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α4-Integrin antagonism with natalizumab

Effects and adverse effects

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Abstract

Based on the results of two phase III clinical trials, the humanized recombinant monoclonal antibody natalizumab was approved for the treatment of relapsing forms of multiple sclerosis (MS). Since its initial approval in November 2004, it has been announced that six patients who received natalizumab in the context of clinical studies acquired an infection with the human polyoma virus JC and were diagnosed with progressive multifocal leukoencephalopathy (PML). Two of these individuals had a fatal outcome. Our groups recently showed that natalizumab therapy results in a reduction of CD4+ T cells within the cerebrospinal fluid (CSF) that is ten-fold more pronounced than the reduction in the number of CD8+ T lymphocytes. Interestingly, it appears that the effect of natalizumab on cell numbers in the CSF persists for at least 6 months after cessation of treatment. More recently, we studied the expression of major histocompatibility complex (MHC) I and II, and the number and phenotypes of leukocytes in cerebral perivascular spaces (CPVS). We observed that natalizumab therapy was associated with a significant decrease in the cell surface expression of MHC class II molecules, and the numbers of dendritic cells in CPVS. In addition, no CD4+ T cells were detectable in this compartment. Our observations may explain the differential and prolonged effects of natalizumab therapy on different leukocyte subsets in the central nervous system. They also suggest that natalizumab treatment may result in prolonged immunosuppression in peripheral organs, and the delayed onset of adverse events.

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References

  1. Anthoons JA, Van Marck EA, GigasePL, Stevens WJ (1989) Immunohistochemicalcharacterization of themononuclear cells in the brain of therat with an experimental chronicTrypanosoma brucei gambiense infection.Parasitol Res 75:251–256

    Article  PubMed  CAS  Google Scholar 

  2. Becher B, Bechmann I, Greter M (2006)Antigen presentation in autoimmunityand CNS inflammation: how Tlymphocytes recognize the brain. J MolMed 84:532–543

    CAS  Google Scholar 

  3. Carman CV, Springer TA (2003) Integrinavidity regulation: are changes inaffinity and conformation underemphasized?Curr Opin Cell Biol 15:547–556

    Article  PubMed  CAS  Google Scholar 

  4. Doring A, Wild M, Vestweber D,Deutsch U, Engelhardt B (2007) E- andP-selectin are not required for thedevelopment of experimental autoimmuneencephalomyelitis in C57BL/6and SJL mice. J Immunol 179:8470–8479

    PubMed  Google Scholar 

  5. Fotheringham J, Jacobson S (2005)Human herpesvirus 6 and multiplesclerosis: potential mechanisms forvirus-induced disease. Herpes 12:4–9

    PubMed  Google Scholar 

  6. Frohman EM, Racke MK, Raine CS(2006) Multiple sclerosis – the plaqueand its pathogenesis. N Engl J Med354:942–955

    Article  PubMed  CAS  Google Scholar 

  7. Greter M, Heppner FL, Lemos MP,Odermatt BM, Goebels N, Laufer T,Noelle RJ, Becher B (2005) Dendriticcells permit immune invasion of theCNS in an animal model of multiplesclerosis. Nat Med 11:328–334

    Article  PubMed  CAS  Google Scholar 

  8. Guillemin GJ, Brew BJ (2004) Microglia,macrophages, perivascularmacrophages, and pericytes: a reviewof function and identification. J LeukocBiol 75:388–397

    Article  CAS  Google Scholar 

  9. Heppner FL, Greter M, Marino D,Falsig J, Raivich G, Hovelmeyer N,Waisman A, Rulicke T, Prinz M, PrillerJ, Becher B, Aguzzi A (2005) Experimentalautoimmune encephalomyelitisrepressed by microglial paralysis. NatMed 11:146–152

    CAS  Google Scholar 

  10. Hickey WF, Kimura H (1988) Perivascularmicroglial cells of the CNS arebone marrow-derived and presentantigen in vivo. Science 239:290–292

    Article  PubMed  CAS  Google Scholar 

  11. Huitinga I, van Rooijen N, De Groot CJ,Uitdehaag BM, Dijkstra CD (1990)Suppression of experimental allergicencephalomyelitis in Lewis rats afterelimination of macrophages. J ExpMed 172:1025–1033

