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PubMed2004

Alternatives to current disease-modifying treatment in MS: what do we need and what can we expect in the future?

Disease-modifying treatments (DMTs) for multiple sclerosis (MS) are now widely available, and their beneficial effects on relapse rates, magnetic resonance imaging outcomes and, in some cases, relapse-related disability have been shown in numerous clinical studies. However, as these treatments are only partially effective in halting the MS disease process, the search for improved treatment regimens and novel therapies must continue. Strategies to improve our therapeutic armamentarium have to take into account the different phases or parts of the pathogenesis of the disease. Available treatments address systemic immune dysfunction, blood-brain barrier permeability and the inflammatory process in the central nervous system. Currently, patients who fail to respond adequately to first-line DMTs are often considered as candidates for intensive immunosuppression with cytostatic agents or even autologous stem cell transplantation. However, new approaches are being developed. Combination therapies offer an alternative approach that may have considerable potential to improve therapeutic yield and, although likely to present considerable challenges in terms of trial design, this certainly seems to be a logical step forward in view of the complex pathology of MS. Several new drugs are also being developed with the aim of providing more effective, convenient and/or specific modulation of the inflammatory component of the disease. These treatments include humanised monoclonal antibodies such as the anti-VLA-4 antibody natalizumab, inhibitors of intracellular activation, signalling pathways and T-cell proliferation, and oral immunomodulators such as sirolimus, teriflunomide or statins. There remains, however, an urgent need for treatments that protect against demyelination and axonal loss, or promote remyelination/regeneration. Due to the chronicity of MS, the therapeutic window for neuroprotective agents is wider than that following stroke or acute spinal cord injury, and may therefore allow the use of some drugs that have proven disappointing in other situations. Novel potential neuroprotective agents such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonists and ion-channel blockers will be entering Phase II trials in MS in the near future, and it is hoped that these agents will mark the start of a new era for DMTs for MS.

Adjuvants, Immunologic↗
PubMed2006

Lymph node cells from BALB/c mice with chronic visceral leishmaniasis exhibiting cellular anergy and apoptosis: involvement of Ser/Thr phosphatase.

Visceral leishmaniasis (VL) produced in BALB/c mice through intracardial administration of Leishmania donovani amastigotes was accompanied by hepatosplenomegaly with high organ parasite load and lymphadenopathy when followed up to 4-months or so. To elucidate the mechanism of immunosuppression associated with VL, we report here progressive impairment of the proliferative response of lymph node cells (lymphocytes) from infected animals (I-LNC) to in vitro stimulation with the combination of phorbol 12-myristate 13-acetate (PMA) and ionomycin (Io) that could be related to the downregulation of PKC and MAP kinase (ERK 1/2) activation process. Further, pretreatment of I-LNC with the protein phosphatase inhibitor okadaic acid (OA), but not with calyculin A or sodium orthovanadate, significantly restored their proliferative response as well as PMA-induced activation of PKC. A population of LNC (primarily T-lymphocytes) from chronically infected animals was shown to undergo apoptosis, the number of which increased considerably following PMA+ Io stimulation. The apoptotic pathway, which was followed through binding of cells to Annexin V, activation of caspase-3 and fragmentation of DNA, involved destabilization of mitochondria, probably as a result of downregulation of PKC and Bcl-2. Interestingly, prior incubation of I-LNC with OA reversed the state of cell cycle arrest (anergy) and apoptosis through progression of cells from G0/G1 to S and G2/M phases with transcriptional activation of IL-2 and IL-2R genes. Our results suggest that the cellular (immune) dysfunction in VL could be attributed to dephosphorylation of key molecules in the T-lymphocyte signaling pathway by Ser/Thr phosphatase leading to their inactivation.

Animals↗
PubMed2006

Epinephrine biosynthesis: hormonal and neural control during stress.

