Brain Advance Access originally published online on June 16, 2004
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Brain, Vol. 127, No. 8, 1822-1830,
August 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh205
Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat
1 Department of Neuroimmunology, Max Planck Institute for Neurobiology, Martinsried, Germany, 2 Department of Neuroimmunology, Brain Research Institute, Wien, 3 Institute of Neurology, University of Vienna Medical School–Vienna General Hospital (AKH), Austria, 4 Institute of Clinical Neuroimmunology, Klinikum der Universität, Grosshadern, Ludwig-Maximilians Universität München, München, Germany and 5 Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, UK
Correspondence to: Professor Dr Raymond Voltz, Institute of Clinical Neuroimmunology, Klinikum der LMU, Grosshadern, 81666 München, Germany E-mail: rvoltz{at}nro.med.uni-muenchen.de
Received January 23, 2004. Revised March 24, 2004. Accepted March 29, 2004.
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Summary |
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Antibodies directed against onconeuronal antigens provide a specific diagnostic marker for paraneoplastic neurological syndromes (PNS) and suggest that these autoantigens are targeted during disease pathogenesis. However, so far attempts to generate autoimmune models of PNS have been unsuccessful. Here we show that the adoptive transfer of T-cells specific for the autologous onconeuronal antigen Pnma1 cause encephalomyelitis in the Dark Agouti (DA) rat. The sequence of rat Ma1 (rPnma1) was determined by RT–PCR using primers for human PNMA1, followed by 5' and 3' genome walking. Rat Pnma1 is 93.8% identical to human PNMA1 at the amino acid level. Rat Pnma1 was cloned into the expression vector pQE60, and recombinant protein purified by metal chelate chromatography. Female DA rats were immunized with recombinant rPnma1 and rPnma1-specific CD4+ T-helper 1 (Th1) T-cell lines generated from the draining lymph nodes 10 days post-immunization. Freshly activated T-cell blasts were transferred into naive female DA rats, which were killed up to 9 days later. Proliferation assays demonstrated that the CD4+ Th1 T-cells were highly specific for rPnma1. After T-cell transfer the recipients developed a perivascular inflammatory response involving CNS regions affected in human disease. Anti-Pnma1 antibodies were induced by protein immunization, but this was associated with minimal CNS pathology. The induction of an inflammatory response in the CNS following the adoptive transfer of rat Pnma1-specific T-cells demonstrates for the first time that a paraneoplastic autoantigen can initiate a pathogenic effector T-cell response. This animal model strongly supports the hypothesis that the pathogenesis of paraneoplastic CNS neurological syndromes in man involves an autoimmune T-cell component.
Key Words: animal model; experimental autoimmune encephalomyelitis; onconeuronal; paraneoplastic; PNMA1
Abbreviations: DA = Dark Agouti rats; OVA = ovalbumin protein; PNMA = paraneoplastic neurological Ma protein in human; rPnma = paraneoplastic neurological Ma protein in rat; PNS = paraneoplastic neurological syndromes
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Introduction |
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The paraneoplastic neurological syndromes (PNS) represent the only situation in man in which a biologically effective antitumour immunity occurs spontaneously (Darnell and Posner, 2003a
). Unfortunately, as is also the case following the therapeutic induction of immune responses to melanomas (Dudley and Rosenberg, 2003), this protective response is associated with autoaggression (Voltz, 2002; Darnell and Posner, 2003b). Patients with a PNS typically present to the neurologist prior to identification of the associated tumour, their clinical signs being due to neuronal degeneration in specific regions of the CNS. The mechanisms responsible for selective neuronal injury in these disorders are poorly understood, but there is increasing evidence that in certain cases this involves neuron-specific autoimmune responses.
