RESUMEN

Peripheral blood lymphocytes from Alzheimer's patients and apparently healthy elderly individuals were examined for interleukin-1 (IL-1) production. Our results indicate severely low production of IL-1 by patient's peripheral blood monocytes. The low production of IL-1 in vitro correlated with patients' symptoms and therapy with 1-acetamide,2-pyrrolidone (1a,2p). In addition to low IL-1 production, the number of autologous rosette forming cells (ARFC) was significantly decreased in all Alzheimer's patients whereas B-cell glucose metabolism was significantly higher than age-matched healthy individuals.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

Phencyclidine ("PCP" or "angel dust") and some of its derivatives are psychotomimetic drugs that have been used in general anesthesia for some time. This drug blocks potassium ion channels in brain tissue, and there is a specific PCP binding to lymphocytes. In a study of the effects of this drug on immunocyte function, it was found that humoral and cellular immune responses in vitro were depressed when immunocytes were treated with PCP before biological assay. This finding has implications for PCP abuse and also for the use of its derivative in general anesthesia, where it may contribute to postoperative infection.

Asunto(s)

RESUMEN

Based on commonalities between peripheral blood "immunocytes" and central nervous system cells (both have receptors for endorphins, enkephalins, dopamine, acetylcholine, etc.) blocking of potassium ion channels in both brain cell synaptosome and suppressor T cells, and common sharing of antigenic determinants on one or another immunocyte and one or another CNS cells, we postulated that peripheral blood immunocytes can be used to study CNS mechanisms. In the present studies we used peripheral blood lymphocytes to study the effects of phencyclidine (PCP) on various receptors. This agent causes a permanent psychosis similar to chronic schizophrenia in a small percent of users. We observed similar effects in binding to sigma receptors, inhibition of binding and reversibility of binding in receptors of both human peripheral blood receptors and the mouse neuroblastoma, a hamster brain cell hybrid clone. The results are complete with the hypothesis that some cases of schizophrenia are immunologically mediated, perhaps due to antibodies to the sigma receptor. Alternatively, immunologic deficiency might hinder elimination of neurotropic viruses which in genetically predisposed individuals bind to and block the sigma receptor. Functional deficiency of the brain cell equivalent of lymphocyte suppressor T cells by one or another immunologic mechanisms or an excess of T helper cells might also cause schizophrenia by causing an excess of normal brain "B-cell equivalent cell" output response to sensory input.

Asunto(s)

Asunto(s)

RESUMEN

Based on remarkable similarities between the central nervous system and the immune system [e. g., both systems have memory cells, both appear to have identical receptors for dopamine, acetylcholine, enkephalins, endorphins, sharing of antigenic determinants on one or another CNS cell and one or another type of immunocyte cell, both systems communicate by soluble substances (e.g., neurotransmitters and lymphokines, respectively)], we have postulated that some forms of Alzheimer's disease are due not to CNS cell death but rather to excess suppression of the brain "B-cell equivalent". We found a pyrrolidone analog useful in stimulating lymphocyte B-cell mitogenesis and function in vitro; this agent subsequently proved dramatically effective in several patients with severe T cell dysfunction and severe recurrent viral infection due to excess T cell suppression. Its use (3-6 months) proved remarkedly effective in certain patients with Alzheimer's disease (frontal lobe cerebral atrophy on CAT scan, duration at least 2 years). A subset with certain immunological dysfunction responded dramatically both immunologically and clinically. In responders in in vitro studies, the defect was corrected in vitro in the presence of the pyrrolidone analog but not by various neuroleptics. Patients without the defect or with the defect but no in vitro correction by pyrrolidone analog agent did not respond clinically. A switch from pyrrolidone to placebo resulted in immunologic and clinical relapse in 2-4 months.

Asunto(s)

RESUMEN

We studied the effect of 1-acetamide, 2-pyrrolidone (PVP-A), a B-cell mitogen derivative, on interleukin-1 (IL-1) production by peripheral blood monocytes. The compound was capable of inducing monocytes to produce IL-1 to an extent significantly lower than that induced by lipopolysaccharide (LPS). However, addition of PVP-A in conjunction with LPS resulted in IL-1 superinduction. Furthermore, PVP-A addition to monocytes of patients with Alzheimer's disease (AD) restored diminished IL-1 production by these cells to levels comparable with monocytes from age-matched healthy individuals. We also examined the effect of PVP-A on immunoglobulin (Ig) synthesis in vitro. PVP-A increased the production of both IgM and IgG by peripheral blood lymphocytes (PBL) in response to pokeweed mitogen (PWM). We conclude, since Ig synthesis of B-cells requires monocytes, that perhaps PVP-A activated monocytes can boost B-cells resulting in augmented Ig production.

Asunto(s)

RESUMEN

A model is proposed for an autoimmune etiology for schizophrenia. We propose that schizophrenia is a syndrome (not a disease). We suggest that autoantibodies (and/or cell-mediated immunity) directed against autologous neurotransmitter receptors are responsible for the ebb and flow of psychotic symptomatology. The hypothesis is predicated on autoimmune models in other known receptor diseases as well as on the newly emerging recognition that general immune dysfunction exists in certain schizophreniform psychoses.