1. Stress contributes to the pathophysiology of many diseases, including psychiatric disorders, immune dysfunction, nicotine addiction and cardiovascular illness. Epinephrine and the glucocorticoids, cortisol and corticosterone, are major stress hormones. 2. Release of epinephrine from the adrenal medulla and glucocorticoids from the adrenal cortex initiate the biological responses permitting the organism to cope with adverse psychological, physiological and environmental stressors. Following its massive release during stress, epinephrine must be restored to replenish cellular pools and sustain release to maintain the heightened awareness and sequelae of responses to re-establish homeostasis and ensure survival. 3. Epinephrine is regulated in part through its biosynthesis catalyzed by the final enzyme in the catecholamine pathway, phenylethanolamine N-methyltransferase (E.C. 2.1.1.28, PNMT). PNMT expression, in turn, is controlled through hormonal and neural stimuli, which exert their effects on gene transcription through protein stability. 4. The pioneering work of Julius Axelrod forged the path to our present understanding of how the stress hormone and neurotransmitter epinephrine, is regulated, in particular via its biosynthesis by PNMT.

Animals↗
PubMed1987

Evaluation of monoclonal gammopathies in the "well" elderly.

The study of monoclonal gammopathies in the elderly provides an opportunity to define immunologic and neoplastic changes with aging. Previous reports using paper and cellulose acetate electrophoresis have documented an age-related increase in monoclonal gammopathies. In this study, the more sensitive techniques of high-resolution agarose gel electrophoresis and immunofixation were used, in conjunction with other protein studies, to further evaluate the prevalence of monoclonal gammopathies in 111 ambulatory residents (aged 62 to 95) of a retirement home. Eleven of the 111 residents (10 percent) were found to have a monoclonal gammopathy, ranging in concentration from 0.2 to 1.8 g/dl. All monoclonal gammopathies were confirmed by immunofixation, which also documented the presence of additional unsuspected monoclonal components in three of the 11 residents. The prevalence of monoclonal gammopathies by age ranged from 6 percent in the group younger than 80 years of age to 14 percent in the group older than 90 years of age. Only one of the 11 residents had any clinical or routine laboratory suggestion of a monoclonal gammopathy. The other 10 had normal ratios of total protein and albumin to globulin. Five of the 11 (45 percent) had an otherwise clinically unexplained erythrocyte sedimentation rate of more than 20 mm/hour, compared with only two of 100 in the group without monoclonal gammopathies. Follow-up studies one to three years after initial evaluation revealed that five of the 11 patients had died, two with evidence of disease progression. In the other six patients, monoclonal protein concentration and other protein values remained stable. An unexplained elevation of the erythrocyte sedimentation rate in the elderly warrants investigation for the presence of a monoclonal gammopathy. Agarose gel electrophoresis and immunofixation identify a higher percent of monoclonal gammopathies in the elderly than has previously been recognized. Identification of monoclonal components in this population is useful for the subsequent study of plasma cell dyscrasias, neoplastic disease, or other immune dysfunction in the aged.

Aged↗
PubMed1991

Decreased serum dipeptidyl peptidase IV activity in major depression.

It has been recently shown that severe depression is characterized by immune dysfunctions such as blunted mitogen-induced blast transformation, which is linked to interleukin-2 (IL-2) mechanisms, and to autoimmune responses. In order to explore one of the putative pathophysiological mechanisms underlying both factors, we have measured the predexamethasone and postdexamethasone serum dipeptidyl-peptidase IV (DPP IV) activity in depressed inpatients and normal controls. This enzyme is an important mediator of IL-2-related blast proliferation, and it may play a role in autoimmunity. We found significantly lower DPP IV levels in major depressives as compared with healthy controls, and melancholics exhibited significantly lower enzyme activity than minor depressives. There was a significant negative correlation between serum DPP IV activity and the severity of illness. However, we were unable to detect any significant relationships between DPP IV on the one hand, and mitogen-induced blast transformation, soluble IL-2 receptor accumulation in PHA culture supernatant, total number of leukocytes and lymphocytes, T lymphocytes, CD4+ and CD25+ cells, on the other. Men exhibited significantly higher serum DPP IV levels than women.

Adjustment Disorders↗
PubMed1984

Human autologous rosettes. IV. Their relation with interleukin 2 activity production and natural killer cells in cancer patients.

