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Biomedical subjects

K Toyka

Publications and source records attributed to K Toyka.

At least 19 recordsLinked to original sources
PubMed2006

Intravenous immunoglobulin for myasthenia gravis.

BACKGROUND: Myasthenia gravis is an autoimmune disease in which autoantibodies interfere with neuromuscular transmission. As with other autoimmune diseases, people with myasthenia gravis would be expected to benefit from intravenous immunoglobulin. OBJECTIVES: The objective of this review was to examine the efficacy of intravenous immunoglobulin for treating exacerbations of myasthenia gravis or for chronic myasthenia gravis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (March 2005) and MEDLINE (January 1966 to March 2005) using 'myasthenia gravis' and 'intravenous immunoglobulin' as the search terms. SELECTION CRITERIA: We included all randomised or quasi-randomised trials in which intravenous immunoglobulin was compared with no treatment, placebo or plasma exchange, in people with myasthenia gravis. DATA COLLECTION AND ANALYSIS: One author extracted the data and the two others checked these data and the source from which they were derived. For methodological reasons, no formal meta-analysis was performed. MAIN RESULTS: We identified five randomised controlled trials, all of which investigated short-term benefit. The first study of 87 participants with exacerbation found no statistically significant difference between immunoglobulin and plasma exchange after two weeks. The second study of 12 participants with moderate or severe myasthenia gravis treated in a crossover design trial found no statistically significant difference in the efficacy of immunoglobulin and plasma exchange after four weeks. The third study with 15 participants with mild or moderate myasthenia gravis found no statistically significant difference in efficacy of intravenous immunoglobulin and placebo after six weeks. The fourth study terminated early. It included 33 participants with moderate exacerbations of myasthenia gravis and showed no statistically significant difference in the efficacy of intravenous immunoglobulin and methylprednisolone. The fifth trial including 173 people with myasthenia gravis exacerbations, showed no superiority of intravenous immunoglobulin 1 g/kg on two consecutive days over intravenous immunoglobulin 1 g/kg on a single day. AUTHORS' CONCLUSIONS: In severe exacerbations of myasthenia gravis, one randomised controlled trial did not show a significant difference between intravenous immunoglobulin and plasma exchange. Another showed no significant difference in efficacy between 1 g/kg and 2 g/kg of intravenous immunoglobulin. A further trial showed no significant difference between intravenous immunoglobulin and oral methylprednisolone. In chronic myasthenia gravis, there is insufficient evidence from randomised trials to determine whether intravenous immunoglobulin is efficacious. More research is needed to determine whether intravenous immunoglobulin reduces the need for steroids as suggested by two case series.

Humans↗
PubMed2003

Intravenous immunoglobulin for myasthenia gravis.

BACKGROUND: Myasthenia gravis is an autoimmune disease. In up to 90 per cent of cases IgG autoantibodies to the nicotinic acetylcholine receptor are detectable which mediate the neuromuscular transmission disorder. As with other autoimmune diseases, patients would be expected to benefit from intravenous immunoglobulin. Case series and two randomised controlled trials suggest that intravenous immunoglobulin may be beneficial. OBJECTIVES: The objective of this review is to examine the efficacy of intravenous immunoglobulin for treating exacerbations of myasthenia gravis or for chronic myasthenia gravis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (21 July 2002) and MEDLINE (January 1966 to July 2002) using 'myasthenia gravis' and 'intravenous immunoglobulin' as the search terms. SELECTION CRITERIA: All randomised or quasi-randomised trials in which intravenous immunoglobulin was compared with no treatment, placebo or plasma exchange, in people with myasthenia gravis who were diagnosed by an internationally accepted definition. DATA COLLECTION AND ANALYSIS: One author extracted the data and the two others checked these data and the source from which they were derived. For methodological reasons, no formal meta-analysis was performed. MAIN RESULTS: We identified four randomised controlled trials (147 participants in total), all investigating short-term benefit. In the first study of 87 people with myasthenia gravis exacerbation, comparing intravenous immunoglobulin and plasma exchange, there was no statistically significant difference between the efficacy of the two treatments after two weeks. In the second study 12 people with moderate or severe myasthenia gravis were treated in a cross-over design trial with intravenous immunoglobulin or plasma exchange: no statistically significant difference in the efficacy of the two treatments was found after four weeks. In the third study 15 people with mild or moderate myasthenia gravis received intravenous immunoglobulin or a placebo: no significant difference in efficacy of intravenous immunoglobulin or placebo was found six weeks after treatment. The last study, which included 33 people with moderate exacerbations of myasthenia gravis, compared intravenous immunoglobulin and methylprednisolone and showed no statistically significant difference in the efficacy of the two treatments. REVIEWER'S CONCLUSIONS: One randomised controlled trial did not show a significant difference between intravenous immunoglobulin and plasma exchange for treatment of severe exacerbations of myasthenia gravis. There is no evidence from randomised controlled trials to determine whether intravenous immunoglobulin for moderate or severe myasthenia gravis improves functional outcome or has a sparing effect on steroid dosage, nor is there sufficient evidence to favour intravenous immunoglobulin over steroids in moderate exacerbations. Further randomised controlled trials are needed.