Asunto(s)

RESUMEN

Murine peritoneal macrophages, parabiotically co-cultured with combinations of in vitro H-2 sensitized thymus-derived lymphocytes obtained from drug-pretreated mice, possessed an increased cytotoxicity against alloantibody-coated target cells. This heightened activity appeared to be accentuated by and dependent on T-cell synergy. After 5 days of in vitro allosensitization at 37 degrees C, cortisone-resistant thymocytes allosensitized in combination with cyclophosphamide-pretreated splenic T cells released molecules that produced strong antibody-dependent macrophage-mediated cytotoxicity (ADCC). This enhanced ADCC correlated with increased macrophage rosetting with IgG-sensitized erythrocytes. These heightened activities resulted from soluble mediators released by the activated T cells which diffused across a 0.22-microns Millipore filter and were not dependent on lymphocyte-macrophage contact. Evidence that these molecules originated from the highly enriched T-cell populations and were not synthesized de novo by macrophages was supported by results of pretreatment with protein and RNA synthesis inhibitors. Evidence that soluble Fc receptors released from the alloactivated T cells were responsible for the increased macrophage EA binding and ADCC was obtained in affinity chromatography experiments in which activity could be depleted by passage over a Sepharose-Fc-coupled column and recovered in the column eluate.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

Murine lymphocytes from spleen, lymph node, and thymus were examined for IgM complex receptors. Lymphocytes from all three organs were found to bind SRBC sensitized with IgM from various sources including: primary anti-SRBC serum, murine and rabbit anti-Escherichia coli LPS sera, and a murine IgM myeloma (MOPC 104E). Rosette formation by lymphocytes with IgM-sensitized SRBC was inhibited by soluble antigen-IgM complexes but not by IgM or antigen alone. Rosette formation was also inhibited by human IgM (Fc)5mu but not by Fab mu. Antiserum and complement treatment of the cells and subsequent recovery of the viable cells by trypsinization, filtration, and washing revealed the IgM rosette-forming cell (RFC) in the thymus to be a T cell. Spleen on the other hand was found to contain both B and T cells capable of binding IgM sensitized SRBC. Removal of both B and T cells from spleen cell suspensions eliminated all IgM RFC. The IgM complex receptor was found to be trypsin insensitive. Anti-Ig column fractionation enriched IgM RFC in spleen and lymph node suspensions passed through the columns, whereas cells bearing surface Ig, IgG complex receptors, and C3 receptors were retained in the columns.

Asunto(s)

RESUMEN

Antibody-dependent, cell-mediated cytotoxicity in the Moloney sarcoma virus (MSV) system was analyzed in terms of the ability of autochthonous antibody to induce or potentiate cytotoxicity by lymphocytes from animals infected with MSV. As previously demonstrated in microcytotoxicity assays, the lymphocytes from regressor animals taken 30 days after virus infection were consistently more cytotoxic than those from tumor-bearing animals 15 days after infection. Antisera from the regressors potentiated the activity of regressor lymphocytes from the same animals. Also, antisera from tumor bearers, 15 days after virus injection, induced cytotoxicity by the animals' autochthonous lymphocytes which, by themselves, were not cytotoxic. In an independent assay for antibody, both groups of sera produced cytotoxicity by control nonimmune lymphocytes. Specificity controls indicated that both antibody and lymphocytes were required for the induction of cytotoxicity against the target cells in vitro. Normal sera placed on the target cells in the same concentrations induced no cytotoxicity by the immune lymphocytes, and immune sera alone placed on the target cells caused no cytotoxicity. The cooperative activity between antibody and lymphocytes may be a factor that accounts for the observed high incidence of spontaneous tumor regression.

Asunto(s)

RESUMEN

Antibody-dependent cell-mediated cytotoxicity in the Moloney sarcoma virus (MSV) system was analyzed with respect to the subpopulations of effector cells involved in tumor target cell destruction when IgM was used as the sensitizing antibody. With unfractionated sera from animals that had undergone regression primary MSV tumors it was found that macrophages did not contribute to the cytotoxicity induced by normal spleen cells that were syngeneic to the target cells. The IgM fraction of MSV regressor sera was found to induce cytotoxicity against the target cells by immunoadsorbent column-fractionated normal spleen cells, which were either depleted of T cells or B cells, according to the specificity of the columns. Immune IgM was also found to potentiate the activity of MSV regressor spleen cells that had been similarly fractionated. Furthermore, IgM antibody was found to induced cytotoxicity by normal spleen cells which had been depleted of either T or B cells by the appropriate antiserum (anti-T or anti-Ig) in the presence of complement and subsequent recovery of the viable cells by trysinization, filtration, and washing. However, spleen cells treated with both anti-T and anti-Ig sera simultaneously in the presence of complement and subsequet recovery of viable cells, were not induced to be cytotoxic against the IgM-coated tumor target cells. Further support oy T cells was provided by an experiment showing the induction with IgM of cytotoxicity against the target cells by normal thymocytes.

Asunto(s)

RESUMEN

In summary, we have found that IgM, from mice which have undergone regression of primary MSV tumors, will induce cytotoxicity against the appropriate target cells by normal splenocytes and normal thymocytes. The thymocyte-induced cytotoxicity i

Asunto(s)

RESUMEN

Antisera with specificity for Moloney leukemia virus-(MLV) determined antigen(s) were studied for their ability to induce MLV antigen bearing target cell reduction by lymphocytes in microcytotoxicity assays. Sera from animals which had regressed Moloney sarcoma virus (MSV) tumors as well as sera from animals with progressively growing MSV tumors were found to induce normal lymphocytes to be active against the targets. Regressor serum was found also to induce cytotoxicity by immune lymphocytes from a tumor-bearing animal 15 days after MSV and from a regressor 50 days after MSV infection. Both the 19S and 7S Sephadex G-200 fractions of the antisera were found to induce cytotoxicity by normal lymphocytes and to potentiate the cytotoxicity of MSV immune lymphocytes. These activities were shown to be IgM and IgG, respectively, by the use of Sepharose-coupled anti-mouse IgM and anti-mouse IgG columns. All activity was removed by passing sera over both columns.

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)