Peripheral blood lymphocytes (PBL) of solid-tumor-bearing cancer patients produced a lower interleukin 2 (IL-2) activity after lectin stimulation than did those from normal subjects. Moreover natural killer (NK) cell activity and autologous rosette forming (ARF) cell rate are found significantly correlated with IL-2 production in these patients. No direct relation is observed between ARF cell ratio and NK cell activity in a given patient. A central role for IL-2 in cancer patient immune dysfunctions is suggested. Two lines of pathogenetic mechanisms are documented. First, PBL exhibited cellular function defects, namely, autologous receptor expression, IL-2 production, and NK activity. Second, these dysfunctions involved, at least partly, plasma factors. The possibility of specific deficiency, (e.g., thymic factors) is not documented. Conversely it is demonstrated that patient plasma contain immunosuppressive factor(s) that block(s) IL-2 production and ARF cell expression. Involvement of ARF cell receptor in T-cell activation is discussed.

Adult↗
PubMed1993

Cytotoxic effect on lymphocytes of Tat from human immunodeficiency virus (HIV-1).

The human immunodeficiency virus type 1 (HIV-1) genome codes for trans-activator Tat, an 86-residue protein whose expression is critical for viral replication. Full-length Tat and Tat peptides from HIV-1 were chemically synthesized using optimized solid phase technique. Synthetic Tat2-86 was found not only to inhibit antigen-induced human peripheral blood lymphocyte (PBL) proliferation in vitro, as described by Viscidi et al. [1989, Science 246, 1606-1608], but also mitogen-induced PBL proliferation, with 50% inhibition obtained at 0.9 and 8 microM, respectively. To assess the mechanism by which Tat exert its inhibitory effect, we analysed its interaction and effect on CD4(+)-cells. Direct fluorescence and indirect immunofluorescence assays analysed by flow cytometry showed that fluorescein isothiocyanate-labeled and -unlabeled Tat interact (> 0.2 microM) with CD4-expressing lymphoid cells (CEM cell line). Experiments of chromium-51 release and Trypan blue exclusion on these tumor cells in vitro have demonstrated the capacity of Tat to modify cellular membrane permeability and cell viability, in a dose-dependent manner. The use of Tat peptides revealed that those containing the Tat basic region from 49 to 57 were able to bind to the cell membrane and to exhibit a cytotoxic activity on lymphocytes. Together, the data suggest that the potential cytotoxicity of Tat on lymphocytes could be directly implicated in virus-induced immune dysfunction observed in HIV-1 infected patients.

Amino Acid Sequence↗
PubMed1995

Removal of LDL from plasma by adsorption reduces adhesion molecules on mononuclear cells in patients with arteriosclerosis obliterans.

BACKGROUND: There is increasing evidence that immune processes are important in the development of atherosclerosis. We investigated whether low density lipoprotein (LDL) adsorption therapy affected serum cytokine levels and the expression of adhesion molecules on peripheral blood mononuclear cells (lymphocytes and monocytes) in patients with arteriosclerotic obliterance (ASO). METHODS AND RESULTS: LDL adsorption therapy was repeated ten times over a period of three months in ten ASO patients. The total serum cholesterol and LDL cholesterol levels were significantly reduced at the end of therapy. This was associated with a significant improvement in Fontaine's classification and ankle pressure index. We also measured serum levels of inflammatory cytokines (interleukin-1 beta (IL-1 beta), IL-6 and tissue necrosis factor alpha (TNF-alpha)) and expression of adhesion molecules (lymphocyte function-associated antigen 1 alpha (LFA-1 alpha), LFA-1 beta, CD2, very late antigen (VLA)-4, VLA-5 and CD44) on mononuclear cells in the same patients and a group of healthy subjects. Serum levels of all inflammatory cytokines were markedly higher in ASO patients compared with healthy subjects, but there was no significant difference in the level before and after LDL adsorption. VLA-4 expression on CD3+ cells, but not of other adhesion molecules, was markedly higher in ASO patients compared with healthy subjects. LDL adsorption caused a significant reduction in CD2, VLA4 and VLA-5 expression on CD3+ cells. Furthermore, VLA-4 and VLA-5 expression on monocytes diminished significantly after LDL adsorption. CONCLUSIONS: Our results indicate that LDL adsorption-induced immunoregulation is mediated by an indirect stimulatory effect on the immune system. The results suggests that improved peripheral circulation produced by LDL adsorption may reflect improved immune dysfunctions of atherosclerotic lesions in ASO patients.

