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 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. Interferon-beta prevents attacks of MS. IFN-treated patients have a decrease in 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.

We recently found a significant defect in IFN signal transduction in MS. We are using mRNA arrays, flow cytometery of IFN receptor expression, RT-PCR, gel shift assays, and phosphotyrosine blots 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.

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

Cortisol is regulated by a chain of signals: higher CNS areas to the hypothalmus to the pituitary to the adrenal gland. Cortisol regulation is abnormal in MS and depression. This insensitivity to feedback control interferes with steroid therapy of MS.

Activated lymphocytes produce ACTH, a pituitary hormone. Since MS cells are activated, they may produce ACTH and cortisol and affect feedback control. We are investigating lymphocyte ACTH production and processing by using immunofluorescent stains, Western blots, and mRNA dot and Northern blots to quantify gene expression and regulation.

Experimental allergic encephalomyelitis (EAE) is in some ways a model of multiple sclerosis (MS). We find that IL-10 and prostaglandins inhibit clinical and histological EAE. As a direct result of these animal experiments, we found that PGE dramatically reduced the severe pain of trigeminal neuralgia in MS.

Selected Papers

Books and Chapters

Reder AT. (1997). Interferon Therapy of Multiple Sclerosis.  Marcell Dekker, Inc., New York.

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

Reder AT. (2007). Multiple sclerosis. In: Medlink/Neurobase, Ed. S Gilman, GW Goldstein, SG Waxman, Arbor Publishing, San Diego.

Journal Articles

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

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

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

Reder AT, Thapar M and Jensen MA. (1994). Reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis: Implications for treatment of inflammatory brain disease. Neurol. 44:2289-2294.

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

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

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

Reder AT, Genç K, Byskosh PV and Porrini AM. (1998). Monocyte activation in multiple sclerosis. Multiple Sclerosis, 4:162-168.

Feng X, Yau D, Holbrook C, and Reder AT. (2002). 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.

Feng X, Petraglia, AL, Chen M, Byskosh PV, Boos MD and Reder AT. (2002). Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1. J Neuroimmunol 129:105-115.

Feng X, Eide FF, Jiang H, and Reder AT. (2004). Adeno-associated viral vector-mediated APOE expression in Alzheimer’s disease mice: Low CNS immune response, long-term expression, and astrocyte specificity. Front Biosci 9:1540-1546 URL: http://www.bioscience.org/2004/v9/af/1323/fulltext.htm

Ahn J, Feng X, Patel N, Dhawan N, and Reder AT. (2004). Abnormal levels of interferon-gamma receptors in active multiple sclerosis are normalized by IFN-? therapy: Implications for control of apoptosis. Front Biosci 9:1547-1555 URL: http://www.bioscience.org/2004/v9/af/1331/fulltext.htm

Hamamcιoğlu K and Reder AT. (2007). Interferon-B regulates cytokines and BDNF: Greater effect in relapsing than in progressive MS, Multiple Sclerosis 13(4):459-470.