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Modulation of lymphocytotoxicity by biologic response modifiers
288
31
EVALUATIUN OF AN IMMUNOMODULATOR LF 1695 ON MURINE IMMUNE FUNCTION M. PASCALr P. DESNOYERS~ B. MAJOIE Centre de Recherches - Laboratoires FUURNIER S.A., 42, rue de Longvic - 21300 CHENOVE FRANCE. LF log5 is a chemically defined immunomodulatorwhlch potentiates PHA, Con A and PWM response of DBA/2 splenocytes at an optimum dose of 1 ~g/ml. Higher doses suppress tne response. When admlnistered o r a l l y to outbred mice, suppression was observed on delayed hypersensitivity to sheep red blood cells {SRBC). Optimum sensltizatlon was reached with 100 times lower doses of SR~C. tmmuno suppression was further c o n f i r ~ d on an anti H2 cytotoxicity test, this suppresslon could be adoptlvely transferreo with a non adherent sp]enocytes population. IgG and IgM plaque forming cells to 3RBCwere enhanced in the spleen of the treated animals. This was not due to a i helper effect as shown by experlments using a T independent antigen. Thus LF ~695 appears to potentiate T suppressor mechanism and to behave also as an immunopotentiator maybe by acting on antigen presenting cells.
3
I~AUNOMOOULATING EFFECTS OF A SHORT-TERM ORAL TREATMENT WITH C 1821 PATIENTS
IN UNTREATED CANCER
J.M. Lang, A. Aleksijevic, C. Giron, S. Levy, A. Palkenrodt, S. Mayer, J.C. S t o c l e t and F. O b e r i i n g Service des M a i a d i e s du Sang, Hopztal de Hautepierre, 67098 S t r a s b o u r g cedex, France. C 1821 is a p u r i f i e d g l y c o p r o t e z n extract from k l e b s i e l l a p n e u m o n i a e serotype 2 (LaDoratoires C a s s e n n e et Roussei UCLAF, Parzs, France) with i m m u n o m o d u l a t i n g properties in a n l m a i s (in vzvo and in vitro) and in humans (in vitro). The compound is devoid of any a p p a r e n t toxiczty when given orally. The azm of the present work was to evaluate the effects of a short term oraI a d m i n i s t r a t i o n of C 1821 in untreate0 cancer patients ~mostly lymphomas) combining in vivo ano in vitro tests. C o n s e c u t i v e patients were a l t e r n a t i v e iy a l l o c a t e d to receive either C 1821 or placebo for 14 days. C 1821 restored and significantly e n h a n c e d skin reactions to recall a n t i g e n s as shown with the M u i t i t e s t system. It also restored lymphocyte levels of cAMP and cGMP to normal and even supranormal values. E f f e c t s on NK ceii a c t i v i t y and T lymphocyte subsets will also be presented. This controlled trial d e m o n s t r a t e d the i m m u n o r e s t o r i n g p r o p e r t i e s of C 1821 given orally and showed that the immune defect a s s o c i a t e d with cancer may be corrected with a short course immunotherapy.
78
MODULATION OF LYMP~IOCYTOTO~Z[CITY BY BIOLOGIC RESPONSE M. M i c k s c h e a n d A. U c h l d a Instittitefor Cancer Research, University of Vienna, Vienna, Austria
MODIFIERS
Augmentation of natural killer (NK) cell activity and induction of autologous lymphocytotoxicity (ALC) seem to be important in respect of cancer imrnunotherapy, since these mechanisms are supposed to play an important role in the elimination of malignant cells in vivo. W e have studied several biologic response modifiers (BRM) for their capacity to enhance N K activity and ALL] by in vitro incubation of cancer patient lymphocytes. N K activity was significantly augmented by interferon (IFN-=C, IFN-~), staphyiococcus protein A, poly I:C, and OK432, but not by poly A:U and N P T 15231. A I ~ was induced by treatment of lymphocytes with OK432 but not with IFN. Then, N K activity and A L C were monitored in cancer patients treated with B R M . Treatment of patients with IFN-~: I F N - ~ , poly I:C, OK432, V i t a m i n A a n d N P T r e s u l t e d in s i g n i f i c a n t e n h a n c e m e n t of NK a c t i v i t y , w h e r e a s poly A:U "#as i n e f f e c t i v e i n the dose a n d r o u t e s u s e d . OK432 did f u r t h e r z n o r e i n d u c e ALC i n c a n c e r p a t i e n t s when g i v e n i n t r a p l e u r a i l y . E v i d e n c e e x i s t s t h a t the l a c k of NK a c t i v i t y i n m a l i g n a n t p l e u r a l e f f u s i o n s i s due to the p r e s e n c e of a d h e r e n t e f f u s i o n c e l t s c a p a b l e of s u p p r e s s i n g NK a c t i v i t y (Uchida a n d M i c k s c h e , CII, 1981). OK432 i s found to r e d u c e s u p p r e s s o r a c t i v i t y of a d h e r e n t c e l l s both in vivo a n d i n v i t r o , which c o u l d b e o n e m e c h a n i s m b y which OK432 a c t s to a u g m e n t k i l l i n g a c t i v i t y .
