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Treatment of experimental chronic infection by an immunomodulating drug, bestatin
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I N V I V O EFFECTS OF CHEMICAL CARCINOGENS ON CELL-MEDIATED IMMUNE FUNCTIONS
A. Wojdani and L. J. Alfred, Pathology Department Charles R. Drew Postgraduate Medical School, 1621 E. 120th St, Los Angeles, CA, USA 90059 The in v i v o effects of benzo(a)pyrene (BP) and methylcholanthrene (MCA) on mitogen activation, cell mediated cytotoxicity (CMC) and aryl hydrocarbon hydroxylase (AHH) induction were measured in splenic T-lymphocytes from 3 inbred mouse strains. Mice were injected either with corn oil or with optimal doses of BP or MCA in oil. One to seven days after injection splenic T-cells were isolated and cultured for blastogenesis and other responses. Lymphoproliferation of PHA-activated and non-activated lymphocytes was significantly higher in BP and MCA-treated responsive strains (C57BL, C3H) than in lymphocytes from non-responsive (DBA) mice. The order of strain difference in blastogenic response and AHH induction was: C3H>C57>DBA. A modified radiometric assay was used to measure induced levels of AHH. AHH activity showed a non-linear relationship to blastogenesis. AHH was induced 2-5 fold in C3H and C57 mice, while in DBA mice the enzyme level was very close to basal values. Finally, the effects of BP and MCA on CMC were determined. Using a 51Cr-release assay, we found that in all injected groups the percent of tumor cell killing by lymphocytes was suppressed s i g n i f i c a n t l y Thus, treatment of mice with these chemicals enhanced blastogenesis, induced AH~ activity, but suppressed CMC. (EPA R-807046020).
INFECTIONS AND IMMUNODEFICIENCY '~.9 CLINICAL USE OF THYMULIN (FTS-Zn) IN IMMUNODEFICIENCY SYNDROMES M. DARDENNE, F. BORDIGONI, M.C. BENE and J.F. BACH INSERM U 25 - HSpital Necker - 161, rue de SEvres 75730 PARIS Cedex 15- FRANCE A synthetic thymlc factor (thymuJin) has been administered to patients with various types of T-cell deficiencies including Di George syndrome, ataxia telangiectosla and common variable hypogammagJobuJinemia. Doses given ranged between 1 and 10~g/lcg/day based on the pharmacokinetics study. A significant effect was observed in most cases on T cell markers and functions (E rosettes, T cell antigens and mitogen responses). This in vivo effect correlated with the in vih'o induction of oK'r-defined antigen in the presence ofthymulin. A significant improvement of the clinical state was obtained in several cases followed up for more than 3 months including repeated respiratory infections (IgA deficiency) and a generalized herpes. Serum IgA which was totally absent in two cases appeared within 4 wks of treatment and increased significantly in the third case. Further data will be presented in other clinical indications of thymulin, defined by the study of T cell subset ~nd evaluation of serum levels of thymulin. 30
TREATMENTOF EXPERIMENTALCHRONIC INFECTION BY AN IMMUNOMODULATINGDRUG, BESTATIN. G. Oickneite, T. Hofstaetter, H.U. Schorlemmer and H.H. Sedlacek Research Laboratories of Behringwerke AG, P.O.-Box 11 40, D-3550 Marburg, W. Germany The influence of Bestatin (Umezawa, H Antibiot. Chemother. 24, 9, 1978) on chronic bacterial infections was studied in two animal models: A nephropathogenic strain of E. coIi (04:H5) causes a persisting infection in about 60-80% of the kidneys after i . v . injection of 5xlO7 bacteria into NMRI mice. With Salmonella typhimurium (C5SF1835) a persisting infection of livers and spleens to a degree of 90-I00% develops after i . v . injection of I04 Salmonellae. When Bestatin was admitted either prophylactically or therapeutically ( i . p . or i . v . ) to E. coli infected mice bacterial co|onisation and abscess formation was reduced s i g n i f i c a n t l y . Concomitant]y, histological findings show a reduction of the inflammatory reactions in the kidney tissue. The severity of the chronic infection caused by S. typhimurium could be mitigated when mice were treated with Bestatin. Abscess formation, inflammatory reactions and bacterial colonisation of livers and spleens was reduced in the Bestatin groups. Serum transaminase levels, as a marker for the hepatopathologic effect caused by the S. typhimurium infection was decreased by Bestatin, treatment. Serum antibodies against bacterial antigens were not increased oy Bestatin, however, macrophages and PMN's were stimulated during the course of infection. As Bestatin has no direct bactericidal effect on E. coli or S. typhimurium, we believe that the therapeutic effect of Bestatin on chronic infection acts via the c e l l u l a r immu~e system.
