Abstract
Demyelinating diseases encompass a range of acute and chronic diseases affecting both the central and peripheral nervous systems. Many of these diseases share elements of autoimmune etiology, such as the presence of autoreactive T cells and B cells producing autoantibodies, followed by cell- and complement-mediated tissue damage, often following viral infection. The most common chronic demyelinating disease is multiple sclerosis (MS), a neuroinflammatory disease affecting the central nervous system (CNS). Histologically, the disease is characterized by lymphocytic infiltration of the CNS with oligodendrocyte loss, but its etiology is complex and not fully understood. Epidemiological studies implicate both environmental and genetic factors in its pathogenesis. Approved pharmaceutical treatments are predominantly immunosuppressive agents targeting the inflammatory components of disease. This review will highlight the mechanisms by which these treatments are understood to interact with the complex cast of inflammatory mediators present in MS pathogenesis.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
’t Hart B, Massacesi L (2009) Clinical, pathological, and immunologic aspects of the multiple sclerosis model in common marmosets. Exp Neurol
’t Hart BA, Laman JD, Bauer J, Blezer E, van Kooyk Y, Hintzen RQ (2004) Modelling of multiple sclerosis: lessons learned in a non-human primate. Lancet Neurol 3(10):588–597. doi:10.1016/S1474-4422(04)00879-8
’t Hart BA, Hintzen RQ, Laman JD (2009) Multiple sclerosis—a response-to-damage model. Trends Mol Med 15(6):235–244. doi:10.1016/j.molmed.2009.04.001
Aharoni R, Sasson E, Blumenfeld-Katzir T (2013) Magnetic resonance imaging characterization of different experimental autoimmune encephalomyelitis models and the therapeutic effect of glatiramer acetate. Exp Neurol 240:130–144. doi:10.1016/j.expneurol.2012.11.004
Alonso A, Hernan MA (2008) Temporal trends in the incidence of multiple sclerosis. Neurology 71:129–135
Antel J, Antel S, Caramanos Z, Arnold DL, Kuhlmann T (2012) Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity? Acta Neuropathol 123(5):627–638. doi:10.1007/s00401-012-0953-0
Ascherio A, Munger KL (2010) Epstein-Barr virus infection and multiple sclerosis: a review. J Neuroimmune Pharmacol 5(3):271–277. doi:10.1007/s11481-010-9201-3
Ascherio A, Spiegelman D, Levin LI, Munger KL, Peck CA, Lennette E (2005) Notice of retraction: “multiple sclerosis and Epstein-Barr virus”. JAMA 293(20):2466
Balcer LJ (2006) Optic neuritis. N Engl J Med 354:1273–1280
Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rötzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110:1225–1232. doi:10.1182/blood-2006-12-064527
Bourdette D, Yadav V (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. Curr Neurol Neurosci Rep 8(5):417–418, http://www.ncbi.nlm.nih.gov/pubmed/18713578
Brownell B, Hughes J (1962) The distribution of plaques in the cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry 265(25):315–320, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC495470/
Caiazzo M, Dell’Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova TD, Menegon A, Roncaglia P, Colciago G, Russo G, Carninci P, Pezzoli G, Gainetdinov RR, Gustincich S, Dityatev A, Broccoli V (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476(7359):224–227. doi:10.1038/nature10284
Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, Laubach J, Bawn SD, Gordon LI, Winter JN, Furman RR, Vose JM, Zelenetz AD, Mamtani R, Raisch DW, Dorshimer GW, Rosen ST, Muro K, Gottardi-Littell NR, Talley RL, Sartor O, Green D, Major EO, Bennett CL (2014) Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113(20):4834–4841. doi:10.1182/blood-2008-10-186999
