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Biomedical subjects

C S Constantinescu

Publications and source records attributed to C S Constantinescu.

At least 37 records · Page 2Linked to original sources
PubMed2000

Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis.

Free radicals including peroxynitrite are induced in Multiple Sclerosis (MS). Antioxidant and peroxynitrite inhibitor uric acid (UA), suppresses the MS animal model experimental autoimmune encephalomyelitis (EAE). MS patients have lower average serum UA than controls. An inverse relationship exists between MS and gout Glatiramer acetate (GA) suppresses EAE and is beneficial in relapsing MS. We investigated serum UA changes during open-label treatment of relapsing MS with GAA. Ten patients (six females, four males, aged 19 to 39 years, mean age 32 years) completed 6 months of GAA (Copaxone 20 mg s.c daily). Of these, nine completed 12 months. After 6 months on GAA, serum UA (normal, 173359 micromol/ml for women, 258-491 micromol/ml for men) increased in nine and marginally decreased (302 to 300 micromol/ml) in a single patient. Mean UA significantly increased from 240 to 303 micromol/ml (P=0.0014). At 12 months, UA remained significantly higher than at start (P=0.006) decreasing in only one patient. In contrast, we found no significant UA changes after 6 and 12 months of treatment in 21 MS patients treated with interferon beta1-a (Avonex), or in 11 treated with interferon beta1-a (Rebif), or in five placebo-treated controls. Increasing UA, a natural inhibitor of free radicals, may represent a mechanism of action of glatiramer acetate in MS.

Adjuvants, Immunologic↗
PubMed2000

Anterior uveitis in murine relapsing experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS).

PURPOSE: To investigate whether anterior uveitis (AU), which often accompanies central nervous system (CNS) and systemic inflammatory diseases including multiple sclerosis (MS), also develops in a murine relapsing model of MS, experimental autoimmune encephalomyelitis (EAE) closely resembling relapsing-remitting MS, induced by immunization with myelin basic protein (MBP) in mice. METHODS: (PL/J x SJL) F1 female mice were immunized with MBP in complete Freund's adjuvant (CFA) using Pertussis toxin as co-adjuvant. EAE was scored clinically on a scale of 0-5 based on the degree of paralysis. Uveitis was assessed by slit-lamp biomicroscopy. Histolological analysis of the CNS and eye were performed. RESULTS: All immunized mice developed a characteristic relapsing paralysis. Evidence of AU was present late in the course of EAE, only after the resolution of the first clinical relapse, in 4 of 5 mice (80%) (clinical evidence) and 5 of 5 (100%) (histological evidence). AU was mild to moderate with the exception of one animal, in which it was severe. Involvement was invariably bilateral. Histology showed mononuclear infiltrates in the iris and ciliary body. Bilateral secondary cataracts were observed in the animal with severe inflammation. Paralytic episodes and the AU did not coincide. There were no clinical or histological eye abnormalities in control mice, either non-immunized or immunized with CFA and Pertussis toxin only. CONCLUSION: We report AU in a mouse model of EAE which strongly resembles relapsing MS. These results further suggest shared antigenic determinants between the CNS and the eye, which likely become exposed to the immune system late in the course of CNS inflammation.

Animals↗
PubMed1999

IL-12 reverses the suppressive effect of the CD40 ligand blockade on experimental autoimmune encephalomyelitis (EAE).

Blockade of the CD40 ligand (CD40L)-CD40 interaction suppresses experimental autoimmune encephalomyelitis (EAE). Since this interaction induces IL-12, an essential cytokine for EAE induction, we hypothesized that CD40L blockade may suppress EAE through IL-12 inhibition. Here we show that exogenous IL-12 abolishes the ability of anti-CD40L monoclonal antibodies to prevent EAE. Anti-IL-12 antibodies prevent this reversal and protect from EAE. These results show that IL-12 is sufficient to overcome CD40L blockade and suggest that, of the multiple consequences of the CD40L-CD40 interaction, IL-12 induction is an essential one for induction of EAE.

Animals↗
PubMed1998

Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis.

Immunization of (PL/J x SJL/J)F1 mice with myelin basic protein (MBP) induces relapsing experimental autoimmune encephalomyelitis (EAE). Relapses occur 7 to 10 days after recovery from the initial paralysis. Staphylococcal enterotoxins (SE) A or B, administered after recovery from the initial paralysis, induce immediate relapses. IL-12 is involved in the induction of EAE. Here, we show that SEA and SEB induce IL-12 in splenocytes from (PL/J x SJL/J)F1 mice in vitro and increase the level of IL-12 in the sera of mice treated with these superantigens. IL-12 administration mimics SE in inducing spontaneous relapses and in enhancing the severity and frequency of spontaneous relapses. IL-12 neutralization blocks SE-induced and subsequent relapses of EAE, and, when instituted after recovery from the initial attack, prevents spontaneous relapse. This is the first report of prevention of relapses of EAE with anti-IL-12 Ab, an approach which may prove useful in the prevention of exacerbations in multiple sclerosis.

