H Panitch

University of Maryland, Baltimore, Baltimore, MD, United States

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Publications (21)68.11 Total impact

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    ABSTRACT: The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 +/- 5.2, 4.81 +/- 3.69, and 13.6 +/- 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 +/- 0.82 at baseline to 0.25 +/- 0.34 per year; 57% had stable/improved EDSS scores (change < or = 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 +/- 0.82 to 0.43 +/- 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.
    Multiple Sclerosis 03/2010; 16(3):342-50. · 4.47 Impact Factor
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    ABSTRACT: Although the concept that an initial course of immune-suppression facilitates subsequent immune-modulation (such as Th1 to Th2 deviation) is attractive for several autoimmune diseases, such a mechanism for serial-combination therapy has never been formally demonstrated. Recently, brief mitoxantrone induction-chemotherapy followed by immune-modulation with glatiramer acetate (GA) was significantly more effective at reducing multiple sclerosis disease activity than with GA alone. To examine whether the benefit of initial immune suppression with mitoxantrone before GA treatment is associated with more efficient immune modulation. IgG1/IgG4 GA-reactive antibody profiles, previously established as markers of GA-induced Th2 immune-deviation, were prospectively measured in vivo in patients treated with GA alone or with mitoxantrone induction therapy followed by GA. Significant and sustained increase in IgG4 antibodies (and the anticipated reversal of the IgG1/IgG4 ratio) was seen in patients treated with GA alone. Combination therapy resulted in lesser IgG4 induction (and no reversal of IgG1/IgG4 ratio). Thus, the enhanced efficacy of mitoxantrone-GA combination regimen was associated with decreased, rather than increased, efficiency of shifting the GA-reactive IgG1/IgG4 antibody profile. These results provide important insights into mechanisms of combination therapy and therapeutic strategies for autoimmune diseases.
    Multiple Sclerosis 09/2009; 15(8):959-64. · 4.47 Impact Factor
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    ABSTRACT: Glatiramer acetate (GA) therapy following brief, low-dose induction with mitoxantrone was safe and more effective than GA alone in suppressing inflammatory disease activity, as determined by a significant reduction in gadolinium (Gd)- enhancing MRI lesions, in a 15- month, randomized, single-blind study of relapsing-remitting multiple sclerosis (RRMS) patients. To determine whether effects on MRI markers of disease burden and tissue damage support and extend data on the benefits of mitoxantrone induction therapy before initiation of long-term GA therapy. 40 RRMS patients, aged 18 to 55 years, with 1-15 Gd-enhancing lesions on screening MRI and EDSS score 0-6.5 were randomized to receive GA (20 mg/d SC), starting 2 weeks after the last of 3 monthly mitoxantrone infusions (36 mg/m2 total; n = 21), or to GA alone (20 mg/d SC; n = 19), for a total of 15 months. MRIs were obtained at baseline and months 6, 9, 12, and 15. At baseline, mean (+/- SD) age was 37.2 +/- 9.7 years; disease duration, 3.5 +/- 4.8 years; EDSS score, 2.3 +/- 1.1; and number of Gd-enhancing lesions, 3.75 +/- 3.95. Reductions in Gd-enhancing lesions (RR = 0.30, 95 % CI, 0.11-0.86, p = 0.0147) and relapse activity favoring mitoxantrone- GA were accompanied by significant differences in changes in T2w lesion volume (p = 0.0139), T1w hypointense lesion volume (p = 0.0303), and proportion of Gdenhancing lesions that evolved into black holes (p = 0.0023) compared with GA alone. Longterm continuous GA after brief, low-dose mitoxantrone induction is safe and more effective than GA alone. A trend toward decreased clinical disease activity was accompanied by major effects on MRI measures of disease burden and severe tissue injury.
    Journal of Neurology 11/2008; 255(10):1473-8. · 3.58 Impact Factor
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    ABSTRACT: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.