Cifelli A, Arridge M, Jezzard P, Esiri MM, Palace J, Matthews PM (2002) Thalamic neurodegeneration in multiple sclerosis. Ann Neurol 52(5):650–653. doi:10.1002/ana.10326
Coles A, Compston A, Selmaj K, Lake S, Moran S, Margolin D, Norris K, Tandon P (2008) Alemtuzumab versus interferon beta-1a in early multiple sclerosis. N Engl J Med 359(17):1786–1801, http://www.ncbi.nlm.nih.gov/pubmed/21397567
Compston A, Coles A (2008) Multiple sclerosis. Lancet 372(9648):1502–1517. doi:10.1016/S0140-6736(08)61620-7
Constantinescu CS, Farooqi N, O’Brien K, Gran B (2011) Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 164(4):1079–1106. doi:10.1111/j.1476-5381.2011.01302.x
Crawford AH, Chambers C, Franklin RJM (2013) Remyelination: the true regeneration of the central nervous system. J Comp Pathol 149(2-3):242–254. doi:10.1016/j.jcpa.2013.05.004
Crawford AH, Stockley JH, Tripathi RB, Richardson WD, Franklin RJ (2014) Oligodendrocyte progenitors: adult stem cells of the central nervous system? Exp Neurol 260:50–55. doi:10.1016/j.expneurol.2014.04.027
Dale RC, Branson J a (2005) Acute disseminated encephalomyelitis or multiple sclerosis: can the initial presentation help in establishing a correct diagnosis? Arch Dis Child 90(6):636–639. doi:10.1136/adc.2004.062935
Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, Padmanabhan K, Swoboda JG, Ahmad I, Kondo T, Gage FH, Theofilopoulos AN, Lawson BR, Schultz PG, Lairson LL (2013) A regenerative approach to the treatment of multiple sclerosis. Nature 502(7471):327–332. doi:10.1038/nature12647
Domingues HS, Mues M, Lassmann H, Wekerle H, Krishnamoorthy G (2010) Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLoS One 5(11):e15531. doi:10.1371/journal.pone.0015531
Feger U, Luther C, Poeschel S, Melms A, Tolosa E, Wiendl H (2007) Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immunol 147(3):412–418. doi:10.1111/j.1365-2249.2006.03271.x
Filippini G, Munari L, Incorvaia B, Ebers GC, Polman C, D’Amico R, Rice GPA (2003) Interferons in relapsing remitting multiple sclerosis: a systematic review. Lancet 361:545–552. doi:10.1016/S0140-6736(03)12512-3
Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O’Farrelly C, Tubridy N, Mills KHG (2009) CD39+Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 183(11):7602–7610. doi:10.4049/jimmunol.0901881
Foroozan R, Buono LM, Savino PJ, Sergott RC (2002) Acute demyelinating optic neuritis. Curr Opin Ophthalmol 13(6):375–380. doi:10.1097/00055735-200212000-00006
Franklin RJ, Gallo V (2014) The translational biology of remyelination: past, present, and future. Glia 62(11):1905–1915. doi:10.1002/glia.22622
Goodin DS (2014) Glucocorticoid treatment of multiple sclerosis. Handb Clin Neurol 122:455–464. doi:10.1016/B978-0-444-52001-2.00020-0
Haas J, Hug A, Viehöver A, Fritzsching B, Falk CS, Filser A, Vetter T, Milkova L, Korporal M, Fritz B, Storch-Hagenlocher B, Krammer PH, Suri-Payer E, Wildemann B (2005) Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol 35(11):3343–3352. doi:10.1002/eji.200526065
Harp C, Lee J, Lambracht-Washington D, Cameron E, Olsen G, Frohman E, Racke M, Monson N (2007) Cerebrospinal fluid B cells from multiple sclerosis patients are subject to normal germinal center selection. J Neuroimmunol 183(1-2):189–199. doi:10.1016/j.jneuroim.2006.10.020
Holick MF (2004) Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 80(6 Suppl):1678S–1688S