Animals↗
PubMed1998

The role of IL-12 in the maintenance of an established Th1 immune response in experimental leishmaniasis.

IL-12 initiates the development of cell-mediated immunity by promoting the differentiation of naive T cells into the Th1 phenotype, and is essential in the development of a Th1 immune response to the intracellular protozoan parasite, Leishmania major. The present study investigated whether IL-12 is also required for the maintenance and effector function of an established Th1 immune response in L. major-infected mice. While neutralization of IL-12 compromised the ability of a leishmanial antigen-reactive Th1 cell clone to produce IFN-gamma in vitro, lymph node cells taken from 2-week L. major-infected mice were able to secrete IFN-gamma in an IL-12-independent manner. However, when a short-term T cell line was established in vitro from lymph node cells, the production of IFN-gamma again became IL-12 dependent. These results suggest that other factors may compensate for IL-12 in vivo in promoting IFN-gamma production during L. major infection. To directly assess if IL-12 was required in vivo for resistance to L. major, we studied the effect of IL-12 neutralization on both a primary and secondary L. major infection in C3H mice. L. major infection in C3H mice is characterized by the development of a small lesion that heals by 8 weeks, and these animals are resistant to reinfection. As previously reported, administration of anti-IL-12 monoclonal antibody (mAb) during a primary infection led to severe disease. However, mice that had healed from a primary infection with L. major and were treated with anti-IL-12 mAb were as resistant as control animals. These findings suggest that once Th1 cells have developed, their effector function in vivo is independent of IL-12, and that this independence is not due to an intrinsic property of the T cell, but to the microenvironment created by the infection.

Animals↗
PubMed1998

Pathogenesis of neuroimmunologic diseases. Experimental models.

Animal models of autoimmune diseases have greatly improved our current understanding of the pathogenesis of human autoimmunity and have provided the potential for therapies based on manipulation of the immune system. In our laboratory, we have investigated the immunopathogenesis of autoimmune diseases of the nervous system and muscle. We have developed immune-based approaches for the suppression of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), and experimental autoimmune neuritis (EAN), a model for the Guillain-Barré syndrome (GBS). These approaches included induction of peripheral tolerance, immunotoxin targeting of activated T cells, and cytokine manipulations. In addition, we identified the antigen and characterized immunopathologically an autoimmune inflammatory disease of skeletal muscle, experimental autoimmune myositis (EAM), a model for the human inflammatory muscle disease polymyositis.

Animals↗
PubMed1998

Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells.

Angiotensin converting enzyme (ACE) inhibitors have immunomodulatory functions and can suppress a number of proinflammatory, monocyte/macrophage-derived cytokines. Interleukin-12 is a cytokine produced primarily by monocytes and macrophages, which plays an essential role in cell mediated immunity and stimulates the development of T helper type 1 immune responses. In this study, we investigated the ability of ACE inhibitors, captopril and lisinopril, to suppress IL-12 production by human peripheral blood mononuclear cells (PBMC). We show that both ACE inhibitors significantly inhibit production of IL-12 by PBMC stimulated with bacterial lipopolysaccharide (LPS) or Staphylococcus aureus Cowan (SAC). Although both ACE inhibitors also suppressed IFN-gamma production by human anti-CD3/anti-CD28-stimulated T-cells, the addition of exogenous IFN-gamma to the PBMC stimulation medium does not abrogate the ability of ACE inhibitors to suppress IL-12 production. Inhibition of IL-12 was not associated with inhibition of IL-1beta, but correlated with the suppression of ACE. Therefore, suppression of IL-12 may contribute to the immunomodulatory effect of ACE inhibitors and may be responsible for the beneficial effect of captopril and other ACE inhibitors in inflammatory or autoimmune conditions in which IL-12 is involved.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Free light chains in multiple sclerosis urine.

We measured free kappa (kappa) and lambda (lambda) light chains in urine from patients with definite multiple sclerosis (MS), other neurologic diseases (OND), and normal controls by using an enzyme linked immunosorbent assay. Both kappa and lambda light chains were higher in MS than OND or controls. In seven of eight relapsing-remitting (R-R) MS patients serial studies showed that urinary kappa chains were elevated during periods of worsening, and decreased during clinical recovery. In contrast, the levels of kappa chains did not correlate with clinical activity in 10 progressive (P) MS patients. Further correlation of urinary light chains with neurologic evaluations in R-R and P MS patients over a longer period are needed to determine their clinical and biological relevance.