Approximately 60% of PNS patients mount a high titre antibody response to specific onconeuronal antigens such as Yo, Hu or Ta/Ma, proteins that are expressed constitutively in neurons and ectopically in the associated tumours. The presence of an anti-onconeuronal antibody response greatly helps in the diagnosis of PNS and argues strongly in favour of an autoimmune pathogenesis of these disorders (Darnell, 1996; Dalmau et al., 1999a). The pathological hallmark of PNS is neuronal degeneration associated with infiltrates of inflammatory cells (Panegyres et al., 1993; Rosenblum, 1993; Hainfellner et al., 1996). In these lesions, perivascular infiltrates contain many CD4+ T-cells and B-cells, whereas CD8+ T-cells predominate within the CNS parenchyma (Panegyres et al., 1993; Rosenblum, 1993; Voltz et al., 1998). The composition of this inflammatory infiltrate is similar to that seen in multiple sclerosis and other inflammatory diseases of the CNS (Trapp et al., 1998; Kornek et al., 2000; Neumann et al., 2002), but why inflammation in these disorders is associated with the selective loss of specific neuronal subpopulations is unknown. A purely antibody-dependent mechanism is doubtful in view of the intracellular localization of most onconeuronal antigens and a consistent failure to replicate the CNS pathology of PNS by antibody transfer in an animal model (Tanaka et al., 1994; Tanaka et al., 1995; Sillevis Smitt et al., 1995; Carpentier et al., 1998). More recently, pathological and immunological investigations implicate the T-cell component of the lesions as the primary pathogenic principle in these disorders (Albert et al., 1998; Voltz et al., 1998; Benyahia et al., 1999; Plonquet et al., 2002). However, further studies to dissect the pathomechanisms involved in disease pathogenesis and their importance with respect to the beneficial antitumour response are complicated by the lack of suitable animal models (Voltz, 2002; Darnell and Posner, 2003b).
Onconeuronal antigens were identified traditionally using PNS sera (Darnell, 1996), an approach that allowed us to characterize the novel paraneoplastic Ma (PNMA) family of onconeuronal proteins in humans. These intracellular antigens are constitutively expressed by neurons throughout the nervous system (Dalmau et al., 1999b; Voltz et al., 1999). Using one of these clinically relevant neuronal proteins, PNMA1, we set out to establish an animal model to investigate the pathogenic potential of neuron-specific T-cell responses and their role in the pathogenesis of PNS. Using the autologous rat Pnma1 protein, we report that T-helper 1 (Th1) CD4+ T-cells specific for this onconeuronal antigen are encephalitogenic, and in the rat induce an inflammatory response involving those areas of the CNS affected in PNS patients with anti-PNMA (anti-Ma/Ta) antibodies.
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Material and methods |
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Cloning of rat Pnma1
Adult rat brain mRNA was prepared from shock-frozen rat tissue using oligo-dT linked magnetic beads (Dynal, Hamburg, Germany) and transcribed into cDNA using Omniscript® reverse transcriptase (Qiagen, Hilden, Germany). A partial cDNA sequence for rat Pnma1 was obtained using primers specific for the human PNMA1 sequence (see Table 1). The complete sequence of the coding region was then obtained using a rat ‘genome walker’ kit with rat Pnma1-specific primers according to the manufacturer's instructions (Clontech, Palo Alto, CA, USA). PCR products were analysed by agarose gel electrophoresis, purified using a gel extraction kit (Qiagen) and sequenced in both directions (TopLab, Martinsried, Germany; Sequiserve, Vaterstetten, Germany). Full-length rat Pnma1 coding sequences were obtained by PCR from rat brain cDNA and cloned into the multiple cloning site of pQE60 (Qiagen) using the restriction enzymes NcoI and BglII. Recombinant rat Pnma1 containing a C-terminal hexahistidine tag was expressed in Escherichia coli strain DH5
Fiq and isolated by metal chelating chromatography (Brehm et al., 1999). Protein was eluted from the column using an imidazol gradient and protein containing fractions pooled and dialysed against 20 mM acetate buffer pH3. Human PNMA1 and PNMA2 were cloned into pET30a (Stratagene, Amsterdam, The Netherlands) by PCR cloning using the original expression vectors as templates and prepared as described above (Dalmau et al., 1999b; Voltz et al., 1999). Protein purity was confirmed by SDS–PAGE.
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The GenBank accession numbers used are: rPnma1, NP_570833; human PNMA1, AAN05100; human PNMA2, NP_009188; human MOAP-1, NP_071434.
