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Inflammatory Cytokine (TNF-Alpha) by Targeted DNA Vaccine Confers Long

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Inflammatory Cytokine (TNF-Alpha) by Targeted DNA Vaccine Confers Long Gene Therapy (1999) 6, 1128–1138 1999 Stockton Press All rights reserved 0969-7128/99 $12.00 http://www.stockton-press.co.uk/gt Augmentation of natural immunity to a pro- inflammatory cytokine (TNF-alpha) by targeted DNA vaccine confers long-lasting resistance to experimental autoimmune encephalomyelitis G Wildbaum and N Karin Department of Immunology, Rappaport Family Institute for Research in the Medical Sciences, Bruce Rappaport Faculty of Medicine, Technion, POB 9697, Haifa 31096, Israel TNF-␣ is thought to be a key pro-inflammatory cytokine in titer and conferred EAE resistance. These antibodies were T cell-mediated autoimmune diseases, particularly in rheu- found to be neutralizing in vitro and capable of inhibiting matoid arthritis (RA) and multiple sclerosis (MS). Experi- the development of disease when transferred to other EAE mental autoimmune encephalomyelitis (EAE) serves as an rats. Thus, modulation of EAE with TNF-␣ DNA vaccines animal model for MS. The current study observes a notable enhances the regulation of natural immunity to a self pro- TNF-␣-specific antibody titer generated during the course inflammatory cytokine and provides a tool by which the of EAE, apparently not sufficient to prevent the develop- immune system is encouraged to elicit anti-self protective ment of disease. Administration of TNF-␣-naked DNA vac- immunity to restrain its own harmful reactivity when such cine enhanced the production of TNF-␣-specific antibody a response is needed. Keywords: TNF-␣; DNA vaccination; natural immunity; neutralizing antibodies; experimental autoimmune encephalomyel- itis; CNS Introduction interferon gamma (IFN-␥) and TNF-␣, and, to a much lesser extent, IL-4 and IL-10; Th2 cells that produce IL-4, Experimental autoimmune encephalomyelitis (EAE), is IL-10 and IL-13 and, to a much lesser extent, IFN-␥ and an autoimmune disease of the central nervous system TNF-␣.12–21 Th1 cells selected in response to various auto- (CNS) which serves as a model for the human disease, antigens transfer T cell-mediated autoimmune diseases, multiple sclerosis (MS), since in both diseases circulating whereas IL-4-secreting Th2 cells, selected in response to leukocytes penetrate the blood–brain barrier and damage these same antigens, either inhibit or exert no profound myelin resulting in impaired nerve conduction and paral- effect on the inflammatory process.16,22–34 High levels of 1,2 ysis. We have previously used molecular biological IFN-␥ and low levels of IL-4 positively select for Th1 techniques to follow leukocyte trafficking to the site of cells, whereas low levels of IFN-␥ together with high lev- inflammation in the CNS of EAE rats, and suggested a els of IL-4 mediate Th2 selection.12–17 In a recent study, model that characterizes this process as a sequential we isolated mRNA encoding interferon gamma-inducing multi-step event in which a primary influx of T cells factor (IGIF, IL-18) from the EAE brain, generated neu- interact with its target antigen to activate the blood–brain tralizing antibodies against its gene product and explored barrier and initiate a secondary influx to commence the the critical role of IGIF in T cell selection and regulation 3 disease. We have also developed various ways to inhibit of disease.35 The protective administration of IGIF-spe- the accumulation of the secondary influx at the target cific antibodies selects low IFN-␥, low TNF-␣, high IL-4- organ and thus block, or even reverse an ongoing dis- producing T cells.35 While the role of IFN-␥ in the mani- 4–7 4 ease. This includes adhesion molecule blockade, T cell festation of EAE is enigmatic, the pivotal role of TNF-␣ 5 receptor antagonism, and soluble peptide therapy using has been well studied. TNF-␣ is produced by activated non-pathogenic tolerizing analogs of the encephalitog- T cells (mostly Th1) and macrophages, and its elevated 5–7 enic determinant. Accumulation of the secondary expression at the site of inflammation occurs during the influx at the site of inflammation is dependent on various critical phase of disease,11 at the time when the ‘second- pro-inflammatory cytokines and chemokines that are ary influx’ of leukocytes is apparent.3 Except for a single produced at the site of inflammation.8–11 + recent study carried out in genetically modified ani- Based on their cytokine profile, CD4 T cells can be mals,36 all investigators agree that TNF-␣ contributes to divided into Th1 cells that produce large amounts of the pro-inflammatory process in EAE, and probably MS.25,37–51 Thus, inhibition of TNF-␣ activity by either neutralizing antibodies or soluble TNF receptor therapy, 25,42,45,47–51 Correspondence: N Karin effectively prevents, or even reverses EAE. Received 4 November 1998; accepted 1 February 1999 Overexpression of TNF-␣ in the CNS aggravated the dis- Augmentation of