Humm AM, Beer S, Kool J, Magistris MR, Kesselring J, Rösler KM (2004) Quantification of Uhthoff’s phenomenon in multiple sclerosis: a magnetic stimulation study. Clin Neurophysiol 115(11):2493–2501. doi:10.1016/j.clinph.2004.06.010
Hutchinson M, Fox RJ, Havrdova E, Kurukulasuriya NC, Sarda SP, Agarwal S, Siddiqui MK, Taneja A, Deniz B (2014) Efficacy and safety of BG-12 (dimethyl fumarate) and other disease-modifying therapies for the treatment of relapsing-remitting multiple sclerosis: a systematic review and mixed treatment comparison. Curr Med Res Opin 30:613–627. doi:10.1185/03007995.2013.863755
Isaksson M, Ardesjö B, Rönnblom L, Kämpe O, Lassmann H, Eloranta M-L, Lobell A (2009) Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE. Eur J Immunol 39(10):2925–2935. doi:10.1002/eji.200839179
Jacobson DL, Gange SJ, Rose NR, Graham NMH (1997) Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 84(3):223–243
Jadidi-Niaragh F, Mirshafiey A (2011) Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol 74(1):1–13. doi:10.1111/j.1365-3083.2011.02536.x
Kamphorst W, Ravid R (1998) Histopathologic correlate of hypointense lesions on Tl-weighted spin-echo MRI in multiple sclerosis. Neurology 95:1282–1288
Kanchandani R, Howe JG (1982) Lhermitte’s sign in multiple sclerosis: a clinical survey and review of the literature. J Neurol Neurosurg Psychiatry 45(4):308–312. doi:10.1136/jnnp.45.4.308
Kappos L, Radue E (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362(5):387–401, http://www.nejm.org/doi/full/10.1056/NEJMoa0909494
Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman C, Haas T, Korn AA, Karlsson G, Radue EW, FTY720 D2201 Study Group (2006) Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355(11):1124–1140, http://www.nejm.org/doi/full/10.1056/NEJMoa052643
Kawakami N, Bartholomäus I, Pesic M, Mues M (2012) An autoimmunity odyssey: how autoreactive T cells infiltrate into the CNS. Immunol Rev 248(1):140–155. doi:10.1111/j.1600-065X.2012.01133.x
Kim J, Hematti P (2009) Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol 37(12):1445–1453. doi:10.1016/j.exphem.2009.09.004
Kleinschmidt-DeMasters BK, Tyler KL (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353(4):369–374. doi:10.1056/NEJMoa051782
Kokaia Z, Martino G, Schwartz M, Lindvall O (2012) Cross-talk between neural stem cells and immune cells: the key to better brain repair? Nat Neurosci 15(8):1078–1087. doi:10.1038/nn.3163
Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353(4):375–381. doi:10.1056/NEJMoa051847
Laule C, Vavasour I, Kolind S (2007) Magnetic resonance imaging of myelin. Neurotherapeutics 4(July):460–484, http://www.sciencedirect.com/science/article/pii/S1933721307000888
Leten C, Roobrouck VD, Struys T, Burns TC, Dresselaers T, Vande Velde G, Santermans J, Lo Nigro A, Ibrahimi A, Gijsbers R, Eggermont K, Lambrichts I, Verfaillie CM, Himmelreich U (2014) Controlling and monitoring stem cell safety in vivo in an experimental rodent model. Stem Cells 32(11):2833–2844. doi:10.1002/stem.1819
Levin LI, Munger KL, Rubertone MV, Peck CA, Spiegelman D, Ascherio A (2003) Multiple sclerosis and Epstein-Barr virus. JAMA 289(12):1533–1536
Levin L, Munger K, O’Reilly E (2010) Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol 67(6):824–830. doi:10.1002/ana.21978.Primary
Martino G, Pluchino S (2006) The therapeutic potential of neural stem cells. Nat Rev Neurosci 7(5):395–406. doi:10.1038/nrn1908
Menge T, Hemmer B, Nessler S, Wiendl H, Neuhaus O, Hartung H-P, Kieseier BC, Stüve O (2007) Acute disseminated encephalomyelitis: an update. Neurology 62:1673–1680, http://www.neurology.org/content/68/16_suppl_2/S23.short