Immunization protocols
Female Dark Agouti (DA) rats aged 6–8 weeks were purchased from Harlan Winkelmann GmbH (Borchen, Germany) and injected subcutaneously at the base of the tail with 100 µg recombinant rat Pnma1 (rPnma1) or ovalbumin protein (OVA) (Sigma, Deisenhofen, Germany) in equal volume of complete Freund's adjuvant (Gibco-BRL, Karlsruhe, Germany) supplemented with 4 mg/ml inactivated Mycobacterium tuberculosis (H37 RA; Difco Laboratories, Detroit, MI, USA) in a total volume of 100 µl. Animals were weighed and examined for clinical signs of disease daily. Disease severity was scored as: 0, no disease; 0.5, partial loss of tail tonus; 1, complete tail atony; 2, hind limb paraparesis; 3, hind limb paralysis; 4, moribund; 5, death.
Antigen-specific T-cell lines
Ten days after immunization, single-cell suspensions were prepared from the draining lymph nodes. The primed cells were cultured for 72 h at a concentration of 107 cells/ml in Dulbecco's modified Eagle's medium (DMEM) supplemented with glutamine, penicillin, streptomycin, sodium pyruvate, essential amino acids (Life Technologies, Rockville, MD, USA) and 1% rat serum in the presence of selecting antigen (20 µg/ml). T-cell blasts were isolated 3 days later by density gradient centrifugation and propagated for a further 5–10 days in medium containing interleukin (IL)-2. Rat Pnma1- and OVA-specific class II major histocompatibility complex (MHC) restricted CD4+ T-cell lines were subsequently selected by cycles of antigen-specific stimulation every 10–14 days using irradiated (5000 rad) syngeneic thymus cells as antigen presenting cells, followed by expansion in IL-2 (Gibco-BRL) containing medium, as described previously (Berger et al., 1997).
Proliferation assays were performed in flat-bottomed 96-well tissue culture plates in a total volume of 200 µl using 5 x 105 lymph node cells, or 2 x 104 T-cell lines plus 5 x 105 syngeneic, irradiated (5000 rad) thymus cells as antigen-specific cells. Antigen-specific proliferation was assessed by the incorporation of [3H]thymidine (10 µCi/well) during the final 16 h of a 72 h culture period in the presence of the respective antigens (200 µg/ml) using a Packard (Meriden, CT, USA) Matrix 96 Direct beta counter. MHC restriction of the proliferative response was assessed using class II MHC (OX6)- and class I MHC (OX18)-specific monoclonal antibodies at a final concentration of 20 µg/ml (Serotec, Oxford, UK). Interferon (IFN)-
, IL-10 and tumour necrosis factor (TNF)- levels were measured on the culture supernatants of the rPnma1-specific T-cells obtained after 48 h of antigen specific re-stimulation, using appropriate rat cytokine ELISA kits (Biosource Europe, Nivelles, Belgium).
The surface phenotype of the T-cell lines was determined by indirect immunofluorescence. Viable cells (2 x 105) were washed with phosphate-buffered saline (PBS) containing 0.2% bovine serum albumin (BSA) and 10 mM NaN3 and incubated with the primary mAb for 1 h on ice [CD3, CD4, PharMingen, Hamburg, Germany; OX6, T-cell receptor (TCR)-ß, Serotec, Oxford, UK]. The cells were washed to remove unbound primary antibody and stained with fluorescein-conjugated goat anti-mouse IgG (Jackson ImmunoResearch, Hamburg, Germany) for 1 h on ice. Cells were then washed and immediately analysed using a fluorescence-activated cell sorter (FACScan; Becton Dickinson, Heidelberg, Germany). A live gate was obtained by incubating the cells in PBS containing propidium iodide.
The pathogenic potential of the T-cell lines was investigated by adoptive transfer. Rat Pnma1 or OVA-specific T-cells were harvested after 72 h of antigen driven re-stimulation. T-cells were resuspended in 1–3 ml Eagle's Hepes solution (EH) and injected into the tail vein at doses of 5 x 106 to 2 x 107 T-cell blasts per recipient. Animals were cared for in accordance with German Federal regulations and weighed and examined for clinical signs of disease on a daily basis.