Aged↗
PubMed1978

Cyclic nucleotide levels in resting and mitogen-stimulated spleen cell suspensions from young and old mice.

The levels of cyclic adenosine 3', 5'-monophosphate (cAMP) in suspensions of unstimulated spleen cells from tumor-free 30-month old (C57BL/10Sn X C3H/HeDiSn)F1 hybrid mice averaged only 14% of that of 6-month old mice. By contrast, the level of cyclic guanosine 3', 5'-monophosphate (cGMP) in spleen cell suspensions from old mice was about 270% that of young mice. The cAMP/cGMP ratio for the unstimulated (resting) state showed a decline by 30 months to about 5% of its 6-month value. Cyclic nucleotide levels were also measured in cell suspensions from old and young mice at intervals over a two hour period following in vitro stimulation with the plant mitogens phytohemagglutinin, concanavalin-A and pokeweed mitogen. Quantitative and in some instances qualitative differences in responses were noted. These results might conceivably reflect either age-related changes in the splenic lymphoid cell subpopulations or intrinsic cellular alterations or both. It is unlikely that changes of this degree could be wholly explained by population shifts. An imbalance in cyclic nucleotide levels in both resting and stimulated lymphoid cells in older animals might contribute to the immune dysfunction known to occur with normal aging.

Aging↗
PubMed1991

Soluble interleukin-2 receptor release defect in vitro in elderly subjects.

The evidence from several studies indicates that as individuals age, they may display immune dysfunctions, mostly T cell dysfunctions. Recently, a soluble form of the receptor for interleukin-2 (IL-2) (sIL-2R) has been demonstrated in human sera and in vitro stimulated culture supernatants from human T lymphocytes. In the present paper, we report in vitro sIL-2R production from peripheral blood mononuclear cells in elderly subjects. The results show that no difference exists for unstimulated cultures, whereas after mitogen stimulation the elderly subjects showed the lowest values compared with young ones. These findings suggest that sIL-2R may provide a new tool for the study of T lymphocyte dysfunctions in old age.

Aged↗
PubMed1995

Rapid tyrosine phosphorylation of Grb2 and Shc in T cells exposed to anti-CD3, anti-CD4, and anti-CD45 stimuli: differential effects of aging.

Two adapter proteins, Grb2 and Shc, have recently been implicated in the transmission of activation signals from the stimulated T cell receptor to Ras. We show here that in vitro stimulation of mouse splenic T cells with crosslinked anti-CD3 antibody leads within 30 s to phosphorylation of both Grb2 and Shc. Treatment with crosslinked anti-CD45 antibody leads to phosphorylation of Grb2 and also to a slight retardation in the mobility of this protein in an SDS polyacrylamide gel; both changes are seen within 30 s of crosslinking. Crosslinked anti-CD4 antibody leads to phosphorylation of Shc and to the phosphorylation of a 30-kDa protein that cross-reacts with anti-Grb2 antibodies. Aging leads to a decline in CD3-stimulated phosphorylation of Shc (but not Grb2), and to an increase in CD4-stimulated phosphorylation of Grb2, Shc, and the 30-kDa Grb2-like protein. Increased tyrosine-phosphorylation of Grb2 after exposure to either anti-CD3 or anti-CD45 suggests that Grb2 may be a common substrate for both CD3-linked kinases and the CD45 phosphatase. The differences between T cells from young and old mice suggest that aging may lead to a set of alterations in kinase/substrate coupling that contribute to immune dysfunction in the elderly, and that activation of the Ras pathway might be impaired by aging in T lymphocytes.

Adaptor Proteins, Signal Transducing↗
PubMed1990

Leukocyte function-associated antigen-1 expression on peripheral blood mononuclear cell subsets in HIV-1 seropositive patients.

