Presence of JC virus-specific CTL in the cerebrospinal fluid of PML patients: rationale for immune-based therapeutic strategies

被引:32
作者
Du Pasquier, RA
Autissier, P
Zheng, Y
Jean-Jacques, J
Koralnik, IJ
机构
[1] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA
[2] Div Viral Pathogenesis, Boston, MA USA
关键词
JC virus; progressive multifocal leukoencephalopathy; immunotherapy; cerebrospinal fluid; cytotoxic T lymphocytes; HIV; AIDS;
D O I
10.1097/01.aids.0000194804.97164.86
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Objectives: There is urgent need of a treatment for progressive multifocal leukoence-phalopathy (PML), caused by the polyornavirus JC (JCV). To evaluate the rationale for immunotherapy of PML, we explored whether JCV-specific cytotoxic T lymphocytes (CTL) can penetrate the central nervous system (CNS). In addition, we studied the breadth of their T-cell receptor (TCR) repertoire, and sought to establish a reliable method to expand these cells in vitro. Design and methods: We enrolled 18 patients in this study, including 16 with proven or possible PML (15 HIV-positive and one HIV-negative), and two HIV-positive patients with other neurological diseases. Detection of JCV-specific CTL in the blood and the cerebrospinal fluid was performed by "Cr release and tetramer staining assays in 15 patients. Results: Of 11 PML patients with analyzable cerebrospinal fluid (CSF), two had no detectable JCV-specific CTL in the blood and CSF and died 3.7 and 7.2 months later. The nine remaining patients had an inactive course of PML and detectable JCV-specific CTL in the blood. In addition, four of them (44%) also had detectable JCV-specific CTL in the CSF. Both HIV-positive patients with OND had detectable JCV-specific CTL in the blood and one in the CSF. Using tetramer technology, we obtained highly enriched JCV-specific CTL lines that were able to kill target cells presenting JCV peptides. The breadth of the TCR repertoire was CTL epitope dependent. Conclusions: These results indicate that JCV-specific CTL are present in the CNS of PML patients and pave the way for an immune-based therapeutic approach. (c) 2005 Lippincott Williams & Wilkins.
引用
收藏
页码:2069 / 2076
页数:8
相关论文
共 32 条
[1]   Meningoencephalitis and demyelination are pathologic manifestations of primary polyomavirus infection in immunosuppressed rhesus monkeys [J].
Axthelm, MK ;
Koralnik, IJ ;
Dang, X ;
Wüthrich, C ;
Rohne, D ;
Stillman, IE ;
Letvin, NL .
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 2004, 63 (07) :750-758
[2]   Progressive multifocal leukoencephalopathy in patients with HIV infection [J].
Berger, JR ;
Pall, L ;
Lanska, D ;
Whiteman, M .
JOURNAL OF NEUROVIROLOGY, 1998, 4 (01) :59-68
[3]  
Berger TG, 2003, CURR TOP MICROBIOL, V276, P163
[4]   Progressive multifocal leukoencephalopathy in a renal transplant patient diagnosed by JCV-specific DNA amplification and an intrathecal humoral immune response to recombinant virus protein 1 [J].
Berner, B ;
Krieter, DH ;
Rumpf, KW ;
Grunewald, RW ;
Beuche, W ;
Weber, T ;
Müller, GA .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 1999, 14 (02) :462-465
[5]   In vivo migration and function of transferred HIV-1-specific cytotoxic T cells [J].
Brodie, SJ ;
Lewinsohn, DA ;
Patterson, BK ;
Jiyamapa, D ;
Krieger, J ;
Corey, L ;
Greenberg, PD ;
Riddell, SR .
NATURE MEDICINE, 1999, 5 (01) :34-41
[6]   Ex vivo stimulation of cytomegalovirus (CMV)-specific T cells using CMV pp65-modified dendritic cells as stimulators [J].
Carlsson, B ;
Cheng, WS ;
Tötterman, TH ;
Essand, M .
BRITISH JOURNAL OF HAEMATOLOGY, 2003, 121 (03) :428-438
[7]   The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: Defining a consensus terminology [J].
Cinque, P ;
Koralnik, IJ ;
Clifford, DB .
JOURNAL OF NEUROVIROLOGY, 2003, 9 (Suppl 1) :88-92
[8]   HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy [J].
Clifford, DB ;
Yiannoutsos, C ;
Glicksman, M ;
Simpson, DM ;
Singer, EJ ;
Piliero, PJ ;
Marra, CM ;
Francis, GS ;
McArthur, JC ;
Tyler, KL ;
Tselis, AC ;
Hyslop, NE .
NEUROLOGY, 1999, 52 (03) :623-625
[9]   Dendritic cells pulsed with polyomavirus BK antigen induce ex vivo polyoma BK virus-specific cytotoxic T-Cell lines in seropositive healthy individuals and renal transplant recipients [J].
Comoli, P ;
Basso, S ;
Azzi, A ;
Moretta, A ;
De Santis, R ;
Del Galdo, F ;
De Palma, R ;
Valente, U ;
Nocera, A ;
Perfumo, F ;
Locatelli, F ;
Maccario, R ;
Ginevri, F .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (12) :3197-3204
[10]  
De Luca A, 2004, J NEUROVIROL, V10, P50