    Multiple Sclerosis 10/2008; 14(9):1157-74. · 4.47 Impact Factor
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    ABSTRACT: Forty relapsing multiple sclerosis patients with 1-15 gadolinium (Gd)-enhancing lesions on screening brain magnetic resonance imaging (MRI) and Expanded Disability Status Scale (EDSS) scores 0-6.5 were randomized to receive short-term induction therapy with mitoxantrone (three monthly 12 mg/m(2) infusions) followed by 12 months of daily glatiramer acetate (GA) therapy 20 mg/day subcutaneously for a total of 15 months (M-GA, n = 21) or daily GA 20 mg/day for 15 months (GA, n = 19). MRI scans were performed at months 6, 9, 12 and 15. The primary measure of outcome was the incidence of adverse events; secondary measures included number of Gd-enhanced lesions, confirmed relapses and EDSS changes. Except age, baseline demographic characteristics were well matched in both treatment arms. Both treatments were safe and well tolerated. M-GA induction produced an 89% greater reduction (relative risk (RR) = 0.11, 95% confidence interval (CI): 0.04-0.36, p = 0.0001) in the number of Gd-enhancing lesions at months 6 and 9 and a 70% reduction (RR = 0.30, 95% CI: 0.11-0.86, p = 0.0147) at months 12 and 15 versus GA alone. Mean relapse rates were 0.16 and 0.32 in the M-GA and GA groups, respectively. Short-term immunosuppression with mitoxantrone followed by daily GA for up to 15 months was found to be safe and effective, with an early and sustained decrease in MRI disease activity.
    Multiple Sclerosis 07/2008; 14(5):663-70. · 4.47 Impact Factor
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    ABSTRACT: The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.
    Neurology 04/2008; 70(13 Pt 2):1134-40. · 8.25 Impact Factor
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    ABSTRACT: We investigated soluble vascular cell adhesion molecule-1 (sVCAM) levels and MRI lesions over 24 weeks in 15 Relapsing Remitting MS (RRMS) patients randomized prospectively to receive once-weekly (qw) IFN-beta-1a 30 mug intramuscularly (IM) (Group I, 8 patients) or three-times-weekly (tiw) IFN-beta-1a 44 mug subcutaneously (SC) (Group II, 7 patients). Both groups demonstrated a significant increase in sVCAM during treatment when compared to pre-treatment levels. Patients on IFN-beta-1a 44 mug SC tiw had a significant (p<0.0001) mean increase in sVCAM of 321.9 ng/ml which was significantly greater (p<0.0001) than with IFN-beta-1a 30 mug IM qw (68.6 ng/ml). There was a negative correlation between combined unique (CU) MRI lesions and sVCAM levels within the IFN-beta-1a 44 mug SC tiw group (slope=-0.00106, p=0.009). We postulate that the mode of action of IFN-beta therapy in MS may involve the induction of an increase in sVCAM. sVCAM could bind VLA-4 on T-cells and intercept their adhesion to the blood brain barrier (BBB). This mechanism is consistent with the observed clinical effect of IFN-beta in reducing MRI contrast enhancing lesions.
    Journal of Neuroimmunology 05/2005; 161(1-2):169-76. · 3.03 Impact Factor
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    ABSTRACT: The combined treatment with interferon beta (IFNbeta) and glatiramer acetate (GA) is of current interest in multiple sclerosis (MS). The therapeutic effect of GA in MS is believed to be mediated by GA-specific Th2 cells. IFNbeta has a significant anti-proliferative effect on GA-induced lymphoproliferation in vitro. Therefore, we examined the possibility that IFNbeta may interfere with the generation and phenotype of GA T-cell responses in MS patients receiving combined therapy. Sixty-six GA-specific T-cell lines (TCL) were generated ex vivo from five MS patients enrolled in an open-label dinical trial of combined IFNbeta/GA treatment. Controls included 83 pretreatment and 131 on-treatment GA-TCL from 11 MS patients treated with GA only, and five GA-TCL generated from four patients receiving IFNbeta-1a monotherapy. IFNgamma and IL-5 (markers of Th1 and Th2 responses, respectively) were assayed by ELISA in GA-TCL supematants. Th1/Th2 bias was defined by the IFNgamma/IL-5 level ratio ( >2 = Th1 bias, <0.5 = Th2 bias, and 0.5-2 = Th0 bias). The frequency with which GA-reactive TCL were generated was 37.0% for the patients in the combination trial compared to 33.3% in the patients receiving GA alone. The mean stimulation index of the GA-TCL was 8.41 (range 2-42) for the combination compared to a mean of 6.29 (range 2-37) for the GA-treated group--a nonsignificant difference. Mean GA-TCL IFNgamma production was significantly lower in all treatment groups compared to pretreatment IL-5 levels were enhanced in all treatment groups compared to pretreatment levels, but the change was not statistically significant. The Th1/Th0/Th2 distribution of GA-TCL was 7%/30%/63% for the GA+IFNbeta group, 8%/9%/83% for the GA group, compared to 48%/21%/31% pre-GA treatment. All five GA-TCL from the IFNbeta-1a monotherapy patients were Th2-biased. We conclude that IFNbeta-1a does not affect the generation of GA-reactive T cells in vivo. Although more Th0 G4-TCL occurred with combination therapy than with G4 treatment alone, both groups shared an overall Th2 bias. Therefore, we speculate that combined therapy is unlikely to reduce the efficacy of GA treatment in MS.