Humans↗
PubMed2002

Plasma exchange for myasthenia gravis.

BACKGROUND: Myasthenia gravis is an autoimmune disease mediated by auto-antibodies direct against the nicotinic receptor for acetylcholine. Patients would be expected to benefit from plasma exchange. Non-randomised studies suggest that plasma exchange is beneficial in the short term. OBJECTIVES: To examine the efficacy of plasma exchange in the short and long term treatment of myasthenia gravis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group register (searched 17 July 2002) and MEDLINE (January 1966 to June 2002) for randomised controlled trials using myasthenia gravis as the search term. We checked the bibliographies in reports of randomised trials and contacted one author to identify additional published or unpublished data. SELECTION CRITERIA: Types of studies: All randomised or quasi-randomised studies. TYPES OF PARTICIPANTS: All patients with myasthenia gravis who were diagnosed by an internationally accepted definition. Types of intervention: Treatment with plasma exchange alone or combined with steroids or immunosuppressive drugs. Types of outcome measures: PRIMARY OUTCOME MEASURE: ~bullet~patients treated for exacerbation: change in a specific muscle score after plasma exchange; ~bullet~patients treated for chronic myasthenia gravis: change in a functional scale. SECONDARY OUTCOME MEASURES: ~bullet~patients treated for exacerbation: change in a functional scale and percentage weaned from mechanical ventilation; ~bullet~patients treated for chronic myasthenia gravis: percentage in remission by the end of one year after first plasma exchange; ~bullet~adverse events. DATA COLLECTION AND ANALYSIS: One author extracted the data and the two others checked them. Since there was only one trial no formal meta-analysis was required. MAIN RESULTS: We identified one randomised controlled trial. Improvement in a quantitative muscle score was not significantly greater in patients treated with plasma exchange and prednisone than in patients treated with prednisone alone one month after onset of treatment. More relapses were observed in the plasma exchange and prednisone group in the first year as compared with the prednisone alone group. Problems in recruitment and matching of patients entered into this trial limit the conclusions that can be drawn. On the other hand,experience from many non-randomised studies suggests that plasma exchange is beneficial in myasthenia gravis. Consequently the relative benefits of plasma exchange are still unconfirmed. REVIEWER'S CONCLUSIONS: There are no adequate randomised controlled trials but many case series report short-term benefit from plasma exchange in myasthenia gravis, especially in myasthenic crisis. There are no adequate randomised controlled trials to determine whether plasma exchange improves the long-term outcome for myasthenia gravis. Further research is need to compare plasma exchange with alternative short-term treatments for myasthenic crisis and to determine the value of long-term plasma exchange for treating myasthenia gravis.

Combined Modality Therapy↗
PubMed2001

Suppression of experimental autoimmune neuritis by leflunomide.