ELISA
Antibody reactivity of rat sera with rat Pnma1, human PNMA1 and PNMA2 were assessed by routine ELISA as described previously (Brehm et al., 1999). Briefly, 96-well plates were coated with 10 µg/ml recombinant protein and sera tested in quadruplicate. Rat sera were tested at titrations of 1 : 100 to 1 : 24 300, and the optical density (OD) was measured at 405 nm.
Histology
Rats were perfused through the heart with 4% paraformaldehyde in PBS and tissue post-fixed in the same fixative for 24 h at 4°C. Histological evaluation was performed on paraffin-embedded sections of brains and spinal cords sampled at various time points after T-cell transfer. Paraffin sections were stained with haematoxylin–eosin (HE), luxol fast blue and Bielschowsky silver impregnation to assess inflammation, demyelination and axonal pathology.
Immunohistochemistry was performed on consecutive sections using antibodies directed against the following targets: macrophages/activated microglia (ED1; Serotec), T-cells (W3/13; Seralab, Sussex, UK), ß2-microglobulin (M-20; Santa Cruz Biotechnology, Santa Cruz, CA, USA), MHC class II (OX6; Serotec) and complement C9 (rabbit polyclonal antibody; a gift from Dr Sara Piddlesden, University of Cardiff, Cardiff, UK). For staining, paraffin sections were pretreated with a household food-steamer device for 60 min and bound primary antibody detected with a biotin–avidin technique as described previously in detail (Bauer et al., 2002). Apoptosis was assessed morphologically, and to quantify the inflammation an average of 25 complete cross-sections of spinal cord were examined from each animal. Within these cross sections, the total number of perivenous inflammatory cuffs was counted and divided by the number of sections examined to obtain an inflammatory index (i.e. the average number of inflammatory infiltrates per spinal cord cross-section). This procedure was performed on consecutive sections after staining with HE, ED1 and W3/13.
Statistical analysis
The comparison of the groups of animals with OVA- and Pnma1-specific T-cell transfer was calculated with the non-parametric Mann–Whitney test for two independent groups (SPSS Statistical Package 11.5; SPSS Inc., Chicago, IL, USA).
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Results |
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Characterization of rat Pnma1
Rat Pnma1 was cloned and its deduced sequence compared with human PNMA1 and PNMA2 (Fig. 1). The full-length protein consists of 353 amino acid residues and exhibits a 93.8% sequence identity to its human orthologue PNMA1. The 22 amino acid exchanges between the two proteins are generally conservative in nature and appear distributed randomly. In contrast, the sequence identity between rat Pnma1 and human PNMA2 is only 47.0% identical to human PNMA2, this lack of identity being particularly marked in the glutamic acid rich C-terminal region of the protein. No obvious sequence motifs could be identified, although PNMA1 exhibits an identity of 51% with human MOAP-1 (modulator of apoptosis 1) raising the possibility of a role for Pnma1 in the regulation of apoptosis (Tan et al., 2001
).
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Active immunization with rat Pnma1
Fifteen days after active immunization with rat Pnma1 in adjuvant, DA rats developed high titre antibody responses to rat Pnma1, but remained clinically normal. Histopathologically, one out of four animals showed a discrete T-cell infiltration in the CNS (inflammatory index 0.08), whereas all animals exhibited evidence of low-grade macrophage infiltration in the form of small perivascular cuffs of ED1-positive cells (see below). Despite the high level of sequence homology of rat Pnma1 with its human orthologue, rat anti-Pnma1 anti-sera showed only limited cross-reactivity with human PNMA1, and hardly any with human PNMA2 (Fig. 2). This limited cross-reactivity of the autoantibody response with the human protein stresses the importance of using autologous protein targets when attempting to establish an animal model for PNS. Nevertheless, although our results indicate that the autoantibody response is highly specific for the rat Pnma1 epitopes, this autoantibody response was alone unable to induce disease.
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In vitro characterization of rat Pnma1-specific T-cell lines
After several cycles of restimulation and expansion in IL-2 containing medium in vitro, T-cell lines generated from the draining lymph nodes of actively immunized donors were highly specific for rat Pnma1. As anticipated from the high degree of sequence homology with human PNMA1, T-cells specific for rat Pnma1 cross-react with human PNMA1, but not with human PNMA2 (Fig. 3A). FACS analysis demonstrated that the T-cell lines belonged to the CD3+ CD4+ TCR-
ß+ T-cell subset (data not shown). Antigen recognition was restricted by MHC class II (RT1B; Fig. 3A) and was associated with a Th1-like cytokine profile (Fig. 3B).