    Multiple Sclerosis 01/2003; 8(6):485-91. · 4.47 Impact Factor
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    ABSTRACT: Interferon beta (IFNbeta) reduces relapses and MRI activity in relapsing-remitting MS (RRMS), with variable effects on disability. The most effective dose regimen remains controversial. This randomized, controlled, multicenter trial compared the efficacy and safety of IFNbeta-1a (Rebif) 44 micro g subcutaneously three times weekly (tiw), and IFNbeta-1a (Avonex) 30 micro g IM once weekly (qw) in 677 patients with RRMS. Assessors blinded to treatment performed neurologic and MRI evaluations. The primary endpoint was the proportion of patients who were relapse free at 24 weeks; the principal MRI endpoint was the number of active lesions per patient per scan at 24 weeks. After 24 weeks, 74.9% (254/339) of patients receiving IFNbeta-1a 44 micro g tiw remained relapse free compared with 63.3% (214/338) of those given 30 micro g qw. The odds ratio for remaining relapse free was 1.9 (95% CI, 1.3 to 2.6; p = 0.0005) at 24 weeks and 1.5 (95% CI, 1.1 to 2.1; p = 0.009) at 48 weeks, favoring 44 micro g tiw. Patients receiving 44 micro g tiw had fewer active MRI lesions (p < 0.001 at 24 and 48 weeks) compared with those receiving 30 micro g qw. Injection-site reactions were more frequent with 44 micro g tiw (83% vs 28%, p < 0.001), as were asymptomatic abnormalities of liver enzymes (18% vs 9%, p = 0.002) and altered leukocyte counts (11% vs 5%, p = 0.003) compared with the 30 micro g qw dosage. Neutralizing antibodies developed in 25% of 44 micro g tiw patients and in 2% of patients receiving 30 micro g qw. IFNbeta-1a 44 micro g subcutaneously tiw was more effective than IFNbeta-1a 30 micro g IM qw on all primary and secondary outcomes investigated after 24 and 48 weeks of treatment.
    Neurology 12/2002; 59(10):1496-506. · 8.25 Impact Factor
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    ABSTRACT: Abstract—Background: Interferon � (IFN�) reduces relapses and MRI activity in relapsing-remitting MS (RRMS), with variable effects on disability. The most effective dose regimen remains controversial. Methods: This randomized, controlled, multicenter trial compared the efficacy and safety of IFN�-1a (Rebif®) 44 �g subcutaneously three times weekly (tiw), and IFN�-1a (Avonex®) 30 �g IM once weekly (qw) in 677 patients with RRMS. Assessors blinded to treatment performed neurologic and MRI evaluations. The primary endpoint was the proportion of patients who were relapse free at 24 weeks; the principal MRI endpoint was the number of active lesions per patient per scan at 24 weeks. Results: After 24 weeks, 74.9% (254/339) of patients receiving IFN�-1a 44 �g tiw remained relapse free compared with 63.3% (214/338) of those given 30 �g qw. The odds ratio for remaining relapse free was 1.9 (95% CI, 1.3 to 2.6; p � 0.0005) at 24 weeks and 1.5 (95% CI, 1.1 to 2.1; p � 0.009) at 48 weeks, favoring 44 �g tiw. Patients receiving 44 �g tiw had fewer active MRI lesions (p � 0.001 at 24 and 48 weeks) compared with those receiving 30 �g qw. Injection-site reactions were more frequent with 44 �g tiw (83% vs 28%, p � 0.001), as were asymptomatic abnormalities of liver enzymes (18% vs 9%, p � 0.002) and altered leukocyte counts (11% vs 5%, p � 0.003) compared with the 30 �g qw dosage. Neutralizing antibodies developed in 25% of 44 �g tiw patients and in 2% of patients receiving 30 �g qw. Conclusions: IFN�-1a 44 �g subcutaneously tiw was more effective than IFN�-1a 30 �g IM qw on all primary and secondary outcomes investigated after 24 and 48 weeks of treatment. NEUROLOGY 2002;59:1496–1506
    Neurology 11/2002; 59:1496–1506. · 8.25 Impact Factor
  • Milo R, Panitch H