    Article  CAS  Google Scholar 

  12. Kanwar JR, Harrison JE, Wang D,Leung E, Mueller W, Wagner N, KrissansenGW (2000) Beta7 integrinscontribute to demyelinating disease ofthe central nervous system. J Neuroimmunol103:146–152

    Article  PubMed  CAS  Google Scholar 

  13. Kanwar JR, Kanwar RK, KrissansenGW (2004) Simultaneous neuroprotectionand blockade of inflammationreverses autoimmune encephalomyelitis.Brain 127:1313–1331

    Article  PubMed  Google Scholar 

  14. Kim M, Carman CV, Yang W, Salas A,Springer TA (2004) The primacy ofaffinity over clustering in regulation ofadhesiveness of the integrin αLβ2.J Cell Biol 167:1241–1253

    Article  PubMed  CAS  Google Scholar 

  15. Kleinschmidt-Demasters BK, Tyler KL(2005) Progressive multifocal leukoencephalopathycomplicating treatmentwith natalizumab and interferonbeta-1a for multiple sclerosis. N Engl JMed 353:369–374

    Article  PubMed  CAS  Google Scholar 

  16. Langer-Gould A, Atlas SW, Green AJ,Bollen AW, Pelletier D (2005) Progressivemultifocal leukoencephalopathy ina patient treated with natalizumab.N Engl J Med 353:375–381

    Article  PubMed  CAS  Google Scholar 

  17. Ley K (2003) Arrest chemokines.Microcirculation 10:289–295

    Article  PubMed  CAS  Google Scholar 

  18. Liu S, Calderwood DA, Ginsberg MH(2000) Integrin cytoplasmic domainbindingproteins. J Cell Sci 113(Pt 20):3563–3571

    PubMed  CAS  Google Scholar 

  19. Luster AD, Alon R, von Andrian UH(2005) Immune cell migration ininflammation: present and futuretherapeutic targets. Nat Immunol6:1182–1190

    Article  PubMed  CAS  Google Scholar 

  20. Martin MP, Cravens PD, Winger R,Frohman EM, Racke MK, Eagar TN,Zamvil SS, Weber MS, Hemmer B,Karandikar NJ, Kleinschmidt-DemastersBK, Stuve O (2008) Natalizumabdecreases the numbers of dendriticcells and CD4+ T cells in cerebralperivascular spaces. Arch Neurol 2008Oct 13 (Epub ahead of print)

  21. Martin R, McFarland HF, McFarlin DE(1992) Immunological aspects ofdemyelinating diseases. Annu RevImmunol 10:153–187

    Article  CAS  Google Scholar 

  22. Miller DH, Khan OA, Sheremata WA,Blumhardt LD, Rice GP, Libonati MA,Willmer-Hulme AJ, Dalton CM,Miszkiel KA, O’Connor PW (2003) Acontrolled trial of natalizumab forrelapsing multiple sclerosis. N Engl JMed 348:15–23

    Article  CAS  Google Scholar 

  23. Mountain A, Adair JR (1992) Engineeringantibodies for therapy. BiotechnolGenet Eng Rev 10:1–142

    CAS  Google Scholar 

  24. Nandi A, Estess P, Siegelman M (2004)Bimolecular complex between rollingand firm adhesion receptors requiredfor cell arrest; CD44 association withVLA-4 in T cell extravasation. Immunity20:455–465

    Article  PubMed  CAS  Google Scholar 

  25. Piraino PS, Yednock TA, Freedman SB,Messersmith EK, Pleiss MA, Karlik SJ(2005) Suppression of acute experimentalallergic encephalomyelitis witha small molecule inhibitor of alpha4integrin. Mult Scler 11:683–690

    Article  PubMed  CAS  Google Scholar 

  26. Piraino PS, Yednock TA, Freedman SB,Messersmith EK, Pleiss MA, VandevertC, Thorsett ED, Karlik SJ (2002) Prolongedreversal of chronic experimentalallergic encephalomyelitis using asmall molecule inhibitor of alpha4integrin. J Neuroimmunol 131:147–159