Leflunomide is a new immunosuppressive drug whose active metabolite, A77 1726, impairs cellular nucleotide metabolism by inhibiting the dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme of de novo pyrimidine synthesis. Furthermore, A77 1726 suppresses tyrosine kinases involved in signal transduction pathways. We investigated the immunosuppressive effects of leflunomide in experimental autoimmune neuritis (EAN) in rats, which is a model of immune-mediated neuropathies. In EAN that was actively induced by subcutaneous injection of peripheral nerve myelin, leflunomide completely prevented paraparesis if applied orally from the day of immunization. Leflunomide was much more effective than azathioprine, which did not mitigate EAN at all. Even when leflunomide was administered therapeutically after the appearance of the first neuropathical signs, it halted the progression and markedly reduced the severity and duration of EAN. Inflammatory infiltrates, demyelination and axonal degeneration in sciatic nerve sections of leflunomide-treated EAN rats were strongly reduced. Leflunomide-treated rats did not mount autoantibodies as specified by ELISA (enzyme-linked immunosorbent assay) with a mixture of peripheral myelin proteins, including P2 and myelin basic protein. In EAN that was adoptively transferred by injection of neuritogenic cells of a P2-specific T-helper line, application of leflunomide also clearly reduced signs of disease. Additional injection of uridine did not neutralize the effect of leflunomide. Similarly, transfer of neuritogenic P2-specific T cells, which were activated in the presence of A77 1726 plus uridine in vitro, still resulted in reduced severity of adoptive transfer EAN in vivo, although proliferation of these cells in vitro was identical to that of control cells. The T-cell receptor-mediated in vitro activatability of a P2-specific T-cell hybridoma was diminished by high concentrations of A77 1726, as evidenced by reduced Ca(2+) flux into the cytosol. Together with the findings in adoptive transfer EAN, this indicates that the antiproliferative effect is probably not the only mechanism of immunosuppressive action by leflunomide. In summary, leflunomide suppresses EAN efficiently and may constitute a promising therapy for immune-mediated neuropathies.

Adoptive Transfer↗
PubMed2000

Patients with active relapsing-remitting multiple sclerosis synthesize antibodies recognizing oligodendrocyte progenitor cell surface protein: implications for remyelination.

In multiple sclerosis (MS), remyelination of demyelinated lesions diminishes with disease progression for unknown reasons. Oligodendrocyte progenitor cells contribute to remyelination; however, antibodies specific for oligodendrocyte progenitor antigens could block remyelination by eliminating or impeding these cells. In myelinating cultures, cell lysis with antibody recognizing a progenitor cell-specific surface glycoprotein (AN2) suppressed the synthesis of myelin proteins. Cerebrospinal fluid from patients with relapsing-remitting active MS contains antibodies against AN2, whereas cerebrospinal fluid from patients with nonactive disease does not. This is the first report describing antibodies in MS against a progenitor cell-specific antigen that may contribute to the development and progression of chronically demyelinated lesions.

Adult↗
PubMed1999

Transgenic Lewis rats overexpressing the proteolipid protein gene: myelin degeneration and its effect on T cell-mediated experimental autoimmune encephalomyelitis.

Transgenic Lewis rats overexpressing proteolipid protein (PLP) genes in peripheral and central nervous myelin were produced by microinjecting murine genomic PLP sequences into fertilized eggs. The mouse PLP gene shares 98.7% homology in the nucleotide sequence with its rat counterpart, but both are fully identical on protein level. Homozygous rats show tremors early in postnatal life, eventually develop seizures, and die before they reach weaning age, while hemizygous animals are phenotypically normal and have a normal life expectancy. Transgene expression in the central nervous system (CNS) has profound consequences for myelin formation and maintenance: approximately twofold overexpression of PLP/DM-20, as seen in homozygotes, results in apoptosis of mature, and a developmental arrest of the remaining immature oligodendrocytes. Severe dysmyelination ensues, associated with reactive astrogliosis and microglia activation/proliferation. Activation of microglia is also prominent in hemizygous rats with low levels of transgene overexpression. In these animals, myelin sheaths remain intact, but there is low-grade myelin degeneration throughout life witnessed by myelin uptake and activation of microglia and astrocytes, in the absence of the expression of major histocompatibility complex class II gene products. There were no spontaneous lymphocytic infiltrates in areas of myelin degeneration. However, hemizygous LEW.PLP rats were more sensitive to experimental autoimmune encephalomyelitis mediated by T cells specific for PLP, but not another encephalitogenic myelin protein, MBP.

Animals↗
PubMed1998

Potential implications of a ciliary neurotrophic factor gene mutation in a German population of patients with motor neuron disease.

The frequency of a recently described point mutation of the ciliary neurotrophic factor (CNTF) gene was investigated in a population of 154 German patients with motor neuron disease (MND). Twenty-two percent of the patients were heterozygous, 2% homozygous for the CNTF mutation. Since the gene defect is per se not linked to MND, the identification of additional gene defects occurring simultaneously with this mutation could be informative for the understanding of pathogenic mechanisms of MND.

Adolescent↗
PubMed1998

[Follow-up of myasthenia gravis. Results of a longitudinal study of the significance of psychosocial predictors].