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    ABSTRACT: The 1990s, the decade of the brain, have seen major advances in the management of multiple sclerosis (MS). For the first time, effective agents are available for the treatment of relapsing-remitting MS. These include glatiramer acetate (‘Copaxone’) and 3 varieties of recombinant human interferon- (IFN): IFN-1b (‘Betaseron’/‘Betaferon’) and 2 types of IFN-1a (‘Avonex’ and ‘Rebif’). The modes of action of all these agents are not fully understood; however, recent advances in our understanding of the immunopathogenesis of MS suggest that the immunomodulatory properties of these drugs are involved in their effects in the disease.Based on evidence accumulated in major clinical trials and post-marketing experience, all 4 medications reduce relapse rates by about one-third and may slow disease progression. The interferons have a beneficial effect on disease activity as reflected on magnetic resonance imaging (MRI) scans, whereas only limited MRI data are available for glatiramer acetate.The principal adverse effects of the interferons are transient flu-like symptoms and injection site reactions, but other adverse effects that necessitate clinical and laboratory monitoring may occur. Glatiramer acetate has the most favourable adverse effect profile, with mild injection site reactions and a rare self-limited systemic post-injection reaction. All 4 agents are indicated for ambulatory patients with relapsing-remitting MS, although indications may expand in the future as new clinical data emerge on their effects on other stages of the disease.The 4 agents were tested in different clinical trials that used different designs, patient populations, end-points and methods of statistical analysis, making simple comparisons between them inappropriate. Furthermore, the minor differences in reported efficacy, combined with their overall modest effect on the disease, do not grant superiority to any particular one. Decisions about initiation of therapy and choice of agent should be individualised, based on the severity and activity of the disease process, MRI activity and lesion volume, patient preferences and life style, concomitant illnesses and potential for inducing adverse effects. The current availability of several agents allows for switching from one to another in case of treatment failure. However, if the patient is doing well, treatment with the initially prescribed agent should be maintained.It is hoped that future advances in basic and clinical research will result in the emergence of newer and more effective therapies for MS.
    CNS Drugs 03/1999; 11(4):289-306. · 4.38 Impact Factor
  • Q Li, R Milo, H Panitch, C T Bever
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    ABSTRACT: This study was undertaken to investigate the effects of propranolol, IFN-beta, and the protein kinase modulators on IFN-gamma induction of MHC class II antigen expression and cytokine production in THP-1 human monocytic cells. IFN-gamma induced expression of HLA-DR and DQ molecules and secretion of the monokines IL-1 beta and TNF-alpha in THP-1 cells in a time and dose-dependent manner. The effect of INF-gamma on class II HLA antigens was dose-dependently inhibited by IFN-beta. H-7, phloretin, staurosporine as well as GF 109203X are selective enzyme inhibitors of protein kinase C (PKC), down-regulating IFN-gamma induced MHC class II expression and cytokine production. Stimulators of PKC, like PMA, replaced IFN-gamma in the induction of monokines in THP-1 cells, whereas the addition of HA 1004 or arachidonic acid to the culture had no effect on IFN-gamma mediated changes. Blocking of phospholipase D (PLD)-derived diacylglycerol (DAG) formation by propranolol abrogated IFN-gamma increased HLA class II expression and IL-1 beta secretion, but had little effect on IFN-gamma induced TNF-alpha production. These findings appear to suggest that PLD-derived phosphatidate is not the primary source of DAG production in IFN-gamma-induced TNF-alpha secretion, but may be necessary for IFN-gamma-mediated MHC class II induction and IL-1 beta production in human monocytes, whereas phospholipase A2 may not be required for IFN-gamma activation of PKC in the process.