    Article  PubMed  CAS  Google Scholar 

  27. Piraino PS, Yednock TA, MessersmithEK, Pleiss MA, Freedman SB, HammondRR, Karlik SJ (2005) Spontaneousremyelination following prolongedinhibition of alpha4 integrin in chronicEAE. J Neuroimmunol 167:53–63

    Article  PubMed  CAS  Google Scholar 

  28. Polman CH, O’Connor PW, HavrdovaE, Hutchinson M, Kappos L, Miller DH,Phillips JT, Lublin FD, Giovannoni G,Wajgt A, Toal M, Lynn F, Panzara MA,Sandrock AW (2006) A randomized,placebo-controlled trial of natalizumabfor relapsing multiple sclerosis.N Engl J Med 354:899–910

    Article  PubMed  CAS  Google Scholar 

  29. Poser CM, Paty DW, Scheinberg L,McDonald WI, Davis FA, Ebers GC,Johnson KP, Sibley WA, Silberberg DH,Tourtellotte WW (1983) New diagnosticcriteria for multiple sclerosis:guidelines for research protocols. AnnNeurol 13:227–231

    CAS  Google Scholar 

  30. Rivers TM, Sprunt DH, Berry GP(1933) Observations on attempts toproduce acute disseminated encephalomyelitis.J Exp Med 58:39–53

    Article  Google Scholar 

  31. Rudick RA, Stuart WH, Calabresi PA,Confavreux C, Galetta SL, Radue EW,Lublin FD, Weinstock-Guttman B,Wynn DR, Lynn F, Panzara MA,Sandrock AW (2006) Natalizumab plusinterferon beta-1a for relapsing multiplesclerosis. N Engl J Med 354:911–923

    Article  PubMed  CAS  Google Scholar 

  32. Shamri R, Grabovsky V, Gauguet JM,Feigelson S, Manevich E, Kolanus W,Robinson MK, Staunton DE, vonAndrian UH, Alon R (2005) Lymphocytearrest requires instantaneousinduction of an extended LFA-1 conformationmediated by endothelium-boundchemokines. Nat Immunol6:497–506

    Article  PubMed  CAS  Google Scholar 

  33. Sheremata WA, Vollmer TL, Stone LA,Willmer-Hulme AJ, Koller M (1999) Asafety and pharmacokinetic study ofintravenous natalizumab in patientswith MS. Neurology 52:1072–1074

    PubMed  CAS  Google Scholar 

  34. Steinman L (1996) Multiple sclerosis: acoordinated immunological attackagainst myelin in the central nervoussystem. Cell 85:299–302

    Article  PubMed  CAS  Google Scholar 

  35. Stuve O, Marra CM, Bar-Or A, Niino M,Cravens PD, Cepok S, Frohman EM,Phillips JT, Arendt G, Jerome KR, CookL, Grand’Maison F, Hemmer B,Monson NL, Racke MK (2006) AlteredCD4+/CD8+ T-cell ratios in cerebrospinalfluid of natalizumab-treatedpatients with multiple sclerosis. ArchNeurol 63:1383–1387

    Article  PubMed  Google Scholar 

  36. Stuve O, Marra CM, Cravens PD, SinghMP, Hu W, Lovett-Racke A, Monson NL,Phillips JT, Cohen Tervaert JW, NashRA, Hartung HP, Kieseier BC, RackeMM, Frohman EM, Hemmer B (2007)Potential risk of progressive multifocalleukoencephalopathy with natalizumabtherapy: possible interventions.Arch Neurol 64:169–176

    Article  PubMed  Google Scholar 

  37. Stuve O, Marra CM, Jerome KR, Cook L, Cravens PD, Cepok S, Frohman EM,Phillips JT, Arendt G, Hemmer B,Monson NL, Racke MK (2006) Immunesurveillance in multiple sclerosispatients treated with natalizumab.Ann Neurol 59:743–747

    Article  PubMed  CAS  Google Scholar 

  38. Swanborg RH (1995) Experimentalautoimmune encephalomyelitis inrodents as a model for human demyelinatingdisease. Clin ImmunolImmunopathol 77:4–13

