Multiple sclerosis (MS), a disease of presumably autoimmune aetiology, is character ized by inflammation, demyelination and axonal degeneratio n in the central nervous system. C urrent treatment concepts target the inflammatory activity, reducing the number of relapses and inflammatory lesions on magnetic resonance imaging as well as the proinflammatory cytokine production in blood lymphocytes. Recently, the neuroprotective aspect of inflammation has been documented and is thought to be mediated by neurotrophins, like brain-derived neurotrophic factor (BDNF). The question whether the in vitro BDNF production in MS patients and healthy controls is influenced by the immunomodulatory agents interferon beta (IFN-beta) and immunoglobulin G (Ig) is addressed. A significantly increased BDNF production in MS patients was found compared with normal controls (mean±SD: 492±172 pg/mL versus 217±55 pg/mL, P-0.001). IFN-beta and low-dose Ig had no effect on BDNF production, whereas high-dose Ig reduced in vitro BDNF production in MS patients significantly (to 409±125 pg/mL, P-0.001). These in vitro findings might indicate that Igs in high doses potentially interfere with neuroprotective mechanisms despite their potent anti-inflammatory properties.
Yan Q , Elliott J , Snider WD.Brain-derived neurotrophic factor rescues spinal motor neurons from axonotomy-induced cell death . Nature1992; 360: 753-755 .
2.
Novikov L , Novikova L , Kellerth JO.Brain derived neurotrophic factor promotes survival and blocks nitric oxide synthase expression in adult spinal motoneurons after ventral root avulsion . Neurosci Lett1995; 200: 45-48 .
3.
Kishino A , Ishige Y , Tatsuno T , Nakayama C , Noguchi H.BDNF prevents and reverses adult rat motor neuron degeneration and induces axonal outgrowth . Exp Neurol1997; 144: 273-286 .
4.
Lewin SL , Utley DS , Chenget, Verity AN , Terris DJ.Simultaneous treatment with BDNF and CNTF after peripheral nerve transection and repair enhances rate of functional recovery compared with BDNF treatment alone . Laryngoscope1997; 107: 992-999 .
Ebadi M , Bashir RM , Heidrick ML , Hamada FM , El Refaey H , Hamed A , Helal G , Baxi MD , Cerutis DR , Lassi NK.Neurotrophins and their receptors in nerve injury and repair . Neurochem Int1997; 30: 347-374 .
7.
Cho HJ , Kim JK , Zhou XF , Rush RA.Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root gang-lia and spinal cord following peripheral inflammation . Brain Res1997; 764: 269-272 .
8.
Cho HJ , Kim SY , Park MJ , Kim DS , Kim JK , Chu MY.Expression of mRNA for brain-derived neurotrophic factor in the dorsal root ganglion following peripheral inflammation . Brain Res1997; 749: 358-362 .
9.
Tonra JR , Curtis R , Wong V , Cliffer KD , Park JS , Timmes A , Ngyen T , Lindsay RM , Acheson A , DiStefano PS.Axotomy upregulates the anterograde transport and expression of brain derived neurotrophic factor in sensory neurons . J Neurosci1998; 18: 4371-4383 .
10.
Batchelor PE , Liberatore GT , Wong JYF , Porrit MJ , Frerichs F , Donnan GA , Howells DW.Activated macrophages and micro-glia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor . J Neurosci1999; 19: 1708-1716 .
11.
Soontornniyomkij V , Wang G , Pittmann CA , Wiley CA , Achim CL.Expression of brain-derived neurotrophic factor protein in activated microglia of human immunodeficiency virus type 1 encephalitis . Neuropathol Appl Neurobiol1999; 24: 453-460 .
12.
Mitsumoto H , Ikeda K , Klinkosz B , Cedarbaum JM , Wong V , Lindsay RM.Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF . Science1994; 265: 1107-1110 .
13.
McTigue DM , Horner PJ , Stokes BT , Gage FH.Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord . J Neurosci1998; 18: 5354-5365 .
14.
Kerschensteiner M , Gallmeier E , Behrens L , Leal VV , Misgeld T , Klinkert WEF , Kolbeck R , Hoppe E , Oropeza-Wekerle RL , Bartke I , Stadelmann C , Lassmann H , Wekerle H , Hohlfeld R.Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation?J Exp Med1999; 189: 865-870 .
15.
Hohlfeld R , Kerschensteiner M , Stadelmann C , Lassmann H , Wekerle H.The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis . J Neuroimmunol2000; 107: 161-166 .
16.
Rosenfeld RD , Zeni L , Haniu M , Talvenheimo J , Radka SF , Bennett L , Miller JA , Welcher AA.Purification and identification of brain-derived neurotrophic factor from human serum . Protein Expr Purif1995; 6: 465-471 .
17.
Moalem G , Gdalyahu A , Shani Y , Otten U , Lazarovici P , Cohen IR , Schwartz M.Production of neurotrophins by activated T cells: implications for neuroprotective autoimmunity . J Auto-immun2000; 15: 331-345 .
18.
The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group . Interferon beta- 1b in the treatment of multiple sclerosis. Final outcome of the randomized controlled trial . Neurology1995; 45: 1277-1285 .
19.
Jacobs LD , Cookfair DL , Rudick RA , Herndon R , Richert JR , Salazar AM , Fischer JS , Goodkin DE , Granger CV , Simon JH , Alam JJ , Bartoszak DM , Bourdette DN , Braiman J , Brownscheidle CM , Coats ME , Cohan SL , Dougherty DS , Kinkel RP , Mass MK , Munschauer FE , Proire RL , Pullicino PM , Scherokman BJ , Weinstock-Guttman B , Whitham RH , and the MSCRG . Intramuscular Interferon beta-1a for disease progression in relapsing multiple sclerosis . Ann Neurol1996; 39: 285-294 .
