Background: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML).
Objectives: We present a patient study through therapy, the diagnosis of PML (after 29 infusions), plasma exchange (PE) and development of immune reconstitution inflammatory syndrome (IRIS).
Methods: Routine diagnostics, magnetic resonance imaging (MRI), immunological status (flow cytometry, T-cell migration assays and T-cell repertoire analysis), and brain biopsy with immunohistological analysis.
Results: CD49d decreased after 12 months of treatment. At PML diagnosis, CD49d expression and migratory capacity of T cells was low and peripheral T-cell receptor (TCR) complexity showed severe perturbations. The distribution of peripheral monocytes changed from CCR5+ to CCR7+. After PE some changes reverted: CD49d increased and overshot earliest levels, migratory capacities of T cells recovered and peripheral TCR complexity increased. With no clinical, routine laboratory or cerebrospinal fluid (CSF) changes, MRI 2 months after PE demonstrated progressive lesion development. Brain histopathology confirmed the presence of infiltrates indicative of IRIS without clinical signs, immunologically accompanied by CCR7/CCR5 recovery of peripheral monocytes.
Conclusion: Natalizumab-associated immunological changes accompanying PML were reversible after PE; IRIS can occur very late, remain asymptomatic and be elusive to CSF analysis. Our study may provide insights into the changes under treatment with natalizumab associated with JC virus control.
YednockTACannonCFritzLCSanchez-MadridFSteinmanLKarinN. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature1992; 356: 63–66.
2.
RudickRAStuartWHCalabresiPAConfavreuxCGalettaSLRadueE-W. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med2006; 354: 911–923.
3.
PolmanCHO’ConnorPWHavrdovaEHutchinsonMKapposLMillerDH. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med2006; 354: 899–910.
4.
WenningWHaghikiaALaubenbergerJCliffordDBBehrensPFChanA. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med2009; 361: 1075–1080.
5.
RansohoffRM. Natalizumab and PML. Nat Neurosci2005; 8: 1275.
6.
KoralnikIJ. Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name?Ann Neurol2006; 60: 162–173.
7.
GorelikLLernerMBixlerSCrossmanMSchlainBSimonK. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol2010; 68: 295–303.
8.
HuangY-HZozulyaALWeidenfellerCMetzIBuckDToykaKV. Specific central nervous system recruitment of HLA-G(+) regulatory T cells in multiple sclerosis. Ann Neurol2009; 66: 171–183.
9.
SchwabNZozulyaALKieseierBCToykaKVWiendlH. An imbalance of two functionally and phenotypically different subsets of plasmacytoid dendritic cells characterizes the dysfunctional immune regulation in multiple sclerosis. J Immunol2010; 184: 5368–5374.
10.
DebesGFArnoldCNYoungAJKrautwaldSLippMHayJB. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat Immunol2005; 6: 889–894.
11.
LeeBPImhofBA. Lymphocyte transmigration in the brain: a new way of thinking. Nat Immunol2008; 9: 117–118.
12.
WiendlHMalotkaJHolzwarthBWeltzienHUWekerleHHohlfeldR. An autoreactive gamma delta TCR derived from a polymyositis lesion. J Immunol2002; 169: 515–521.
13.
SeitzSSchneiderCKMalotkaJNongXEngelAGWekerleH. Reconstitution of paired T cell receptor alpha- and beta-chains from microdissected single cells of human inflammatory tissues. Proc Natl Acad Sci U S A2006; 103: 12057–12062.
14.
SchwabNBienCGWaschbischABeckerAVinceGHDornmairK. CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery. Brain2009; 132: 1236–1246.
15.
KhatriBOManSGiovannoniGKooAPLeeJCTuckyB. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology2009; 72: 402–409.
16.
SchröderALeeD-HHellwigKLukasCLinkerRAGoldR. Successful management of natalizumab-associated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis. Arch Neurol2010; 67: 1391–1394.
17.
StennerMPWaschbischABuckDDoerckSEinseleHToykaKV. Effects of natalizumab treatment on Foxp3+ T regulatory cells. PLoS ONE2008; 3: e3319.
18.
TakanamiI. Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis. Int J Cancer2003; 105: 186–189.
19.
DingYShimadaYMaedaMKawabeAKaganoiJKomotoI. Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma. Clin Cancer Res2003; 9: 3406–3412.
20.
MashinoKSadanagaNYamaguchiHTanakaFOhtaMShibutaK. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res2002; 62: 2937–2941.
21.
UboguEECallahanMKTuckyBHRansohoffRM. CCR5 expression on monocytes and T cells: modulation by transmigration across the blood-brain barrier in vitro. Cell Immunol2006; 243: 19–29.
22.
NiinoMBodnerCSimardMLAlatabSGanoDKimHJ. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol2006; 59: 748–754.
23.
Du PasquierRAClarkKWSmithPSJosephJTMazulloJMDe GirolamiU. JCV-specific cellular immune response correlates with a favorable clinical outcome in HIV-infected individuals with progressive multifocal leukoencephalopathy. J Neurovirol2001; 7: 318–322.
24.
Du PasquierRAKurodaMJZhengYJean-JacquesJLetvinNLKoralnikIJ. A prospective study demonstrates an association between JC virus-specific cytotoxic T lymphocytes and the early control of progressive multifocal leukoencephalopathy. Brain2004; 127: 1970–1978.
25.
RoseDMHanJGinsbergMH. Alpha4 integrins and the immune response. Immunol Rev2002; 186: 118–124.
26.
GrayFBazilleCAdle-BiassetteHMikolJMoulignierAScaravilliF. Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol2005; 11(Suppl 3): 16–22.
27.
MirallesPBerenguerJLacruzCCosínJLópezJCPadillaB. Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy. AIDS2001; 15: 1900–1902.
28.
VendrelyABienvenuBGasnaultJThiebaultJBSalmonDGrayF. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol2005; 109: 449–455.
29.
Richardson-BurnsSMKleinschmidt-DeMastersBKDeBiasiRLTylerKL. Progressive multifocal leukoencephalopathy and apoptosis of infected oligodendrocytes in the central nervous system of patients with and without AIDS. Arch Neurol2002; 59: 1930–1936.
30.
KuhlmannTLassmannHBrückW. Diagnosis of inflammatory demyelination in biopsy specimens: a practical approach. Acta Neuropathol2008; 115: 275–287.
