunctional ImmunoModulatory Cytokine with profound effects on the Cytokine Cascade including several AntiInflammatory properties.

Whereas IFN- remains a classical ProInflammatory Cytokine.

These different effects on critical mediators of Inflammation may also explain why Type 1 and 2 IFNs are clinically successful in different diseases.

These newly identified ImmunoRegulatory and AntiInflammatory functions of Type 1 IFNs may be of importance in the treatment of diseases such as Chronic Viral Hepatitis or Multiple Sclerosis and help to explain some of the mechanisms of IFNs.

Treatment of Multiple Sclerosis (MS) with Interferon-beta (IFN-ß) Reduces Relapse Rate, Magnetic Resonance Imaging (MRI) Activity and Progression Of Disability.

It has been suggested that this beneficial effect is paralleled by an inhibition of ProInflammatory Cytokines such as Interferon gamma (IFN-) and Tumor Necrosis Factor alpha (TNF-) and an induction of AntiInflammatory Cytokines such as InterLeukin-4 (IL-4) and InterLeukin-10 (IL-10).

In this study, we record a reduced number of spontaneously IFN- mRNA-expressing CerebroSpinal Fluid MonoNuclear Cells (CSF-MC) and IFN-, TNF- and IL-10 mRNA-expressing Peripheral Blood MonoNuclear Cells (PBMC) after 6 months of IFN-ß-1a treatment, paralleled by a decreased Purified Protein Derivate (PPD)-stimulated and unstimulated IFN- secretion by PBMC.

These effects were not apparent after 2 weeks of treatment, and IFN-ß-1a induced IFN- production by naive PBMC in vitro.

We did not record increased numbers of IL-4 mRNA-expressing CSF-MC or PBMC, increased Plasma IL-10 levels, increased numbers of IgG, A or M secreting Plasma Cells or in vitro induction of IL-10 production by IFN-ß-1a.

We conclude that long-term Cytokine modulation by IFN-ß-1a differs from acute effects and that downregulation of both pro- and AntiInflammatory Cytokines, rather than a shift in the Cytokine profile, is apparent after 6 months of IFN-ß-1a treatment of MS patients.

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#3

Cross-Reactivity Of T-Cell Clones Specific For Altered Peptide Ligands Of Myelin Basic Protein

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#4

Direct Analysis Of Viral-Specific CD8⁺ T-Cells With Soluble HLA-A2/Tax11-19 Tetramer Complexes In Human T-Cell Lymphotropic Virus-Associated Myelopathy

Acute Disseminated EncephaloMyelitis (ADEM), a postinfectious illness of the Central Nervous System (CNS), is thought to be an AutoImmune Disease.

Here, we characterized the Cytokines secreted by Myelin-reactive T-Cells generated from patients with ADEM. The frequency of MBP-reactive T-Cell lines was ten-fold higher in patients with ADEM compared to patients with Encephalitis and normal subjects.

Whereas there was no significant IFN- secretion, the predominant Cytokine secreted by MBP-reactive T-Cell lines was IL-4 in patients with ADEM. In contrast, IL-4 secretion was only rarely detected in the controls.

The presence of high frequencies of MBP-reactive IL-4 secreting T-Cells in subjects with ADEM during their recovery phase may be similar to Myelin reactive IL-4 secreting T-Cells observed during the spontaneous recovery of animals with EAE.

The objective of this study was to determine whether AutoReactive T-Cells in patients with Multiple Sclerosis (MS) are polarized and committed in their differentiation to a stable Cytokine phenotype or whether the Cytokine secretion can be altered.

We examined the Cytokines secreted by Myelin Basic Protein (MBP) as compared to Tetanus Toxoid-reactive (TT) T-Cells in 12 patients with Relapsing/Remitting MS (RR-MS), 9 patients with Chronic/Progressive MS (CP-MS), and 14 normal individuals.

A total of 5094 short term T-Cell lines to MBP and TT were generated in the presence of growth conditions promoting Th1 (IL-12/-IL-4 mAb) or Th2 (IL-4/-IL-12 mAb) Cytokine secretion.

Antigen-specific Cytokine secretion from normals and MS patients could be shifted to a Th1 or Th2 Type phenotype depending upon culture conditions, indicating that the phenotype of MBP reactive T-Cells can be altered even in longstanding Chronic/Progressive MS.

There were no significant differences in the Cytokine patterns secreted by MBP reactive T-Cells in patients with MS as compared to normal individuals.

However, CP-MS patients tended to have fewer MBP reactive T-Cells secreting IL-4 when cultured with IL-12/anti-IL-4 mAb and more IFN- secreting MBP reactive T-Cells when cultured with IL-4/anti-IL-12 mAb.

As compared to both normal controls and RR-MS, suggesting thaT-Cells from these patients might be more polarized or that fewer undifferentiated MBP-reactive cells are present in these individuals.

The most striking observation was that in contrast to the RR-MS patients and normal controls, almost none of the MBP reactive T-Cells secreting Cytokines in CP-MS incorporated 3[H]Thymidine.

This may be due to chronic in vivo stimulation in the presence of IL-12, or because these T-Cells may have entered a terminally differentiated state.

Nonetheless, the ability to alter the Cytokine secretion of AutoReactive T-Cell lines even in longstanding AutoImmune Disease indicates that Cytokine therapy might have therapeutic benefits by switching the function of Myelin reactive T-Cells such that they are Non-Pathogenic.

Interferon-beta (IFN-ß) reduces exacerbations of the Relapsing/Remitting form of Multiple Sclerosis (MS), but the exact mechanisms by which it exerts its beneficial effects are unknown.

In this study, we examined the effects of IFN-ß on Microglial functions, as either Antigen Presenting Cells or Effector Cells for inflammatory DeMyelination. IFN-ß significantly suppressed the expression of Class II MHC Antigen and the Co-Stimulatory molecule B7-1 in Microglia.

It also suppressed Microglial IL-12 production and differentiation of Myelin Oligodendrocyte Glycoprotein (MOG)-sensitized T-Cells into the T-Helper 1 phenotype, which use Microglia as Antigen Presenting Cells.

However, IFN-ß significantly and dose-dependently enhanced the production of inflammatory mediators for DeMyelination, such as TNF-, IL-1ß, IL-6, and Nitric Oxide (NO).

The upregulation of inflammatory mediators was effectively suppressed with a Phosphodiesterase Inhibitor. Thus, IFN-ß may exert its suppressive effects in the induction phase, but not in the effector phase of MS.

Side effects of IFN-ß treatment may be due to elevation of pro-inflammatory Cytokines, and may be reduced by co-treatment with Phosphodiesterase Inhibitors.