Merkler D, Ernsting T, Kerschensteiner M, Brück W, Stadelmann C (2006) A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain 129(Pt 8):1972–1983. doi:10.1093/brain/awl135
Miron VE, Franklin RJ (2014) Macrophages and CNS remyelination. J Neurochem 130(2):165–171. doi:10.1111/jnc.12705
Miron VE, Boyd A, Zhao J-W, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ, ffrench-Constant C (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218. doi:10.1038/nn.3469
Noseworthy J, Lucchinetti C, Rodriquez M, Weinshenker B (2000) Multiple sclerosis. N Engl J Med 343(13):938–952. doi:10.1056/NEJM200009283431307
Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Südhof TC, Wernig M (2011) Induction of human neuronal cells by defined transcription factors. Nature 476(7359):220–223. doi:10.1038/nature10202
Paolillo A, Pozzilli C, Gasperini C, Giugni E, Mainero C, Giuliani S, Tomassini V, Millefiorini E, Bastianello S (2000) Brain atrophy in relapsing-remitting multiple sclerosis: relationship with “black holes”, disease duration and clinical disability. J Neurol Sci 174(2):85–91. doi:10.1016/S0022-510X(00)00259-8
Peterson JW, Bö L, Mörk S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400. doi:10.1002/ana.1123
Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Björklund A, Lindvall O, Jakobsson J, Parmar M (2011) Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci U S A 108(25):10343–10348. doi:10.1073/pnas.1105135108
Pirko I, Lucchinetti C, Sriram S, Bakshi R (2007) Gray matter involvement in multiple sclerosis. Neurology 68:634–642, http://www.neurology.org/content/68/9/634.short
Pluchino S, Gritti A, Blezer E, Amadio S, Brambilla E, Borsellino G, Cossetti C, Del Carro U, Comi G, ’t Hart B, Vescovi A, Martino G (2009) Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol 66(3):343–354. doi:10.1002/ana.21745
Politi LS, Bacigaluppi M, Brambilla E, Cadioli M, Falini A, Comi G, Scotti G, Martino G, Pluchino S (2007) Magnetic-resonance-based tracking and quantification of intravenously injected neural stem cell accumulation in the brains of mice with experimental multiple sclerosis. Stem Cells 25(10):2583–2592. doi:10.1634/stemcells.2007-0037
Popescu BFG, Lucchinetti CF (2012) Pathology of demyelinating diseases. Annu Rev Pathol 7:185–217. doi:10.1146/annurev-pathol-011811-132443
Popescu BFG, Pirko I, Lucchinetti CF (2013) Pathology of multiple sclerosis: where do we stand? Continuum 19(4 Multiple Sclerosis), 901–921. doi:10.1212/01.CON.0000433291.23091.65
Prineas JW, Graham JS (1981) Multiple sclerosis: cap** of surface immunoglobulin G on macrophages engaged in myelin breakdown. Ann Neurol 10:149–158. doi:10.1002/ana.410100205
Putheti P, Pettersson A, Soderstrom M, Link H, Huang YM (2004) Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J Clin Immunol 24(2):155–161. doi:10.1023/B:JOCI.0000019780.93817.82
Qin Y, Duquette P, Zhang Y, Talbot P, Poole R, Antel J (1998) Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis. J Clin Invest 102(5):1045–1050. doi:10.1172/JCI3568
Qiu Z, Farnsworth S (2013) Patient-specific induced pluripotent stem cells in neurological disease modeling: the importance of nonhuman primate models. Stem Cells Cloning 6:19–29, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850364/
Ramagopalan SV, Sadovnick AD (2011) Epidemiology of multiple sclerosis. Neurol Clin 29(2):207–217. doi:10.1016/j.ncl.2010.12.010
Saadoun S, Waters P, Macdonald C, Bridges LR, Bell BA, Vincent A, Verkman AS, Papadopoulos MC (2011) T cell deficiency does not reduce lesions in mice produced by intracerebral injection of NMO-IgG and complement. J Neuroimmunol 235(1–2):27–32. doi:10.1016/j.jneuroim.2011.03.007