31
EVALUATIUN OF AN IMMUNOMODULATOR LF 1695 ON MURINE IMMUNE FUNCTION M. PASCALr P. DESNOYERS~ B. MAJOIE Centre de Recherches - Laboratoires FUURNIER S.A., 42, rue de Longvic - 21300 CHENOVE FRANCE. LF log5 is a chemically defined immunomodulatorwhlch potentiates PHA, Con A and PWM response of DBA/2 splenocytes at an optimum dose of 1 ~g/ml. Higher doses suppress tne response. When admlnistered o r a l l y to outbred mice, suppression was observed on delayed hypersensitivity to sheep red blood cells {SRBC). Optimum sensltizatlon was reached with 100 times lower doses of SR~C. tmmuno suppression was further c o n f i r ~ d on an anti H2 cytotoxicity test, this suppresslon could be adoptlvely transferreo with a non adherent sp]enocytes population. IgG and IgM plaque forming cells to 3RBCwere enhanced in the spleen of the treated animals. This was not due to a i helper effect as shown by experlments using a T independent antigen. Thus LF ~695 appears to potentiate T suppressor mechanism and to behave also as an immunopotentiator maybe by acting on antigen presenting cells.
3
I~AUNOMOOULATING EFFECTS OF A SHORT-TERM ORAL TREATMENT WITH C 1821 PATIENTS
IN UNTREATED CANCER
J.M. Lang, A. Aleksijevic, C. Giron, S. Levy, A. Palkenrodt, S. Mayer, J.C. S t o c l e t and F. O b e r i i n g Service des M a i a d i e s du Sang, Hopztal de Hautepierre, 67098 S t r a s b o u r g cedex, France. C 1821 is a p u r i f i e d g l y c o p r o t e z n extract from k l e b s i e l l a p n e u m o n i a e serotype 2 (LaDoratoires C a s s e n n e et Roussei UCLAF, Parzs, France) with i m m u n o m o d u l a t i n g properties in a n l m a i s (in vzvo and in vitro) and in humans (in vitro). The compound is devoid of any a p p a r e n t toxiczty when given orally. The azm of the present work was to evaluate the effects of a short term oraI a d m i n i s t r a t i o n of C 1821 in untreate0 cancer patients ~mostly lymphomas) combining in vivo ano in vitro tests. C o n s e c u t i v e patients were a l t e r n a t i v e iy a l l o c a t e d to receive either C 1821 or placebo for 14 days. C 1821 restored and significantly e n h a n c e d skin reactions to recall a n t i g e n s as shown with the M u i t i t e s t system. It also restored lymphocyte levels of cAMP and cGMP to normal and even supranormal values. E f f e c t s on NK ceii a c t i v i t y and T lymphocyte subsets will also be presented. This controlled trial d e m o n s t r a t e d the i m m u n o r e s t o r i n g p r o p e r t i e s of C 1821 given orally and showed that the immune defect a s s o c i a t e d with cancer may be corrected with a short course immunotherapy.
78
MODULATION OF LYMP~IOCYTOTO~Z[CITY BY BIOLOGIC RESPONSE M. M i c k s c h e a n d A. U c h l d a Instittitefor Cancer Research, University of Vienna, Vienna, Austria
MODIFIERS
Augmentation of natural killer (NK) cell activity and induction of autologous lymphocytotoxicity (ALC) seem to be important in respect of cancer imrnunotherapy, since these mechanisms are supposed to play an important role in the elimination of malignant cells in vivo. W e have studied several biologic response modifiers (BRM) for their capacity to enhance N K activity and ALL] by in vitro incubation of cancer patient lymphocytes. N K activity was significantly augmented by interferon (IFN-=C, IFN-~), staphyiococcus protein A, poly I:C, and OK432, but not by poly A:U and N P T 15231. A I ~ was induced by treatment of lymphocytes with OK432 but not with IFN. Then, N K activity and A L C were monitored in cancer patients treated with B R M . Treatment of patients with IFN-~: I F N - ~ , poly I:C, OK432, V i t a m i n A a n d N P T r e s u l t e d in s i g n i f i c a n t e n h a n c e m e n t of NK a c t i v i t y , w h e r e a s poly A:U "#as i n e f f e c t i v e i n the dose a n d r o u t e s u s e d . OK432 did f u r t h e r z n o r e i n d u c e ALC i n c a n c e r p a t i e n t s when g i v e n i n t r a p l e u r a i l y . E v i d e n c e e x i s t s t h a t the l a c k of NK a c t i v i t y i n m a l i g n a n t p l e u r a l e f f u s i o n s i s due to the p r e s e n c e of a d h e r e n t e f f u s i o n c e l t s c a p a b l e of s u p p r e s s i n g NK a c t i v i t y (Uchida a n d M i c k s c h e , CII, 1981). OK432 i s found to r e d u c e s u p p r e s s o r a c t i v i t y of a d h e r e n t c e l l s both in vivo a n d i n v i t r o , which c o u l d b e o n e m e c h a n i s m b y which OK432 a c t s to a u g m e n t k i l l i n g a c t i v i t y .