    Article  CAS  Google Scholar 

  39. Theien BE, Vanderlugt CL, Eagar TN,Nickerson-Nutter C, Nazareno R,Kuchroo VK, Miller SD (2001) Discordanteffects of anti-VLA-4 treatmentbefore and after onset of relapsingexperimental autoimmune encephalomyelitis.J Clin Invest 107:995–1006

    Article  PubMed  CAS  Google Scholar 

  40. Theien BE, Vanderlugt CL, Nickerson-Nutter C, Cornebise M, Scott DM,Perper SJ, Whalley ET, Miller SD (2003)Differential effects of treatment with asmall-molecule VLA-4 antagonist beforeand after onset of relapsing EAE.Blood 102:4464–4471

    Article  PubMed  CAS  Google Scholar 

  41. Vajkoczy P, Laschinger M, EngelhardtB (2001) Alpha4-integrin-VCAM-1binding mediates G protein-independentcapture of encephalitogenic T cellblasts to CNS white matter microvessels.J Clin Invest 108:557–565

    PubMed  CAS  Google Scholar 

  42. Van Assche G, Van Ranst M, Sciot R,Dubois B, Vermeire S, Noman M,Verbeeck J, Geboes K, Robberecht W,Rutgeerts P (2005) Progressive multifocalleukoencephalopathy after natalizumabtherapy for Crohn’s disease.N Engl J Med 353:362–368

    Article  PubMed  CAS  Google Scholar 

  43. Van D, V, De Groot CJ (2000) Staging ofmultiple sclerosis (MS) lesions: pathologyof the time frame of MS. NeuropatholAppl Neurobiol 26:2–10

    Article  Google Scholar 

  44. Yao K, Gagnon S, Akhyani N, WilliamsE, Fotheringham J, Frohman E, StuveO, Monson N, Racke MK, Jacobson S(2008) Reactivation of human herpesvirus-6 in natalizumab treated multiplesclerosis patients. PLoS ONE3:e2028

    Article  PubMed  Google Scholar 

  45. Yednock TA, Cannon C, Fritz LC,Sanchez-Madrid F, Steinman L, KarinN (1992) Prevention of experimentalautoimmune encephalomyelitis byantibodies against alpha 4 beta 1integrin. Nature 356:63–66

    Article  PubMed  CAS  Google Scholar 

  46. Yousry TA, Major EO, Ryschkewitsch C,Fahle G, Fischer S, Hou J, Curfman B,Miszkiel K, Mueller-Lenke N, SanchezE, Barkhof F, Radue EW, Jager HR,Clifford DB (2006) Evaluation ofpatients treated with natalizumab forprogressive multifocal leukoencephalopathy.N Engl J Med 354:924–933

    Article  PubMed  CAS  Google Scholar 

  47. Zamvil SS, Steinman L (1990) The Tlymphocyte in experimental allergicencephalomyelitis. Annu Rev Immunol8:579–6213

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Rd., Dallas, TX, 75216, USA

    Olaf Stüve

  2. Dept. of Neurology, University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA

    Olaf Stüve

  3. Dept. of Immunology, University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA

    Olaf Stüve

  4. Dept. of Neurology, St. Josef Hospital Ruhr, Ruhr University Bochum, Bochum, Germany

    Ralf Gold &  Andrew Chan

  5. Dept. of Neurology, University of Rostock, Rostock, Germany

    Eilhard Mix &  Uwe Zettl

  6. Dept. of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Bernd C. Kieseier

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  1. Olaf Stüve
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Correspondence to Olaf Stüve.

Additional information

Conflict of interest O. Stüve, E. Mix and U. K. Zettl have no conflict of interest to declare. A. Chan has received speakers honoraria and research support from Bayer Schering, Biogen Idec and Merck Serono as well as speakers honoraria from Teva Aventis. Bernd C. Kieseier has received honoraria for lecturing, travel expenses for attending meetings and financial support for research from Bayer Health Care, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, and TEVA. Ralf Gold declared no conflict of interest.

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Stüve, O., Gold, R., Chan, A. et al. α4-Integrin antagonism with natalizumab. J Neurol 255 (Suppl 6), 58–65 (2008). https://doi.org/10.1007/s00415-008-6011-0

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