Santón A, Cristóbal E, Aparicio M, Royuela A, Villar LM, Alvarez-Cermeño JC (2011) High frequency of co-infection by Epstein-Barr virus types 1 and 2 in patients with multiple sclerosis. Mult Scler 17(11):1295–1300. doi:10.1177/1352458511411063
Schmitz K, Barthelmes J, Stolz L, Beyer S, Diehl O, Tegeder I (2015) “Disease modifying nutricals” for multiple sclerosis. Pharmacol Ther 148:85–113. doi:10.1016/j.pharmthera.2014.11.015
Shaikh S, Verma H, Yadav N, Jauhari M, Bullangowda J (2012) Applications of steroid in clinical practice: a review. ISRN Anesthesiol 2012:1–11. doi:10.5402/2012/985495
Shirani A, Zhao Y, Karim M, Evans C, Kingwell E, Van Der Kop ML, Oger J, Gustafson P, Petkau J, Tremlett H (2014) Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA 308(3):247–256
Simpson S, Blizzard L, Otahal P, Van der Mei I, Taylor B (2011) Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry 82(10):1132–1141. doi:10.1136/jnnp.2011.240432
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676. doi:10.1016/j.cell.2006.07.024
Thier M, Wörsdörfer P, Lakes YB, Gorris R, Herms S, Opitz T, Seiferling D, Quandel T, Hoffmann P, Nöthen MM, Brüstle O, Edenhofer F (2012) Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 10(4):473–479. doi:10.1016/j.stem.2012.03.003
Tripathi RB, Clarke LE, Burzomato V, Kessaris N, Patrick N (2014) Dorsally- and ventrally-derived oligodendrocytes have similar electrical properties but myelinate preferred tracts. J Neurosci 31(18):6809–6819. doi:10.1523/JNEUROSCI.6474-10.2011
Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041. doi:10.1038/nature08797
Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA (2004) Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199:971–979. doi:10.1084/jem.20031579\rjem.20031579
Wilson-Pauwels L, Stewart P, Akesson EJ, Spacey SD (2010) Cranial nerves: function and dysfunction. PMPH-USA, p 247. http://books.google.com/books?id=AV7j1rSWKUcC&pgis=1
Wolinsky JS, Narayana PA, O’Connor P, Coyle PK, Ford C, Johnson K, Miller A, Pardo L, Kadosh S, Ladkani D, PROMiSe Trial Study Group (2007) Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 61:14–24. doi:10.1002/ana.21079
Zhu Q, Whittemore SR, Devries WH, Zhao X, Kuypers NJ, Qiu M (2011) Dorsally-derived oligodendrocytes in the spinal cord contribute to axonal myelination during development and remyelination following focal demyelination. Glia 59(11):1612–1621. doi:10.1002/glia.21203
Zivadinov R (2007) Can imaging techniques measure neuroprotection and remyelination in multiple sclerosis? Neurology 68(22 Suppl 3), S72–S82; discussion S91–S96. doi:10.1212/01.wnl.0000275236.51129.d2
Zozulya AL, Wiendl H (2008) The role of regulatory T cells in multiple sclerosis. Nat Clin Pract Neurol 4(7):384–398. doi:10.1038/ncpneuro0832
Zozulya AL, Ortler S, Lee J, Weidenfeller C, Sandor M, Wiendl H, Fabry Z (2009) Intracerebral dendritic cells critically modulate encephalitogenic versus regulatory immune responses in the CNS. J Neurosci 29(1):140–152. doi:10.1523/JNEUROSCI.2199-08.2009
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Falk, I., Jacobson, S. (2017). Multiple Sclerosis. In: Ikezu, T., Gendelman, H. (eds) Neuroimmune Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-44022-4_23
Download citation
DOI: https://doi.org/10.1007/978-3-319-44022-4_23
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-44020-0
Online ISBN: 978-3-319-44022-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)