Forty-two patients suffering from myasthenia gravis were examined in a longitudinal study design. The aim of the study was to investigate possible psychosocial predictors for the course of the disease. At the time of the first examination (T1) the diagnosis myasthenia gravis had been established for no longer than 1 year. Two further examinations were done at 6 months (T2) and 18 months (T3) after T1. Methods consisted of a personality questionnaire (FPI), a coping questionnaire (FKV), an assessment of neurotic symptoms by interviewers (PSKB) and an assessment of the doctor-patient relationship by the attending physicians. Two different severity scores (Oosterhuis Index, Myasthenia Score) served as criteria for the course of the disease. There was no connection between the course of myasthenia gravis and neurotic symptoms like anxiety or depression and the quality of the doctor-patient relationship (both assessed at T1). Also demographic data were independent from the development of severity scores. The personality factor extraversion was associated with a positive course of the disease, aggressiveness and worrying about health with a negative one. Among the coping behaviors religiousness and looking for sense were associated with a favorable course but that was shown only regarding the Oosterhuis Index and not the Myasthenia Score. As several T1 personality factors were predictive for the severity scores at T3, these results may suggest a causal influence of personality factors on the severity of the illness. Whether or not this relationship is actually in operation, however, remains ellusive. Further studies using an experimental design are needed to strengthen this hypothesis.

Adaptation, Psychological↗
PubMed1998

Distribution, tolerability and tissue compatibility of intrathecal tizanidine in the sheep.

BACKGROUND: Tizanidine (TZD) is an alpha-2-adrenergic drug with potential spinal analgesic action and could be a substitute or additive for intrathecal (i.t.) opiates in chronic pain treatment. However, long-term tolerability and tissue compatibility are not yet established. METHODS: Three sheep were infused intrathecally with TZD up to 4000 micrograms/d over a time period of up to 440 d using implantable drug administration devices; one control animal was infused with vehicle only; standard values were collected from untreated sheep. CSF samples and blood samples were analyzed to determine pharmacokinetics and systemic redistribution. Behavioral effects were studied. The spinal cord tissue was investigated using standard laboratory histology. RESULTS: Bolus kinetics after i.t. injection of TZD are best described by a two-phase model. Elimination half-lives of TZD in CSF were 15 min and 152 min, respectively. Clearance of TZD from lumbar CSF was 0.48 ml/min. Doses higher than 500 microgram i.t. caused dose-dependent motor inactivity and sleepiness. Continuous i.t. TZD up to 4 micrograms/d was well tolerated regarding behavioral, physical activity, heart rate, muscle counts and total protein were detected both in saline and TZD-treated animals, presumably due to local irritation by the catheter and repeated sampling procedures. Histological evaluation of the spinal cord and adjacent tissues showed no abnormalities. CONCLUSION: The long-term intrathecal infusion of TZD is well tolerated and non-toxic in the sheep. The data favor clinical trials in patients with chronic pain.

Adrenergic alpha-Agonists↗
PubMed1997

Quantification of cytokine mRNA expression by RT PCR in samples of previously frozen blood.

In order to facilitate cytokine mRNA detection in blood cells, we have developed a highly reproducible and easily performed RNA isolation method for use with whole blood. Previously frozen human whole blood samples were lysed in guanidine thiocyanate solution to isolate total RNA. After reverse transcription a PCR method was applied to detect beta-actin and cytokine mRNA expression (interleukin-(IL)2, IL4, IL10, tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma)). The presence of cDNA was confirmed by agarose gel electrophoresis and quantitated on-line using sequence-specific fluorochrome labeled internal oligonucleotide probes. This quantitative method is based on the cleavage of fluorescent dye labeled probes by the 5' --> 3' endonuclease activity of the Taq DNA polymerase during PCR and measurement of fluorescence intensity by a Sequence Detector System. The signal generated was directly proportional to the starting copy number of target molecules in the sample over 6 log concentrations and quantitative analysis of cDNA concentrations was performed in comparison to beta-actin or cytokine cDNA standards. mRNAs coding for beta-actin and TNF alpha were readily detectable in cDNAs prepared from the whole blood of eight healthy donors, while the other cytokines were expressed in lower amounts (IFN gamma, IL10) or were undetectable (IL2, IL4). The assay described is highly reproducible, requires no post PCR manipulation of the amplicons and permits the analysis of several hundred PCR reactions per day. Using this method it is possible to detect and quantify cytokine mRNA expression reliably in small amounts of previously frozen blood even after storage of samples for at least several months.

Cytokines↗
PubMed1997

Modulation of experimental autoimmune neuritis in Lewis rats by oral application of myelin antigens.