natural immunity to a pro-inflammatory cytokine G Wildbaum and N Karin 1129 ease,46 whereas genetically impaired expression of this attained its maximal severity (day 13), and marked gene inhibited the development and progression of dis- regression following recovery (Figure 1d). ease.43 Its pivotal role in T cell-mediated autoimmune dis- eases makes TNF-␣ a favorable target for clinical trials Prevention of EAE using TNF-␣ naked DNA vaccines aiming at inhibiting MS and rheumatoid arthritis (RA). Cloned PCR products of rat TNF-␣, obtained as described From a clinical perspective, a major disadvantage in tre- above, were ligated into a pcDNA3 eukaryotic expression ating these chronic diseases with xenogenic neutralizing vector and used as constructs for naked DNA vacci- antibodies, or even chimeric humanized antibodies nation. Rats were subjected to 3 weekly injections of the (reviewed in Ref. 52), lies in their immunogenicity. Fol- above construct. Control rats were either injected with lowing repeated immunization, even these engineered the pcDNA3 vector alone, or with PBS. Two months after antibodies do trigger an apparently allotypic response. the last immunization all rats were immunized with p68– We have recently utilized the novel technology of naked 86/CFA to induce active EAE. All control (PBS- DNA vaccination53–62 to generate self-specific protective immunized) and pcDNA3-vaccinated rats developed immunity against C-C chemokines and inhibit EAE.63 active disease that persisted for 5–6 days (Figure 2, six of Resistance could be transferred by C-C chemokine-spe- six in each group with a maximum clinical score of cific neutralizing antibodies.63 The apparent advantage of 3 ± 0.28 in control, 2.83 ± 0.18 in pcDNA3-immunized this method of therapy motivated us to evaluate its thera- rats). In contrast, rats injected with the TNF-␣-naked peutic potential against TNF-␣. DNA vaccine were resistant to EAE (incidence of two of six with a maximum clinical score of 0.33 ± 0.2, P Ͻ 0.003 for treatment with TNF-␣-naked DNA vaccine compared Results with either control or pcDNA3 treatments). Thus, the subsequent in vivo immune response to TNF-␣-naked Levels of mRNA encoding TNF-␣ increase in the DNA vaccine augmented in rats during the development inflamed brain before onset and during disease of EAE prevented the disease. progression RT-PCR analyses of the levels of mRNA encoding Lewis rats immunized with guinea-pig myelin basic pro- TNF-␣ in the brain and spinal cord of naked DNA-vacci- tein (MBP) emulsified in complete Freund’s adjuvant nated EAE-resistant rats (samples were obtained 12 days (CFA) develop the active form of EAE. At the onset of after active EAE induction) revealed a marked decrease disease, the immune T cell response is directed against a (data not shown), which was probably due to the marked major encephalitogenic determinant comprising the resi- reduction in the pro-inflammatory process, which occurs dues 68–86 of the peptide and then to a secondary deter- in the CNS of control EAE rats. minant encompassed by the residues 87–89 of this pep- tide.64–66 We generated long-term CD4+ T cell lines in Generation of natural immunity to TNF-␣ in EAE rats response to each of the above determinants.3,5 We named The development of anti-self immunity to TNF-␣ in EAE these lines according to their target determinant, L68–86 rats was evaluated. Just before active induction of disease and L87–99.3,5 Each line is encephalitogenic, that is the (day 0) and when EAE attained its maximum severity line is capable of transferring EAE to naive recipients. (day 13) blood samples were analyzed for the production Rats injected with L68–86 developed transferred EAE of antibodies against TNF-␣. Rats with developing EAE that persisted for 5–6 days (Figure 1a). Before adoptive displayed a significantly increased TNF-␣-specific anti- transfer of disease (day 0), and at various time-points body titer as compared with rats immunized in hind foot (before the onset of disease (day 3), at the day of onset pads with CFA alone (Figure 3d versus b, log2 Ab titer (day 5), the peak (day 7), following recovery (day 10), of 11 ± 0.85 versus 7 ± 0.66, P Ͻ 0.05). These results are and 10 days after recovery (day 20)) midbrain–brain stem remarkable since both groups exhibited an extensive local samples were obtained from six different rats at each inflammatory process at the site of CFA immunization time-point. From each sample mRNA was isolated and (hind foot pads), with enhanced levels of TNF-␣ mRNA subjected to RT-PCR analysis using specific oligonucleo- (data not shown). Nevertheless, only rats with tide primers which we constructed. Each amplification developing EAE manifested an apparent level of mRNA was calibrated to ␤-actin and verified by Southern blot- encoding TNF-␣ at the CNS that substantially increased ting analysis. This enabled semi-quantitative analysis of at the time when clinical disease attained maximum the levels of mRNA encoding TNF-␣ at the site of severity (Figure 1d).
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