    Immunopharmacology and Immunotoxicology 02/1998; 20(1):39-61. · 1.36 Impact Factor
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    ABSTRACT: Glatiramer acetate (previously known as copolymer 1) is a synthetic copolymer of four amino acids that has been approved for use in the treatment of multiple sclerosis. It has been shown to suppress myelin antigen specific T cell activation by competing with these antigens at the major histocompatibility complex class II binding site and by inducing antigen specific suppressor T cells. In this study we investigated the effects of glatiramer acetate on the human monocytic cell line, THP-1, activated by lipopolysaccharide and interferon-gamma as a model for macrophages. At non-toxic concentrations of glatiramer acetate there were dose dependent reductions in the percentage of cells expressing human leukocyte DR and DQ antigen as well as in mean fluorescence intensity by flow cytometry. Production of tumor necrosis factor-alpha and the lysosomal cysteine proteinase cathepsin B were markedly inhibited, but production of interleukin-1 increased. These results suggest that glatiramer acetate might alter macrophage effector function and suggest that further studies in human monocytes and macrophages are warranted.
    European Journal of Pharmacology 01/1998; 342(2-3):303-10. · 2.59 Impact Factor
  • R Milo, H Panitch
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    ABSTRACT: Copolymer-1 (Cop-1) inhibits the T cell response to myelin basic protein (MBP), suppresses experimental autoimmune encephalomyelitis in many animal species, and was recently shown to be effective in the treatment of multiple sclerosis (MS). Interferon beta-1b (IFN-beta), an immune modulator with no antigenic specificity, is already approved for treatment of relapsing-remitting MS. We investigated the combined effect of these two agents on the cellular immune response to MBP. Antigen-specific Th1-like cell lines were generated from two healthy individuals with different MHC phenotypes. Cop-1 inhibited the proliferation of all MBP-specific lines but had no suppressive effect on tuberculin (PPD) or tetanus toxoid (TT)-specific T cell lines from either donor, while IFN-beta non-specifically reduced proliferation of all T cell lines. When combined in vitro, Cop-1 and IFN-beta had additive suppressive effects on proliferation of MBP-specific T cell lines, with 70-100% inhibition depending on the concentration of antigen. Synthesis of the pro-inflammatory cytokines interleukin-2 and IFN-gamma by MBP-specific lines was also inhibited additively (up to 100%). When antigen-presenting cells (APC) were pretreated with Cop-1, IFN-beta or both, T cell proliferation was inhibited in the same additive pattern, even though the inhibitors were not present in culture, indicating that they acted primarily through modulation of APC function. Additive effects were not found with PPD- or TT-specific cell lines. Pretreatment of APC with IFN-beta resulted in dose-dependent reduction in HLA-DR and HLA-DQ expression, which paralleled inhibition of T cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
    Journal of Neuroimmunology 10/1995; 61(2):185-93. · 3.03 Impact Factor
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    ABSTRACT: Interferon (IFN) beta-1b has been shown to alter the course of multiple sclerosis and to inhibit MHC class II expression, but its effect on antigen presentation has not been examined in a functional assay (Neurology 43 (1993) 655-661). The effect of IFN beta-1b on alloantigen presentation by human antigen-presenting cells (APC) including human fetal astrocytes (HFA) and microglia was examined. The effect of IFN beta-1b on the ability of B cells to present tetanus toxoid (TT) to TT-specific T cell lines was also examined. APC were pre-treated with IFN gamma (100 units/ml), IFN beta-1b (10-2000 units/ml), or a combination of IFN gamma and IFN beta-1b for 3 days and washed thoroughly prior to culture with allogeneic peripheral blood lymphocytes (PBL) for a period of 6 days. Lymphocyte proliferation was then measured by tritiated thymidine uptake. Treatment of the APC with IFN beta-1b resulted in a reduction in the IFN gamma-enhanced alloantigen-induced T cell responses. This reduction ranged between 50 and 70%, was associated with a 30-50% reduction in HLA class II (DR) and 35-40% reduction in ICAM-1 expression on the HFA used as APC. IFN beta-1b pretreatment of B cells reduced their constitutive and IFN gamma enhanced capacity to present TT to TT-specific T cell lines by 50-80%. This was associated with a 30 +/- 11% mean reduction in class II (DR) expression and approximately 50 +/- 1% reduction in ICAM-1 expression in IFN beta-1b + IFN gamma-treated B cells compared to IFN gamma-treated B cells (mean of three experiments).(ABSTRACT TRUNCATED AT 250 WORDS)
    Journal of Neuroimmunology 09/1995; 61(1):17-25. · 3.03 Impact Factor
  • Journal of Neuroimmunology - J NEUROIMMUNOL. 01/1995; 56:70-70.