Experimental autoimmune neuritis (EAN) in Lewis rats is a T cell-mediated disease and serves as an animal model of human inflammatory demyelinating neuropathies. EAN can be induced by immunization with complete bovine peripheral nerve myelin (BPM), the myelin protein P2 or its neuritogenic peptide, each emulsified in complete Freund's adjuvant (CFA). The present study evaluates the effect of oral tolerization with BPM or P2 protein on the development of actively induced EAN. Oral administration of BPM strongly suppressed clinical and histological signs of EAN subsequently induced by BPM/CFA, but feeding of P2 protein alone did not affect its course. In contrast, feeding of BPM did not mitigate the course of EAN subsequently induced by immunization with neuritogenic P2 peptide/CFA. Oral therapy with BPM after onset of myelin-induced EAN only slightly ameliorated the further course of disease, but significantly reduced lethality of this severe form of disease. The findings suggest that immunogenicity of the antigens fed determine strength of tolerance, that downregulation of EAN occurs at the site of immunization and not in the nerve, and that active suppression rather than specific anergization is operative in mediating resistance to EAN. However, only partial tolerance to myelin-induced EAN was achieved in naive animals by transfer of spleen/LN cells from rats orally tolerized with BPM. Although methodic factors may have limited the effect of the cells, the result is suggestive of some contribution of anergy to oral tolerance in the present model. Cholera toxin and LPS were identified as oral adjuvants for BPM and prolonged the state of tolerance. However, LPS exhibited proinflammatory properties if EAN was induced early after BPM/LPS-feeding. Thus, oral application of a mixture of myelin components in combination with cholera toxin may be a useful treatment for chronic inflammatory neuropathies considered autoimmune in nature.

Adjuvants, Immunologic↗
PubMed1996

Preventive but not therapeutic application of Rolipram ameliorates experimental autoimmune encephalomyelitis in Lewis rats.

Experimental autoimmune encephalomyelitis (EAE) in Lewis rats, an animal model mimicking some aspects of multiple sclerosis, was treated with the type IV-specific phosphodiesterase inhibitor Rolipram. Actively induced EAE evoked by immunization with myelin basic protein (MBP) in complete Freund's adjuvant was delayed but only slightly ameliorated in its maximal severity by preventive treatment with Rolipram (2 x 3 mg/kg per day) starting on the day of immunization. Therapeutic administration of Rolipram (2 x 5 mg/kg per day) was begun within hours after onset of first clinical signs of EAE but could not modify the further course of the disease. Both doses had significant side effects. Injection of 5 mg Rolipram/kg provoked transient slackening and unsteady gait while chronic application of 6 mg/kg/day strongly accelerated the weight gain in adolescent rats. EAE adoptively transferred by injection of encephalitogenic T line blasts was shortened and significantly suppressed in its severity by application of Rolipram (2 x 5 mg/kg per day) starting on the day of cell transfer. In corresponding lumbar spinal cord sections density of inflammatory infiltration by T cells and macrophages was reduced. Rolipram did not prevent generation of an antigen-specific immune response in vivo. In vitro the drug inconsistently inhibited MBP-induced activation of encephalitogenic T cells. TNF-alpha secretion by encephalitogenic T cells was limited only when T cell proliferation was also affected. In contrast, TNF-alpha production by LPS-activated macrophages was consistently and markedly suppressed by Rolipram. However, since the encephalitogenic T line cells produced at least 100 times more TNF-alpha than the same number of Rolipram-sensitive macrophages, the impact of Rolipram on the total amount of TNF-alpha synthesized in EAE may be limited. Together with our histological findings, the data suggest that relevant immunosuppressive mechanisms of Rolipram may be the inhibition of migration of leukocytes into the central nervous system and to some extent its inhibitory effect on T cell proliferation and macrophage activity. The downregulatory effects of Rolipram may be partially counteracted by its augmenting impact on the production of nitric oxide by macrophages.

Animals↗
PubMed1996

T cell directed immunotherapy of inflammatory demyelination in the peripheral nervous system. Potent suppression of the effector phase of experimental autoimmune neuritis by anti-CD2 antibodies.

