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Immunomodulatory properties of NPT 15392 in man: In vitro and in vivo
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ISOPRINOSINE (INOSIPLEX) : IF~IUNOLOGICAL AND CLINICAL EFFECTS IN MAN. J. Wybran. Department of Immunology and Hematology, Erasme Hospital, Universit~ Libre de Bruxelles, 1070 Brussels, Belgium. Isoprinosine increases the response in mixed lymphocyte culture and in phytohemagglutinin stimulation even i f the lymphocytes are only incubated for one hour with the drug. I t also enhances the phytohemagglutinin response of purified T cell populations. After incubation with isoprinosine, the mononuclear cells induce in the supernatant the property of enhancing the mitogenic response of normal lymphocytes. Isoprinosine increases the phytohemagglutinin response of the lymphocytes of cancer patients. Isoprinosine enhances the percentages of active T rosettes. I t also amplifies the phagocytic properties of blood monocytes. In vivo, in various disease state, isoprinosine modifies the percentages of blood OK T4 and OK T8 lymphocyte populations. This effect is depending upon the dosage and perhaps the immunological status before treatment. Clinically, inosiplex, in open studies, has been shown to be beneficial in various viral diseases like subacute sclerosing panencephalitis, cutaneous herpes and aphtous stomatit i s , cytom~galovirus hepatitis and rheumatoid a r t h r i t i s . In summary, inosiplex is a synthetic immunomodulatory agent and i t is l i k e l y that i t s immunological properties explain p a r t i a l l y or t o t a l l y its clinical beneficial effects. IMMUNOMODULATORY PROPERTIES OF NPT 15392 IN MAN : IN VITRO AND IN VIVO. J. Wybran(Chairman of the Tumor Immunology Project Group),B.Serrou, D.Belpomme, J.Boneterre, A.Desplaces, R.Favre, T.Ginsberg, J.M.Lang, G.Mayer, D.T.McKenzie, M.Miksche, D.C. Petit, G.Renoux, C.Rosenfeld, J.Schmerber, M.Schneider, L.N.Simon, L.Toujas, A.Uchida. Department of Hematology and Immunology, Erasme Hospital, Universit~ Libre de Bruxelles, 1070 Brussels, Belgium. NPT 15392 markedly increases the percentages of active T rosettes without affecting other T rosette assays. This property seems due to the synthesis of a rosetting factor by mononuclear cells incubated with the drug. I t also enhances T cell induced cytotoxicity in mixed lymphocyte culture. NPT 15392 markedly increases the polynw)rph neutrophil phagocytosis of yeast particles. In cancer patients, a unique oral dose of 0.4 mgr or 0.7 mgr increases blood T rosette percentages in systems like active, autologous and total T rosettes. Twentycancer patients also received 0.4 or 0.7 n~jr of NPT 15392 every 3 days for 10 days. Although skin tests were not modified by the drug, other T cell assays showed a significant increase : number of blood T lymphocytes, percentages of E rosettes, percentages of autologous T rosettes and PHA stimulation. Furthermore, a decrease in OK T4 percentages was also observed. NK function was increased to normal values in patients with low NK cytotoxicity before treatment. I t can be concluded that NPT 15392 possesses neutrophil, T cell and NK immunostimulatory properties.
RECEPTORS
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UTILIZATION OF ANTIBODIES AGAINST RAT ADIPOCYTE MEMBRANES AS A PROBEOF INSULIN ACTION Dennis J. Pillion Dept. of Pharmacology, Univ. of Alabama in Birmingham, Birmingham, Alabama 35294, U.S.A. Rabbit antibodies aganist rat adipocyte plasma membranes have been used to investigate the mechanism of insulin action. Anti-membraneantiserum reacts with several different membrane proteins as shown by crossed immunoelectrophoresis. Lectin a f f i n i t y crossed immunoelectrophoresis shows that several of the major adipocyte antigens are glycoproteins which react with concanavalin A. Rabbit anti-membrane serumcauses con~olementmediated lysis of intact rat adipocytes, an effect which is eliminated by heatinactivation. Heat-inactivated antiserum causes an increase in glucose uptake and metabolism by rat adipocytes similar to that seen with maximal levels of insulin. The antiserum does not competitively block the binding of insulin to fat cells. Fab fragments of the I gG fraction of this antiserum f a i l s to e l i c i t an insulin-like response on rat fat cell glucose uptake, but anti-Fab serum added to the Fab fragments in the presence of rat adipocytes can restore this activity. Studieswith flouroscein-labelled anti-lgG serum indicate that anti-membrane antiserum causes capping of rat fat cells. The results suggest that anti-membrane antibodies bind to cell surface proteins, cause agglutination and trigger an insulin-like response in isolated rat adipocytes.