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Rat Pnma1-specific CD4+ T-cell lines induce an autoimmune encephalitis
Six days after the adoptive transfer of Pnma1-specific T-cells, naïve syngenic recipients developed a significant inflammatory response in the CNS (Table 2; Figs 4 and 5), but this did not result in overt clinical signs of disease (data not shown). This inflammatory response was most intense 6 days after cell transfer, and consisted of distinct meningeal and perivascular infiltrates containing both T-cells and macrophage/microglia. The majority of T-cells were localized within the perivascular and meningeal infiltrates, and those T-cells that had entered the parenchyma were in part undergoing apoptosis, as defined by the presence of W3/13-positive cells exhibiting nuclear condensation and fragmentation (data not shown). The antigen specificity of this pathological inflammatory response in the CNS was confirmed by the failure of OVA-specific T-cells to induce a significant inflammatory response in the CNS following adoptive transfer (n = 6; P = 0.001).
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The inflammatory response induced in the CNS by rat Pnma1-specific T-cells was similar to that seen after transfer of myelin-specific T-cell lines (Berger et al., 1997
), and was associated with the expression of MHC class II on macrophages/activated microglia and lymphocytes. Class I MHC/ß2-microglobulin complexes were also present on these cells, but we found no evidence for the expression of MHC class I expression by oligodendrocytes, astrocytes or neurons. There was no evidence of demyelination (data not shown).
However, in contrast to the predominant involvement of the spinal cord in classical models of experimental autoimmune encephalomyelitis, the intensity of the inflammatory response in the CNS of rats injected with rat Pnma1-specific T-cells was similar in spinal cord, mesencephalon, medulla oblongata, diencephalon and telencephalon (Fig. 5, nucleus caudatus, putamen). Of these areas, the mesencephalon and diencephalon are also affected in patients suffering from a paraneoplastic syndrome associated with anti-PNMA (anti-Ma/Ta) antibodies (Dalmau et al., 1999b; Voltz et al., 1999; Rosenfeld et al., 2001).
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Discussion |
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This study demonstrates for the first time that the adoptive transfer of Th1 effector CD4+ T-cells specific for an onconeuronal autoantigen, rat Pnma1, induces an encephalomyelitis in regions of the CNS that are also affected in patients with a paraneoplastic syndrome associated with anti-Ma/Ta antibodies (Dalmau et al., 1999b
; Voltz et al., 1999; Rosenfeld et al., 2001). These data provide proof of principle that autoimmune T-cell responses to onconeuronal antigens can be pathogenic and induce encephalitis. The limited cross-reactivity of rat Pnma1-specific B- and T-cell responses with human PNMA1 stresses the importance of using the autologous autoantigen when developing autoimmune disease models. This may be the reason why previous attempts to produce an animal model of PNS using human onconeuronal antigens such as HuD and cdr2 were unsuccessful (Tanaka et al., 1994; Tanaka et al., 1995; Sillevis Smitt et al., 1995; Carpentier et al., 1998).
In terms of its pathology, the encephalomyelitis induced by rat Pnma1-specific T-cells is indistinguishable from that induced by Th1 CD4+ T-cells directed against either astroglial (S100ß) or myelin proteins [myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG)] (Berger et al., 1997). However, unlike MOG- or MBP-specific T-cells, the adoptive transfer of rat Pnma1-specific T-cells failed to induce either clinical disease or substantial neuronal injury in the DA rat. A similar situation is seen in the Lewis rat following the adoptive transfer of S100ß- or MOG-specific T-cells, which induce an intense inflammatory response in the CNS but without a corresponding clinical deficit (Linington et al., 1993; Kojima et al., 1994). This inability of antigen-specific T-cell responses to certain CNS antigens to induce clinical disease is determined by the genotype of the recipient (Kawakami et al., 2004), and we are currently exploring the ability of autologous onconeuronal antigen-specific T-cells to induce disease in other strains and species.