Experimental autoimmune neuritis (EAN) of Lewis rats, an inflammatory demyelinating neuropathy and model of the human Guillain-Barré syndrome (GBS), was used to evaluate the novel T cell directed immunotherapy with the anti-CD2 monoclonal antibody (mAb) OX34. Clinical signs of EAN actively induced by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant (CFA) were totally prevented or markedly suppressed by preventative injections of OX34 starting 8 days post-immunization (p.i.). Moreover, therapeutic application of the mAb beginning on the day of first clinical signs of EAN markedly inhibited progression of disease. Electrophysiological and histological investigation of sciatic nerves 17 and 18 days p.i. respectively, also revealed an inhibitory effect of OX34 on EAN-associated functional and morphological nerve damage. Similarly, therapeutic injections of OX34 after onset of EAN actively induced by immunization with a neuritogenic peptide of the P2 protein completely halted further deterioration of clinical disease. Finally, clinical, electrophysiological and histological signs of adoptive transfer EAN mediated by injection of neuritogenic T helper line cells were prevented or strongly suppressed by OX34-application on the day of cell transfer and 4 days later, underlying the impact of the mAb on the effector phase of the disease. Since the anti-CD2 mAb did not exert its effect by inhibition of T cell activation, induction of anergy, modulation of CD2 antigens, or by T cell depletion, we assume that it may affect migration of T lymphocytes across the blood-nerve barrier. The immediate and marked suppression of ongoing EAN by the mAb lead to the recommendation of anti-CD2 mAbs as candidates for T cell directed immunotherapy of the GBS.

Animals↗
PubMed1996

Expression of neurofilaments and of a titin epitope in thymic epithelial tumors. Implications for the pathogenesis of myasthenia gravis.

Autoantibodies against both striated muscle proteins, particularly titin, and the acetylcholine receptor are a hallmark of thymoma-associated myasthenia gravis. However, the stimulus for these responses remains enigmatic as whole titin is not detectable in these tumors. This study reports that in thymomas with cortical differentiation many of the neoplastic epithelial cells expressed low and medium molecular weight neurofilaments detected with several antibodies (on selections and blots) and at the RNA level (by reverse transcriptase polymerase chain reaction). Moreover, higher molecular weight forms sharing at least one epitope with titin were detectable slightly less frequently, as were the more strongly phosphorylated epitopes. In stark contrast, in medullary and mixed thymomas, and especially in the normal thymus, immunoreactivity with anti-neurofilament antibodies was rare. This aberrant overexpression of a titin epitope by epithelial cells with antigen-presenting phenotype in an inappropriate cortical microenvironment suggests that they might autosensitize maturing T cells there and so initiate anti-titin autoimmunity in these patients.

Adolescent↗
PubMed1995

Suppression of experimental autoimmune encephalomyelitis in Lewis rats by antibodies against CD2.

The immunotherapeutic potential of three anti-rat CD2 monoclonal antibodies (mAb) (OX34, OX54, OX55) and the combination of OX54 with OX55 was tested in Lewis rat experimental autoimmune encephalomyelitis (EAE). In actively induced EAE, a single injection of OX34 2 days before immunization with myelin basic protein (MBP) in complete Freund's adjuvant (CFA) completely prevented or greatly attenuated EAE in all animals. Injection of OX54 acted moderately suppressive while OX55 or OX54/55 did not affect disease severity. Abrogation of EAE by OX34 was not restricted to its application before immunization. Therapeutic administration of all three mAb and the Ab combination from onset of first clinical signs efficiently blocked progression of disease and prevented all animals from developing hind limb paresis. In adoptive transfer EAE induced with in vitro activated cells of an encephalitogenic T helper line, clinical and histological signs were completely prevented by injection of OX34 on the day of cell transfer and 4 days later, underlining the strong impact of anti-CD2 mAb on the effector phase of disease. Immunocytofluorometric analysis of peripheral blood lymphocytes after a single Ab injection demonstrated that all mAb induced a variable degree of transient reduction in T cell numbers and modulation of CD2 antigens. In contrast to the other mAb, OX34 persisted on lymphocytes for at least 11 days, which may explain its unique suppressive effect on EAE after a single injection before immunization. The assumption that prophylactic administration of OX34 also inhibits MBP-induced EAE, due to persistence into the effector phase, was substantiated by the finding that none of the mAb prevented generation of an antigen-specific cellular response in MBP/CFA-immunized animals. Since none of the Ab induced T cell unresponsiveness or inhibited T cell activation by antigen- or Ab-mediated stimulation of the T cell receptor, we suggest that their marked action on the effector phase of EAE may rely on inhibition of T cell infiltration into the central nervous system. The demonstrated efficacy of these anti-CD2 mAb in EAE suggests a potential therapeutic role that may be equal to that of anti-CD4 or anti-T cell receptor Ab.

Animals↗