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ISOPRINOSINE (INOSIPLEX) : IF~IUNOLOGICAL AND CLINICAL EFFECTS IN MAN. J. Wybran. Department of Immunology and Hematology, Erasme Hospital, Universit~ Libre de Bruxelles, 1070 Brussels, Belgium. Isoprinosine increases the response in mixed lymphocyte culture and in phytohemagglutinin stimulation even i f the lymphocytes are only incubated for one hour with the drug. I t also enhances the phytohemagglutinin response of purified T cell populations. After incubation with isoprinosine, the mononuclear cells induce in the supernatant the property of enhancing the mitogenic response of normal lymphocytes. Isoprinosine increases the phytohemagglutinin response of the lymphocytes of cancer patients. Isoprinosine enhances the percentages of active T rosettes. I t also amplifies the phagocytic properties of blood monocytes. In vivo, in various disease state, isoprinosine modifies the percentages of blood OK T4 and OK T8 lymphocyte populations. This effect is depending upon the dosage and perhaps the immunological status before treatment. Clinically, inosiplex, in open studies, has been shown to be beneficial in various viral diseases like subacute sclerosing panencephalitis, cutaneous herpes and aphtous stomatit i s , cytom~galovirus hepatitis and rheumatoid a r t h r i t i s . In summary, inosiplex is a synthetic immunomodulatory agent and i t is l i k e l y that i t s immunological properties explain p a r t i a l l y or t o t a l l y its clinical beneficial effects. IMMUNOMODULATORY PROPERTIES OF NPT 15392 IN MAN : IN VITRO AND IN VIVO. J. Wybran(Chairman of the Tumor Immunology Project Group),B.Serrou, D.Belpomme, J.Boneterre, A.Desplaces, R.Favre, T.Ginsberg, J.M.Lang, G.Mayer, D.T.McKenzie, M.Miksche, D.C. Petit, G.Renoux, C.Rosenfeld, J.Schmerber, M.Schneider, L.N.Simon, L.Toujas, A.Uchida. Department of Hematology and Immunology, Erasme Hospital, Universit~ Libre de Bruxelles, 1070 Brussels, Belgium. NPT 15392 markedly increases the percentages of active T rosettes without affecting other T rosette assays. This property seems due to the synthesis of a rosetting factor by mononuclear cells incubated with the drug. I t also enhances T cell induced cytotoxicity in mixed lymphocyte culture. NPT 15392 markedly increases the polynw)rph neutrophil phagocytosis of yeast particles. In cancer patients, a unique oral dose of 0.4 mgr or 0.7 mgr increases blood T rosette percentages in systems like active, autologous and total T rosettes. Twentycancer patients also received 0.4 or 0.7 n~jr of NPT 15392 every 3 days for 10 days. Although skin tests were not modified by the drug, other T cell assays showed a significant increase : number of blood T lymphocytes, percentages of E rosettes, percentages of autologous T rosettes and PHA stimulation. Furthermore, a decrease in OK T4 percentages was also observed. NK function was increased to normal values in patients with low NK cytotoxicity before treatment. I t can be concluded that NPT 15392 possesses neutrophil, T cell and NK immunostimulatory properties.
RECEPTORS
44
UTILIZATION OF ANTIBODIES AGAINST RAT ADIPOCYTE MEMBRANES AS A PROBEOF INSULIN ACTION Dennis J. Pillion Dept. of Pharmacology, Univ. of Alabama in Birmingham, Birmingham, Alabama 35294, U.S.A. Rabbit antibodies aganist rat adipocyte plasma membranes have been used to investigate the mechanism of insulin action. Anti-membraneantiserum reacts with several different membrane proteins as shown by crossed immunoelectrophoresis. Lectin a f f i n i t y crossed immunoelectrophoresis shows that several of the major adipocyte antigens are glycoproteins which react with concanavalin A. Rabbit anti-membrane serumcauses con~olementmediated lysis of intact rat adipocytes, an effect which is eliminated by heatinactivation. Heat-inactivated antiserum causes an increase in glucose uptake and metabolism by rat adipocytes similar to that seen with maximal levels of insulin. The antiserum does not competitively block the binding of insulin to fat cells. Fab fragments of the I gG fraction of this antiserum f a i l s to e l i c i t an insulin-like response on rat fat cell glucose uptake, but anti-Fab serum added to the Fab fragments in the presence of rat adipocytes can restore this activity. Studieswith flouroscein-labelled anti-lgG serum indicate that anti-membrane antiserum causes capping of rat fat cells. The results suggest that anti-membrane antibodies bind to cell surface proteins, cause agglutination and trigger an insulin-like response in isolated rat adipocytes.