•0
I N V I V O EFFECTS OF CHEMICAL CARCINOGENS ON CELL-MEDIATED IMMUNE FUNCTIONS
A. Wojdani and L. J. Alfred, Pathology Department Charles R. Drew Postgraduate Medical School, 1621 E. 120th St, Los Angeles, CA, USA 90059 The in v i v o effects of benzo(a)pyrene (BP) and methylcholanthrene (MCA) on mitogen activation, cell mediated cytotoxicity (CMC) and aryl hydrocarbon hydroxylase (AHH) induction were measured in splenic T-lymphocytes from 3 inbred mouse strains. Mice were injected either with corn oil or with optimal doses of BP or MCA in oil. One to seven days after injection splenic T-cells were isolated and cultured for blastogenesis and other responses. Lymphoproliferation of PHA-activated and non-activated lymphocytes was significantly higher in BP and MCA-treated responsive strains (C57BL, C3H) than in lymphocytes from non-responsive (DBA) mice. The order of strain difference in blastogenic response and AHH induction was: C3H>C57>DBA. A modified radiometric assay was used to measure induced levels of AHH. AHH activity showed a non-linear relationship to blastogenesis. AHH was induced 2-5 fold in C3H and C57 mice, while in DBA mice the enzyme level was very close to basal values. Finally, the effects of BP and MCA on CMC were determined. Using a 51Cr-release assay, we found that in all injected groups the percent of tumor cell killing by lymphocytes was suppressed s i g n i f i c a n t l y Thus, treatment of mice with these chemicals enhanced blastogenesis, induced AH~ activity, but suppressed CMC. (EPA R-807046020).
INFECTIONS AND IMMUNODEFICIENCY '~.9 CLINICAL USE OF THYMULIN (FTS-Zn) IN IMMUNODEFICIENCY SYNDROMES M. DARDENNE, F. BORDIGONI, M.C. BENE and J.F. BACH INSERM U 25 - HSpital Necker - 161, rue de SEvres 75730 PARIS Cedex 15- FRANCE A synthetic thymlc factor (thymuJin) has been administered to patients with various types of T-cell deficiencies including Di George syndrome, ataxia telangiectosla and common variable hypogammagJobuJinemia. Doses given ranged between 1 and 10~g/lcg/day based on the pharmacokinetics study. A significant effect was observed in most cases on T cell markers and functions (E rosettes, T cell antigens and mitogen responses). This in vivo effect correlated with the in vih'o induction of oK'r-defined antigen in the presence ofthymulin. A significant improvement of the clinical state was obtained in several cases followed up for more than 3 months including repeated respiratory infections (IgA deficiency) and a generalized herpes. Serum IgA which was totally absent in two cases appeared within 4 wks of treatment and increased significantly in the third case. Further data will be presented in other clinical indications of thymulin, defined by the study of T cell subset ~nd evaluation of serum levels of thymulin. 30
TREATMENTOF EXPERIMENTALCHRONIC INFECTION BY AN IMMUNOMODULATINGDRUG, BESTATIN. G. Oickneite, T. Hofstaetter, H.U. Schorlemmer and H.H. Sedlacek Research Laboratories of Behringwerke AG, P.O.-Box 11 40, D-3550 Marburg, W. Germany The influence of Bestatin (Umezawa, H Antibiot. Chemother. 24, 9, 1978) on chronic bacterial infections was studied in two animal models: A nephropathogenic strain of E. coIi (04:H5) causes a persisting infection in about 60-80% of the kidneys after i . v . injection of 5xlO7 bacteria into NMRI mice. With Salmonella typhimurium (C5SF1835) a persisting infection of livers and spleens to a degree of 90-I00% develops after i . v . injection of I04 Salmonellae. When Bestatin was admitted either prophylactically or therapeutically ( i . p . or i . v . ) to E. coli infected mice bacterial co|onisation and abscess formation was reduced s i g n i f i c a n t l y . Concomitant]y, histological findings show a reduction of the inflammatory reactions in the kidney tissue. The severity of the chronic infection caused by S. typhimurium could be mitigated when mice were treated with Bestatin. Abscess formation, inflammatory reactions and bacterial colonisation of livers and spleens was reduced in the Bestatin groups. Serum transaminase levels, as a marker for the hepatopathologic effect caused by the S. typhimurium infection was decreased by Bestatin, treatment. Serum antibodies against bacterial antigens were not increased oy Bestatin, however, macrophages and PMN's were stimulated during the course of infection. As Bestatin has no direct bactericidal effect on E. coli or S. typhimurium, we believe that the therapeutic effect of Bestatin on chronic infection acts via the c e l l u l a r immu~e system.