Biomarkers↗
PubMed1997

Tumor necrosis factor alpha and lymphotoxin alpha are not required for induction of acute experimental autoimmune encephalomyelitis.

Immunization of mice with myelin components results in experimental autoimmune encephalomyelitis (EAE), which is mediated by myelin-specific CD4(+) T cells and anti-myelin antibodies. Tumor necrosis factor alpha (TNF-alpha) and lymphotoxin alpha (LT-alpha) are thought to be involved in the events leading to inflammatory demyelination in the central nervous system. To ascertain this hypothesis 129 x C57BL/6 mice with an inactivation of the tnf and lta genes (129 x C57BL/6(-/-)) and SJL/J mice derived from backcrosses of the above mentioned mutant mice (SJL-/-) were immunized with mouse spinal cord homogenate (MSCH) or proteolipid protein. Both 129 x C57BL/6(-/-) mice and SJL-/- mice developed EAE. In SJL-/- mice immunized with MSCH, a very severe form of EAE with weight loss, paralysis of all four limbs, and lethal outcome was observed. The histologic hallmark was an intense perivascular and parenchymal infiltration with predominantly CD4(+) T cells and some CD8(+) T cells associated with demyelination in both brain and spinal cord. These results indicate that TNF-alpha and LT-alpha are not essential for the development of EAE.

Acute Disease↗
PubMed1997

Serum angiotensin-converting enzyme in multiple sclerosis.

OBJECTIVE: To determine the extent and significance of serum angiotensin-converting enzyme (ACE) elevation in multiple sclerosis (MS) and the correlation between serum ACE activity and clinical and magnetic resonance imaging (MRI) indicators of disease activity. DESIGN: A retrospective cross-sectional study of 45 consecutive patients with clinically definite MS and a longitudinal study of 30 additional patients with clinically definite MS involved in a long-term study of neurologic function and MRI in MS. SETTING: Comprehensive MS center of a tertiary care university hospital. SUBJECTS: A total of 75 patients with clinically definite MS and 31 healthy controls. METHODS: Serum ACE activity was measured using a spectrophotometric assay and correlated with clinical indicators of disease activity and with total cerebral MS lesion volume measured by MRI. RESULTS: An elevated ACE activity was found in 17 (23%) of 75 patients with MS as compared with 2 (6%) of 31 healthy controls. Changes in serum ACE activity correlated with changes in total plaque volume on MRI. CONCLUSIONS: Serum ACE activity may be an indicator of disease activity in longitudinal analysis. Also, elevated ACE activity in a patient with otherwise typical MS need not raise suspicions of alternative diagnoses.

Adult↗
PubMed1997

Lymphocyte-specific inducible expression of potassium channel beta subunits.

Many studies have shown that voltage-gated potassium (Kv) channel activity is essential for T-lymphocyte proliferation. The IL-2-inducible neuroimmune gene, I2rf5 is the mouse homologue of the rat Kv beta 2 subunit. In this study we show that in addition to constitutive expression in adult murine brain, expression of Kv channel subunits beta 1.1 and beta 2.1 is inducible in a cloned T-helper cell line stimulated with IL-2 and in normal murine splenocytes stimulated with Con A or LPS. This expression pattern appears to be lymphocyte specific, because stimulated fibroblasts and vascular smooth muscle cells do not express Kv beta channel subunit mRNA. These observations suggest that Kv beta subunit expression is tissue specific and inducible in stimulated lymphocytes. Because Kv beta subunits modulate K+ channel activity, the inducible and variable expression of these subunits in lymphocytes may represent an additional regulatory mechanism for lymphocyte proliferation.

3T3 Cells↗
PubMed1997

Luzindole, a melatonin receptor antagonist, suppresses experimental autoimmune encephalomyelitis.

Melatonin has immune-enhancing effects and can exacerbate autoimmunity. Pinealectomy or light exposure, which suppress melatonin, inhibit T cell autoimmunity. To investigate the involvement of melatonin in experimental autoimmune encephalomyelitis (EAE), a T-cell-mediated autoimmune demyelinating disease, we tested the effect of luzindole, a melatonin receptor antagonist, on EAE. Luzindole-treated mice did not develop EAE after immunization with spinal cord homogenate, whereas control mice developed EAE. This study suggests that pharmacological inhibition of the immunoenhancing effects of melatonin may prevent autoimmune demyelination.

Animals↗
PubMed1996

Suppression of experimental autoimmune neuritis by phosphodiesterase inhibitor pentoxifylline.