20.
PRISMS Study Group . Randomised placebo-controlled double-blind study of interferon b-1a in relapsing/remitting multiple sclerosis . Lancet1998; 352: 1498-1504 .
21.
Petereit HF , Bamborschke S , Esse AD , Heiss WD.Interferon gamma producing blood lymphocytes are decreased by inter-feron beta therapy in patients with multiple sclerosis . Mult Scler1997; 3: 180-183 .
22.
Khademi Met al.Reduction of both pro- and anti-inflammatory cytokines after 6 months of interferon beta-1a treatment of multiple sclerosis . J Neuroimmunol2000; 103: 202-210 .
23.
Zang YC , Yang D , Hong J , Tejada-Simon MV , Rivera VM , Zhang JZ.Immunoregulation and blocking antibodies induced by interferon beta treatment in MS . Neurology2000; 55: 397-404 .
24.
Ocenzi V , Kouwenhoven M , Teleshova M , Pashenkov M , Fredrikson S , Link H.Multiple sclerosis: pro- and anti- inflammatory cytokines and metalloproteinases are affected differentially by treatment with IFN-beta . J Neuroimmunol2000; 108: 236-243 .
25.
Arnason BGW , Dayal A , Qu ZX , Jensen MA , Genc K , Reder AT.Mechanisms of action of interferon-ß in multiple sclerosis. In Chofflon M , Steinman L eds. Immunoneurology. Berlin: Springer , 1996: 243-266.
26.
Stangel M , Toyka KV , Gold R.Mechanisms of high-dose intravenous immunoglobulins in demyelinating diseases . Arch Neurol1999; 56: 661-663 .
27.
Poser CM , Paty DW , Scheinberg LC , McDonald WI , Davis FA , Ebers GC , Johnson KP , Sibley WA , Silberberg DH , Tourtelotte WW.New diagnostic criteria for multiple sclerosis: Guidelines for research protocols . Ann Neurol1983; 13: 227-231 .
28.
Noronha A , Toscas A , Jensen MA.Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis . J Neuroimmunol1993; 46: 145-154 .
29.
Andersson U , Bjö rk L , Skansen-Saphir U , Andersson J.Pooled human IgG modulates cytokine production in lymphocytes and monocytes . Immunol Rev1994; 139: 21-42 .
30.
Michael GJ , Averill S , Nitkunan A , Rattray M , Bennett DLH , Yan Q , Priestly HV.Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expres-sing dorsal root ganglion cells and in their central terminations within the spinal cord . J Neurosci1997; 17: 8476-8490 .
31.
Laudiero LB , Aloe L , Levi-Montalcini R , Buttinelli C , Schilter D , Gillessen S , Otten U.Multiple sclerosis patients express increased levels of beta-nerve growth factor in cerebrospinal fluid . Neurosci Lett1992; 147: 9-12 .
32.
Bracci-Laudiero L , Aloe L , Levi-Montalcini R , Calsassi M , Schilter D , Ocully JL , Otten U.Increased levels of NGF in sera of systemic lupus erythematosus patients . Neuroreport1993; 4: 563-565 .
33.
Stanisz AM , Stanisz JA.Nerve growth factor and neuroimmune interactions in inflammatory disease . Ann N YAcad Sci2000; 917: 268-272 .
34.
Otten U , Gadient RA.Neurotrophins and cytokines-intermediaries between the immune and nervous system . Int J Dev Neurosci1995; 13: 147-151 .
35.
Khan OA , Xia Q , Bever CT Jr. , Johnson KP , Panitch HS , Dhib-Jalbut SS.Interferon beta-1b serum levels in multiple sclerosis patients following subcutaneous administration . Neurology1996; 46: 1639-1643 .
36.
Ochs HD , Fischer SH , Wedgwood RJ , Wara DW , Cowan MJ , Ammann AJ , Saxon A , Budinger MD , Allred RU , Rousell RH.Comparison of high-dose and low-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases . Am J Med1984; 76: 78-82 .
37.
Fazekas F , Deisenhammer F , Strasser-Fuchs S , Nahler G , Mamoli B for the Australian Immunoglobulin in Multiple Sclerosis Stusy Group . Randomised placebo-controlledtrial of monthly intravenous immunoglobulin therapy in relapsingremitting multiple sclerosis . Lancet1997; 349: 589-593 .
38.
Sorensen PS , Wanscher B , Jensen CV , Schreiber K , Blinkenberg M , Ravnborg M , Kirsmeier H , Larsen VA , Lee ML.Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis . Neurology1998; 50: 1273-1281 .
39.
Lapchak PA , Araujo DM , Hefti F.Systemic interleukin-1b decreases brain-derived neurotrophic factor messenger RNA expression in the rat hippocampal formation . Neuroscience1993; 53: 297-301 .
40.
Poutsiaka DD , Clark BD , Vannier E , Dinarello CA.Production of interleukin-1 receptor antagonist and interleukin-1 beta by peripheral blood mononuclear cells is differentially regulated . Blood1991; 78: 1275-1281 .
41.
Sharief MK , Ingram DA , Swash M , Thompson EJ.I.v. immunoglobulin reduces circulating proinflammatory cytokines in Guillain-Barre syndrome . Neurology1999; 52: 1833-1838 .
42.
Heese K , Hock C , Otten U.Inflammatory signals induce neurotrophin expression in human microglial cells . J Neurochem1998; 70: 699-707 .
