Anthony T. Reder, M.D.

Interactions Between Nervous and Immune Systems; Immunology of Multiple Sclerosis; Cytokine-Induced Transcription Factors

Research Summary

Interaction of the CNS and the immune system, with emphasis on the immunology of multiple sclerosis.

In MS, immune cells are intermittently out of control.  White blood cells invade the brain and cause plaques of demyelination and damage neurons. 

We recently found a significant defect in interferon signal transduction in MS and an RNA profile that indicates that IFN regulation is abnormal early in MS.  IFN-beta is the main therapy for MS but its mechanism of action is unknown.  We are using mRNA arrays, flow cytometery of IFN receptor expression, RT-PCR, gel shift assays, phospho-protein blots. and mRNA microarrays to extend these investigations of cell-specific regulation of cytokine mRNA by IFNs.  This should lead to more effective treatments of MS and other inflammatory diseases.

There are other abnormalities in immune regulation in MS.  We find that the B7 protein on lymphocytes is increased 4-fold in active disease.  B7 is needed for costimulation and lymphocyte activation, and it could be a target for treatments.  IFN-treatment decreases the number of B7-1 positive B cells--a potential mechanism of action for this drug.  IFN-beta also inhibits monocyte secretion of anti-inflammatory cytokines but stimulates T cell cytokine production of these same proteins.

We also study interactions of the immune and nervous systems, linked through common cytokines, endocrine hormones, and direct innervation of lymphoid organs.  The brain influences the immune system, and shares some of the blame for its own demise. 

Lymphocyte products affect brain cell growth (IL-1), destroy brain cells (TNF), excite neurons (IFNs), and induce histocompatibility antigens (IFN-gamma, TNF-alpha).  We have used cytokines to orchestrate expression of adhesion and MHC Ags on astrocytes.  CD4+ CTL clones destroy the astrocytes, a model for rejection of transplanted brain tissues in Parkinson's disease.

Activated lymphocytes produce ACTH, a pituitary hormone; cortisol regulation is abnormal in MS.  Since MS cells are activated, they may produce ACTH and cortisol and affect feedback control.  We are investigating lymphocyte ACTH production and processing to quantify gene expression and regulation.

Selected Papers

Books and Chapters

Reder AT:  Neural regulation of the immune system.  In: Clinical Neuroimmunology, J Antel, G Birnbaum, H-P Hartung, (eds.), Blackwell Science, Inc., Malden, MA, pp. 55-71, 1998.

Reder AT:  Multiple sclerosis.  In: Medlink/Neurobase, S Gilman, GW Goldstein, SG Waxman, (eds.), Arbor Publishing, San Diego, CA, 2008.

Reder AT:  Interferon Therapy of Multiple Sclerosis. Marcell Dekker, Inc., New York, Reder AT, editor, 549 pp., 1997, second printing 2000.

Journal Articles

Reder AT.  Regulation of production of adrenocotricotropin-like proteins in human mononuclear cells.  Immunology 77:436-442, 1992.  PMID:  1335962

Reder AT, Lascola CD, Flanders SA, Maimone D, Jensen MA, Skias DD, and Lancki DW  Astrocyte cytolysis by MHC class II-specific mouse T cell clones.  Transplantation. 56:393-399, 1993. PMID:  7689259

Reder AT, Thapar M, Sapugay AM, and Jensen MA.  Prostaglandins and inhibitors of arachidonate metabolism ameliorate EAE.  J. Neuroimmunol. 54:117-127, 1994.  PMID:  7523442

Reder AT, Thapar M, and Jensen M.  A reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis: Implications for treatment of inflammatory brain disease.  Neurol. 44:2289-2294, 1994.  PMID:  7991114

Reder AT and Arnason BGW.  Trigeminal neuralgia in multiple sclerosis relived by a prostaglandin E analogue.  Neurol. 45:1097-1100, 1995.  PMID:  7783870

Byskosh PV and Reder AT.  Interferon-beta effects on cytokine mRNA in peripheral mononuclear cells in multiple sclerosis.  Mult. Scler. 1:262-269, 1996.  PMID:  9345428

Genç K, Dona DL, and Reder AT.  Increased CD80+ (B7-1) cells in active multiple sclerosis and reversal by interferon beta-1b therapy.  J Clin Invest 99:2664-2671, 1997.  PMID:  9169496

Feng X, Yau D, Holbrook C, and  Reder AT.  Type I interferons inhibit IL-10 production in activated human monocytes and stimulate IL-10 in T cells:  Implications for Th1-mediated diseases.   J Interferon Cytokine Res 22:311-319, 2002.  PMID:  12034038

Feng X, Petraglia, AL, Chen M, Byskosh PV, Boos, MD and Reder AT.  Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1.  J Neuroimmunol 129:105-115, 2002. PMID:  12161037
 
Ahn J, Feng X, Patel N, Dhawan N, and Reder AT.  Abnormal levels of interferon-gamma receptors in active multiple sclerosis are normalized by IFN-b therapy:  Implications for control of apoptosis.  Front Biosci 9:1547-1555 2004

Hamamcιoğlu K and Reder AT.  Interferon-b regulates cytokines and BDNF:  Greater effect in relapsing than in progressive MS.  Multiple Sclerosis 13:459-470, 2007.  PMID: 17463069

Yamaguchi KD, Ruderman DL, Croze E, Wagner TC, Velichko S, Reder AT, and Salamon H.  IFN‑b‑regulated genes show abnormal expression in therapy‑naïve relapsing-remitting MS mononuclear cells:  Gene expression analysis employing all reported protein-protein interactions.  J Neuroimmunology 195:116-120, 2008.  PMID: 18279974

Reder AT, Velichko S, Yamaguchi KD, Hamamcıoğlu K, Ku K, Beekman J, Wagner TC, Perez HD, Salamon H, and Croze E.  Interferon-b1b induces transient and variable gene expression in relapsing-remitting multiple sclerosis patients, independent of neutralizing antibodies or changes in IFN receptor RNA expression.  J Interferon Cytokine Res, 28:317-331, 2008.  PMID: 18547162

Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT.  Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis.  Neurology 71:1390-1395, 2008.  PMID: 18525027