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    ABSTRACT: Interferon (IFN) β-1b has been shown to alter the course of multiple sclerosis and to inhibit MHC class II expression, but its effect on antigen presentation has not been examined in a functional assay (Neurology 43 (1993) 655–661). The effect of IFNβ-1b on alloantigen presentation by human antigen-presenting cells (APC) including human fetal astrocytes (HFA) and microglia was examined. The effect of IFNβ-1b on the ability of B cells to present tetanus toxoid (TT) to TT-specific T cell lines was also examined. APC were pre-treated with IFNγ (100 units/ml), IFNβ-1b (10–2000 units/ml), or a combination of IFNγ and IFNβ-1b for 3 days and washed thoroughly prior to culture with allogeneic peripheral blood lymphocytes (PBL) for a period of 6 days. Lymphocyte proliferation was then measured by tritiated thymidine uptake. Treatment of the APC with IFNβ-1b resulted in a reduction in the IFNγ-enhanced alloantigen-induced T cell responses. This reduction ranged between 50 and 70%, was associated with a 30–50% reduction in HLA class II (DR) and 35–40% reduction in ICAM-1 expression on the HFA used as APC. IFNβ-1b pretreatment of B cells reduced their constitutive and IFNγ enhanced capacity to present TT to TT-specific T cell lines by 50–80%. This was associated with a 30 ± 11% mean reduction in class II (DR) expression and approximately 50 ± 1% reduction in ICAM-1 expression in IFNβ-1b + IFNγ-treated B cells compared to IFNγ-treated B cells (mean of three experiments). The reduction in antigen presentation and class II expression was not due to cellular toxicity as cell viability and tritiated thymidine uptake by APC were not altered significantly with treatment. The results suggest that IFNβ-1b can downregulate antigen presentation which could be related to altered expression of cell surface molecules on the APC and possibly also an effect on antigen processing.
    Journal of Neuroimmunology - J NEUROIMMUNOL. 01/1995; 61(1):17-25.
  • Ron Milo, Hillel Panitch
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    ABSTRACT: Copolymer-1 (Cop-1) inhibits the T cell response to myelin basic protein (MBP), suppresses experimental autoimmune encephalomyelitis in many animal species, and was recently shown to be effective in the treatment of multiple sclerosis (MS). Interferon beta-1b (IFN-β), an immune modulator with no antigenic specificity, is already approved for treatment of relapsing-remitting MS. We investigated the combined effect of these two agents on the cellular immune response to MBP. Antigen-specific Th1-like cell lines were generated from two healthy individuals with different MHC phenotypes. Cop-1 inhibited the proliferation of all MBP-specific lines but had no suppressive effect on tuberculin (PPD) or tetanus toxoid (TT)-specific T cell lines from either donor, while IFN-β non-specifically reduced proliferation of all T cell lines. When combined in vitro, Cop-1 and IFN-β had additive suppressive effects on proliferation of MBP-specific T cell lines, with 70–100% inhibition depending on the concentration of antigen. Synthesis of the pro-inflammatory cytokines interleukin-2 and IFN-γ by MBP-specific lines was also inhibited additively (up to 100%). When antigen-presenting cells (APC) were pretreated with Cop-1, IFN-β or both, T cell proliferation was inhibited in the same additive pattern, even though the inhibitors were not present in culture, indicating that they acted primarily through modulation of APC function. Additive effects were not found with PPD- or TT-specific cell lines. Pretreatment of APC with IFN-β resulted in dose-dependent reduction in HLA-DR and HLA-DQ expression, which paralleled inhibition of T cell proliferation. Pretreatment of APC with Cop-1 had no effect on MHC class II expression. Reductions in proliferation and MHC class II expression were not the result of toxicity, as viability of T cell lines and APC was not altered by exposure to Cop-1 or IFN-β. These results suggest that inhibition of proliferation and pro-inflammatory cytokine production by MBP-specific T cell lines may be mediated through complementary effects on antigen presentation, with IFN-β down-regulating the expression of MHC class II molecules on APC, and Cop-1 competing with MBP for antigen binding sites on the remaining MHC molecules.
    Journal of Neuroimmunology - J NEUROIMMUNOL. 01/1995; 61(2):185-193.
  • R Milo, H Panitch
    Harefuah 05/1994; 126(8):451-8.
  • Journal of Neuroimmunology - J NEUROIMMUNOL. 01/1994; 54:160-160.