Interferons And Their Role In Inflammation
Tilg H, Kaser A
Curr Pharm Des 1999 Oct 1;5(10):771-785
Univ Hospital, Dept of Animal Biology, Dept of Medicine, Division of Gastroenterology and Hepatology, Innsbruck, Austria
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.
Reduction Of Pro- And Anti-Inflammatory Cytokines After 6 Months Of Interferon-ß-1a Treatment Of Multiple Sclerosis
Khademi M, Wallstrom E, Andersson M, Piehl F, Di Marco R, Olsson T
J NeuroImmunol 2000 Mar 1;103(2):202-10
Karolinska Institute, Dept of Medicine, Karolinska Hospital, Stockholm, Sweden
PMID# 10696916; UI# 20159989
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.
Cross-Reactivity Of T-Cell Clones Specific For Altered Peptide Ligands Of Myelin Basic Protein
Ausubel LJ, Bieganowska KD, Hafler DA
Cell Immunol 1999 Apr 10;193(1):99-107
Center for Neurologic Diseases, Laboratory of Molecular Immunology, Boston, Massachusetts, 02115, USA
PMID# 10202117; UI# 99219849
We have determined that certain Altered Peptide Ligands (APLs) can induce T-Cells specific for the native Peptide Myelin Basic Protein (MBP) p85-99 to secrete Th2-Type Cytokines such as IL-4 and IL-5 in the absence of significant Th1-Type Cytokines.
However, it is not known whether stimulation with APLs will activate AutoReactive T-Cells or a distinct population of cells. In the present study, 18 T-Cell clones that reacted with either MBP p85-99 or one of three APLs of the Peptide substituted at TCR contact residues were generated.
T-Cells were tested functionally for their reactivity to the original stimulating Peptide as well as to the MBP APLs. In addition, the T-Cell Receptor (TCR) alpha and beta chains of each of these clones were sequenced.
In a series of T-Cell clones isolated from a Multiple Sclerosis patient, stimulation of T-Cells with the APL 93A, which has an Alanine for Lysine substitution at the TCR contact residue 93, did not induce substantial proliferation of MBPp85-99-specific T-Cell clones.
Indicating that a distinct set of T-Cell Clones was induced. However, this was not the case for another set of T-Cell clones from a different individual in which the 93A Peptide induced Clonal expansion of T-Cells highly reactive with the native MBPp85-99 Antigen.
Thus, the potential beneficial effect of using APLs to induce downregulatory Cytokines appears to depend on the specific T-Cell repertoire of the individual patient.
Copyright 1999 Academic Press.
Direct Analysis Of Viral-Specific CD8+ T-Cells With Soluble HLA-A2/Tax11-19 Tetramer Complexes In Human T-Cell Lymphotropic Virus-Associated Myelopathy
Bieganowska K, Hollsberg P, Buckle GJ, Lim DG, Greten TF, Schneck J, Altman JD, Jacobson S, Ledis SL, Hanchard B, Chin J, Morgan O, Roth PA, Hafler DA
J Immunol 1999 Feb 1;162(3):1765-71
Brigham and Women's Hospital and Harvard Medical School, Center for Neurologic Diseases, Boston, MA 02115, USA
PMID# 9973440; UI# 99138863
Human T-Cell Lymphotropic Virus-I (HTLV-I)-associated Myelopathy is a slowly Progressive Neurologic Disease characterized by Inflammatory infiltrates in the Central Nervous System accompanied by clonal expansion of HTLV-I-reactive CD8+ T-Cells.
In patients carrying the HLA-A2 allele, the Immune Response is primarily directed to the Tax11-19 Peptide.
The frequency, activation state, and TCR usage of HLA-A2/Tax11-19 binding T-Cells in patients with HTLV-I-associated Myelopathy was determined using MHC Class I Tetramers loaded with the Tax11-19 peptide.
Circulating Tax11-19-reactive T-Cells were found at very high frequencies, approaching 1:10 circulating CD8+ T-Cells.
T-Cells binding HLA-A2/Tax11-19 consisted of heterogeneous populations expressing different Chemokine receptors and the IL-2R ß-chain but not the IL-2R -chain.
Additionally, Tax11-19-reactive CD8+ T-Cells used one predominant TCR Vbeta-chain for the recognition of the HLA-A2/Tax11-19 complex.
These data provide direct evidence for high frequencies of circulating Tax11-19-reactive CD8+ T-Cells in patients with HTLV-I-associated Myelopathy.