In order to further investigate immune dysfunctions in HIV-1 infection, we studied the intensity of leukocyte function-associated antigen-1 (LFA-1) expression using a novel application of immunofluorescence analysis in 14 adults and 5 children seropositive for HIV-1 and in 14 healthy adults and 5 healthy children seronegative for HIV-1. While almost all lymphocytes in human peripheral blood expressed LFA-1 and while the percentage of the LFA-1 positive cells was not modified during the course of the HIV-1 infection in both adults and children, our results showed an increase of the LFA-1 expression on selected peripheral blood mononuclear cell subsets. Some LFA-1-labeled functional peripheral blood mononuclear cell subsets such as the CD16, CD14, CD3, and CD8 lymphocyte subpopulations expressed higher levels of the LFA-1 molecule during the HIV-1 infection. The LFA-1 dim cell subsets (CD4 cells) and the LFA-1 low cell subpopulation (CD19 lymphocytes) were not affected by the HIV-1 infection. Moreover, in the CD8 and CD3 cell subsets displaying a heterogeneous LFA-1 expression (dim and bright), we also observed a decrease of the LFA-1 dim/LFA-1 bright cell ratio.

Antibodies, Monoclonal↗
PubMed1992

Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.

Nitric oxide (NO), synthesised from L-arginine, contributes to the regulation of blood pressure and to host defence. We describe in-vitro and in-vivo evidence that NO synthesis can be inhibited by an endogenous compound, NG,NG-dimethylarginine (asymmetrical dimethylarginine, ADMA). In man, this inhibitor is found in plasma and more than 10 mg is excreted in urine over 24 h. However, in patients with end-stage chronic renal failure, who have little or no urine output, elimination is blocked and circulating concentrations of the inhibitor rise sufficiently to inhibit NO synthesis. Accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction associated with chronic renal failure.

Adult↗
PubMed1992

High frequency of antibodies to Mycoplasma penetrans in HIV-infected patients.

Mycoplasma penetrans, a novel mycoplasma isolated from HIV-1-infected patients with AIDS, has pathogenic properties associated with in-vivo virulence. Enzyme-linked immunosorbent assay and western blotting detected a more than 100 times higher frequency of antibodies to the mycoplasma in serum from HIV-1-infected patients with AIDS (40%) than from HIV-negative controls (0.3%). Serum from 20% of HIV-1-infected, symptom-free individuals also had M penetrans specific antibodies. The antibodies' major immunoreactivity was directed against P35 and P38, the two main lipid-associated membrane protein antigens of the organism. Patients attending sexually transmitted disease clinics had a low frequency of antibody (0.9%). None of 178 HIV-negative patients with different non-AIDS diseases, many associated with immune dysfunction and/or low white cell counts, tested positive for the antibodies. M penetrans, apparently not a commensal and not a simple opportunist, is uniquely associated with HIV-1 infection and AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1989

Immunohistological assessment of bone marrow biopsies from patients with hairy cell leukemia: changes following treatment with alpha-2-interferon and deoxycoformycin.

Forty-six bone marrow biopsies from twelve hairy cell leukemia (HCL) patients, treated with either interferon(IFN)-alpha-2 (n = 8) or 2'deoxycoformycin(DCF) (n = 4), were examined using cryostat sections and an immunoperoxidase technique. Using this sensitive method we were able to demonstrate residual hairy cell (HC) infiltration in five cases, in which evaluation with conventional staining techniques on plastic embedded biopsies revealed complete remission. The amount of HCs in these five samples ranged from 1 to 7% (mean: 3%) of bone marrow cells. Consecutive biopsies in individual HCL patients revealed no changes of the immunological phenotype (CD19, CD22, CD25, CD10, CD11c, FMC7, HLA-DR, surface immunoglobulins) during IFN and DCF treatment. Within the infiltrated bone marrow a considerable number of "reactive" T lymphocytes was identified with prevalence of the T-helper (CD4+) subtype in untreated cases, whereas T-suppressor/cytotoxic (CD8+) cells were within the normal range. IFN treatment resulted in a reduction of CD4+ T lymphocytes (p less than 0.02). Minor alterations of CD8+ T lymphocytes and NK cells (HNK-1 + lymphoid cells) were found in bone marrow during IFN treatment. In DCF-treated patients bone marrow T lymphocytes were markedly reduced below the values of normal bone marrow. This DCF-induced T-cell depression might be related to the clinical observation of persistent cellular immune dysfunctions in HCL patients despite a DCF-induced remission.