Our study demonstrates that whilst CD4+ T-cell responses to onconeuronal antigens are pathogenic, this alone was insufficient to induce selective neuronal degeneration in the rat. The adoptive transfer protocols used in this study induce an acute monophasic inflammatory response in the CNS, and this may be too short to initiate a substantial level of irreversible neuronal injury. Alternatively, autoimmune-mediated neuronal degeneration may require additional factors that are absent in CD4+ T-cell-mediated disease models (Voltz, 2002). This has already been demonstrated in the case of immune-mediated demyelination in the rat, which requires cooperation between an encephalitogenic CD4+ specific T-cell response and a demyelinating autoantibody response (Linington et al., 1988).
In the case of patients with anti-Ma or anti-Ta/Ma2-associated disease, as well as in other paraneoplastic disorders, disease activity is associated with high titre anti-onconeuronal antigen antibody response in serum and the presence of CD8+ T-cells in the CNS, both of which could potentially participate in disease pathogenesis. Theoretically, onconeuronal-specific antibodies might cross-react with surface-expressed neuronal proteins and thereby either induce cell death or interfere with their function (Tora et al., 1997). However, the high titre antibodies found in our protein-immunized animals failed to induce significant neuronal injury or loss, despite the presence of a low-grade inflammatory response in the CNS. This indicates that the antibody response is unable to mediate neuronal injury, an observation consistent with previous failures to produce an animal model by protein immunization or the passive transfer of antibodies (Sillevis Smitt et al., 1995; Tanaka et al., 1995).
In contrast, there is evidence that autoantigen-specific CD8+ T-cell responses can mediate autoimmune CNS disease (Huseby et al., 2001) and that CD8+ cytotoxic T-cells can attack and injure neurons directly (Albert et al., 1998; Voltz et al., 1998; Benyahia et al., 1999; Neumann et al., 2002; Plonquet et al., 2002). Whether or not this is the case for rat Pnma1-specific responses cannot be addressed in the current model, which is triggered by the antigen-specific CD4+ T-cell response. Nonetheless, the selective loss of neurons in PNS may well involve synergy between CD8+ and CD4+ onconeuronal antigen-specific T-cells. As demonstrated in the current study, the CD4+ Th1 T-cell component of the response to rat Pnma1 can induce CNS inflammation. At the same time the local production of proinflammatory cytokines such as IFN- within the CNS may up-regulate MHC class I antigen expression on neurons in genetically susceptible individuals, a prerequisite if they are to be attacked by onconeuronal antigen-specific class I MHC restricted CD8+ T-cells (Neumann et al., 1995). Intriguingly, there is evidence that CD8+ T-cell-mediated mechanisms may also be involved in other CNS diseases, including multiple sclerosis. In both multiple sclerosis and PNS there is a clonal expansion of CD8+ T-cells within the CNS, and in the case of multiple sclerosis, CD8+ T-cells are implicated as mediators of axonal injury (Babbe et al., 2000; Bitsch et al., 2000; Jacobsen et al., 2002).
Our results suggest that caution is called for if unmodified determinants of self are used as possible targets to generate an effective antitumour immune response. In a mouse model, DNA vaccination with a construct encoding human HuD induced an effective growth-limiting immune response, without any pathology described in the CNS (Carpentier et al., 1998). This, however, may not be the case when autologous antigens are used to induce/enhance onconeuronal responses to obtain an effective antitumour immune response, as demonstrated in the current study in which this approach led to pathological changes in the CNS.
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Acknowledgements |
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We wish to thank Marianne Leisser, Martina Scheuer, Angela Kury and Helene Breitschopf for expert technical assistance, and Professor Jörg Hasford, Institute of Biostatistics and Epidemiology and Dr Tania Kümpfel, Institute for Clinical Neuroimmunology, both Ludwig-Maximilians-Universität (LMU) München, for their statistical advice. This work is part of the Medical Thesis by H.P. at the Medical Faculty of the LMU, München, Germany. This work was funded in part by the Hermann und Lilly Schilling Foundation, Wilhelm-Sander Stiftung (AZ2002.121.1), Deutsche Forschungsgemeinschaft (SFB 571, Teilprojekte B4 and D7) and the Multiple Sclerosis Society of Great Britain and Northern Ireland.
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