Phosphodiesterase inhibitor pentoxifylline (POX) has been shown to have multiple immunomodulatory effects in vitro and in vivo. It inhibits T cell proliferation, T helper 1-type cytokines, and tumor necrosis factor. We postulated that POX might have an in vivo immunomodulatory effect on a T-cell-mediated autoimmune peripheral nervous system disease, experimental autoimmune neuritis (EAN). We investigated the effect of POX on EAN in rats immunized with peripheral nerve myelin containing neuritogenic peptide SP26. At 200 mg/kg/day, there was significant suppression of clinical EAN, weight loss, and T cell proliferation to SP26 compared to controls. Proliferation of T cells from immunized rats to SP26 was suppressed by POX in vitro. These studies demonstrate a beneficial role for POX in EAN, with potential applicability to human autoimmune demyelination.

Animals↗
PubMed1995

A longitudinal study of the T cell activation marker CD26 in chronic progressive multiple sclerosis.

Activated T cells are implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Serial measurements of T cell activation molecules and T cell subpopulations were performed over 12 months in patients with chronic progressive multiple sclerosis and healthy controls, and correlated with clinical indices of disease progression measured by standardized disability scores. Of the markers studied, the activation molecule CD26 appeared to exhibit a more consistent pattern and to be elevated in MS patients; therefore we concentrated our attention on this marker, especially in view of recent evidence of its role in T cell activation. In this small patient group, the elevation of CD26 in the MS patients did not reach statistical significance, when compared to the level in the controls. Interestingly, the percentage of CD26 but not CD25 or HLA-DR correlated with the MS patients' disability scores. However, the clinical significance of this observation as an indication of disease activity in chronic progressive MS remains to be demonstrated in studies of larger patient populations.

Adult↗
PubMed1995

Melanin, melatonin, melanocyte-stimulating hormone, and the susceptibility to autoimmune demyelination: a rationale for light therapy in multiple sclerosis.

Multiple sclerosis is a central nervous system demyelinating disease. Significant evidence, including similarities with its animal model, experimental autoimmune encephalomyelitis, supports an autoimmune mechanism, activated by putative environmental factors in genetically predisposed individuals. Genetic factors strongly influence the susceptibility to demyelinating diseases in humans and rodents. Understanding the mechanisms governing susceptibility versus resistance may help to identify individuals at risk or design therapeutic strategies. The hypothesis formulated here is based on the observation that resistance to multiple sclerosis and experimental autoimmune encephalomyelitis is associated with dark skin pigmentation. While this may signify a protective role for melanin against environmental factors producing oxidative damage, the mechanism postulated here is that susceptibility to autoimmune demyelination is influenced by hormonal factors, i.e. the neurohormones melatonin and melanocyte stimulating hormone, which have opposing effects on immune functions and, the same time, are important determinants of the individual's production of melanin.

Animals↗
PubMed1995

Clinical and subclinical neurological involvement in children of conjugal multiple sclerosis patients.

We report the occurrence of clinically definite multiple sclerosis in an offspring of a couple with conjugal multiple sclerosis. Extensive investigation of all members of this family, which includes two additional asymptomatic children, eliminated the possibility of alternative neurological diagnoses. All family members were studied with magnetic resonance imaging (MRI), evoked potentials, and human leukocyte antigen (HLA) typing. An asymptomatic child had subtle white matter abnormalities on MRI, suggesting subclinical neurological involvement. This study documents the third case of multiple sclerosis in the child of conjugal multiple sclerosis patients and provides the first report of MRI lesions in an asymptomatic offspring of the same parents. Neurodiagnostic and immunogenetic investigations of such rare family clusters may contribute to the elucidation of the pathogenesis of multiple sclerosis.

Adolescent↗
PubMed1995

Effects of the angiotensin converting enzyme inhibitor captopril on experimental autoimmune encephalomyelitis.

Angiotensin converting enzyme (ACE)1 mediates inflammation, participates in T cell stimulation by certain antigenic peptides, and influences the permeability of the blood brain barrier (BBB). ACE is elevated in multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), characterized by increased BBB permeability. ACE inhibitor captopril suppresses certain immune functions and inhibits inflammatory or autoimmune diseases. We studied the effect of captopril on Lewis rat EAE, an animal model of MS. Fourteen rats with EAE were treated with captopril 30 mg/kg daily from immunization to day 21 post-immunization, and compared with 14 untreated rats. Severity scores and lymphocyte reactivity to myelin basic protein and mitogen were measured. There was a statistically significant (p < 0.05) difference between the mean and cumulative clinical scores of captopril-treated and untreated animals. Lymphocytes from captopril treated EAE rats at the peak of disease severity had diminished responses to MBP and concanavalin A. The data suggest a significant beneficial effect of captopril in Lewis rat EAE. Further studies including other inhibitors of ACE or of other peptidases with immune, inflammatory or BBB role, may identify potentially valuable immunopharmacologic agents.

Angiotensin-Converting Enzyme Inhibitors↗