Adult↗
PubMedDate not supplied

Short-term somatostatin infusion affects T lymphocyte responsiveness in humans.

Peripheral blood lymphocytes (PBL) function was analysed in 16 young men with duodenal ulcers after one-hour intravenous infusion of somatostatin (SMS) at a dose of 250 micrograms/h. Proliferative responses of PBL from SMS-treated patients were significantly diminished compared with pre-treatment values, after stimulation with PHA, PWM or Con A. Spontaneous IL-2R expression was moderately increased after SMS infusion but PHA-induced IL-2R expression was not affected by this drug. Alloantigen and autoantigen stimulation of PBL showed no significant changes in the proliferative response after SMS infusion. NK cell activity was similarly unaffected. These observations establish a link between SMS exposure and possible development of immune dysfunction.

Adult↗
PubMed1995

In vitro response of lymphocytes from bronchoalveolar lavage fluid and peripheral blood to mitogen stimulation during natural maedi-visna virus infection.

To investigate the effects of maedi-visna virus (MVV) infection on cell-mediated immunity, the in vitro response of bronchoalveolar lavage fluid (BALF) and peripheral blood (BP) lymphocytes (PBL) to exogenous mitogen was analysed. BALF and PBL from control (n = 9) and MVV-infected (n = 7) animals were cultured fro 3 days in the presence and absence of concanavalin A (Con A). Lymphocyte expression of the interleukin-2 receptor (IL-2R) antigen, a parameter of lymphocyte activation, was quantified by dual-colour flow cytometry using the bovine anti-IL-2R monoclonal antibody IL-A111. IL-2R expression by lymphocytes in BALF and PB from control and MVV-infected animals, with and without Con A stimulation, were compared. In the absence of Con A stimulation, the proportion of cultured BALF CD8+ and gamma delta T cells expressing IL-2R was significantly (P < 0.05) lower for MVV-infected animals than for controls. After Con A stimulation the proportion of BALF CD4+ lymphocytes from MVV-infected animals that expressed IL-2R remained significantly (P < 0.05) lower than for controls. Comparisons within group showed that, after Con A stimulation, the proportion of all the T cell subsets in the control group expressing IL-2R, namely CD4+ (P < 0.001), CD8+ (P < 0.001) and gamma delta T cells (P < 0.05), was significantly increased. In the MVV-infected group, this increase was significant (P < 0.05) for CD4+ and CD8+ T cells, but not for gamma delta T cells. In vitro mitogen stimulation of PB T lymphocytes from both control and MVV-infected animals induced a significant elevation in the proportion of all T cell subsets expressing IL-2R when compared to cultured unstimulated control cells. However, there was considerable heterogeneity in the response to Con A of PB T cells from both groups of animals. The expression of IL-2R followed a different pattern to that of BALF lymphocytes, the proportion of unstimulated gamma delta / IL-2R+ T cells from MVV-infected animals being significantly (P < 0.05) higher than that of controls, and the proportion of cultured unstimulated CD8+ / IL-2R+ T cells from MVV-infected animals being significantly (P < 0.05) lower than that from controls. From these studies it can be concluded that the BALF T lymphocyte immune dysfunction observed during natural MVV infection, characterized by impaired IL-2R expression, is maintained under in vitro conditions.

Animals↗
PubMed1983

Diminished interleukin-2 activity production in cancer patients bearing solid tumors and its relationship with natural killer cells.

Interleukin-2 (IL-2) activity production by stimulated peripheral blood lymphocytes (PBL) from solid tumor bearing cancer patients was lower than in normal subjects. Natural-killer (NK) cell activity in the PBL of cancer patients was very significantly correlated to IL-2 activity production (P less than 0.001). These results might suggest a central role for IL-2 in the immune dysfunctions in cancer patients, and the possible use of IL-2 as an immunological response modifier in these patients.

Adult↗