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A novel quinolinecarboxamide with interesting immunomodulatory activity
336
16
TRAXANOX
AUGMENTS
SUPPRESSOR
T CELL
INDUCTION:
ROLE OF M A C R O P H A G E S
K. Goto, M. Hisadome, M. T e r a s a w a , C. Abe* and Y. S h i o k a w a * R e s e a r c h L a b o r a t o r i e s , Y o s h i t o m i P h a r m a c e u t i c a l I n d u s t r i e s Ltd. Y o s h i t o m i - c h o , C h i k u j o - g u n , Fukuoka. * D i v i s i o n of R h e u m a t o l o g y , U n i v e r s i t y School of Medicine, Tokyo, Japan.
Koiwai, Juntendo
T r a x a n o x w i t h an a n t i a l l e r g i c a c t i v i t y has been shown to s u p p r e s s the IgE p r o d u c t i o n in the BN rat, and to m o d u l a t e the d e v e l o p m e n t of d e l a y e d type h y p e r s e n s i t i v i t y in mice. In the p r e s e n t study, we found that t r a x a n o x g i v e n o r a l l y s u p p r e s s e d the p r o d u c t i o n of p l a q u e - f o r m i n g cells (PFC) in the s p l e e n of N Z B / W m i c e i m m u n i z e d w i t h sheep red b l o o d cells (SRBC). In the B A L B / c mice, t r a x a n o x was c a p a b l e of i n d u c i n g s u p p r e s s o r T (Ts) cells and of p o t e n t i a t i n g Ts cells i n d u c t i o n by ConA to SRBC in vivo. The t r a n s f e r of T cells or a d h e r e n t s p l e e n cells (ASC) o b t a i n e d from the B A L B / c mice i m m u n i z e d w i t h SRBC and t r e a t e d w i t h t r a x a n o x to the s y n g e n e i c m i c e r e s u l t e d in s u p p r e s s i o n of s p l e e n PFC p r o d u c t i o n to SRBC. The s p l e e n PFC p r o d u c t i o n to SRBC was also s u p p r e s s e d by t r a n s f e r of A S C t r e a t e d w i t h t r a x a n o x and SRBC in vitro. T he s e results suggest that the i n d u c t i o n of Ts cells by t r a x a n o x may be m e d i a t e d by ASC, and that this drug may be useful for the t r e a t m e n t of p a t i e n t s w i t h Ts cell function deficiency.
17
ADJUVANT EFFECT OF PURIFIED PROTEIN DERIVATIVES OF TUBERCULIN (PPD) ON THE INDUCTION OF CLASSICAL DELAYEDTYPE HYPERSENSITIVITY AGAINST PROTEIN ANTIGEN IN GUINEA PIG S.Kuwajima, A.Kitano, K. Okawa, S.Oka, Y. Tanaka, K.Kobayashi, S. Yama~oto and M.Masui The 3rd Department of Internal Medicine, Department of Bacteriology, Osaka City University Medical School, 1-5-7, Asahi-Machi, Abeno-Ku, Osaka, 545 Japan. In the previous reports, we have already mentioned that T-independent B-cell mitogens in mice, namely lipopolysaccharide(LPS) and dextran(MW;40,000, Pharmacia, Sweden), are able to induce classical delayed type hypersensitivity(DTH) against T-dependent protein antigen(ovalbumin, OVA, grade V,Sigma, USA) in guinea pig, as well as that of waxD of M~dob~zcte~,iz4w ~ul~6I,duZos48 Aoyama B. In this study, PPD(Parke Davis Co., USA) was examined whether it could show the DTH-inducing activity, because PPD has been known to be T-independent B-antigen. (Materials & method) I00 ~g of PPD was injected to i~unize into hind footpad uf randomly bred Haxtley strain of guinea pig together with 1.0 mg of OVA, 0.I ml of Freund incomplete adjuvant(Difco,USA) and 0.i ml of saline per animal in the form of water in oil emulsion. 3 wks later, skin and corneal reaction(48 h) against OVA which was filtered through to sterilize(pore size;0.45 ~m,millipore Co., USA) before use. (Result &conclusion) DTH responses of animals immunized with PPD were positive and well comparable to that of waxD, killed tubercular bacilli, dextran. 12S or MDP(GIRPI,France). Thus, PPD was demonstrafed to have a DTH-inducing activity against protein antigen in guinea pig.
18
A NOVEL
QUINOLINECARBOXAMIDE
WITH
INTERESTING
[MMUNOMODULATORY
ACTIVITY
Torbj~rn StAlhandske, Edgar Eriksoo and Britt-Marle Sandber~ AB Leo, Research Laboratories, Box 9~I 5251 09 Helsin.~borg, Sweden A series of quinolinecarboxamldes screened in a conventional antiinflammatorv program demonstrated marked enhancement of the carra~eenan induced inflammatory response. One of these compounds, LS 2616, was further evaluated. Oral treatment with L5 2616 increased in a wide range of doses (0.65 mq/k~ to 80 m~/k~) the delayed type hypersensitivity (DTH) response to B. pertussis in the pleural cavitv of rats. A significant increase in the volume of exudate and number of macrophages was shown. The effect was evident both after treatment around the period of sensitization and challenge. The DTH response depressed in rats bearin~ D M B A induced m a m m a r y turnouts was restored after 10 m R/k~/day for four days. The growth of the turnouts was inhibited and the mitogenic response of spleen cells to ConA and PHA was increased. A 50% reduction in the number of metastasis produced by the Lewis lung carcinoma was also found after oral treatment with [S 2616. LS 2616 is relatively nontoxic since rats tolerated 960 mg/k,R/day for fourteen days without clinical signs of toxicity. LD50 for rats and mice was found to be approx|mately 1500 mg/kg. LS 2616 possesses an interestinR antitumour and immunomodulatory profile and we are currently investigating its mode of action.
16
TRAXANOX
AUGMENTS
SUPPRESSOR
T CELL
INDUCTION:
ROLE OF M A C R O P H A G E S
K. Goto, M. Hisadome, M. T e r a s a w a , C. Abe* and Y. S h i o k a w a * R e s e a r c h L a b o r a t o r i e s , Y o s h i t o m i P h a r m a c e u t i c a l I n d u s t r i e s Ltd. Y o s h i t o m i - c h o , C h i k u j o - g u n , Fukuoka. * D i v i s i o n of R h e u m a t o l o g y , U n i v e r s i t y School of Medicine, Tokyo, Japan.
Koiwai, Juntendo
T r a x a n o x w i t h an a n t i a l l e r g i c a c t i v i t y has been shown to s u p p r e s s the IgE p r o d u c t i o n in the BN rat, and to m o d u l a t e the d e v e l o p m e n t of d e l a y e d type h y p e r s e n s i t i v i t y in mice. In the p r e s e n t study, we found that t r a x a n o x g i v e n o r a l l y s u p p r e s s e d the p r o d u c t i o n of p l a q u e - f o r m i n g cells (PFC) in the s p l e e n of N Z B / W m i c e i m m u n i z e d w i t h sheep red b l o o d cells (SRBC). In the B A L B / c mice, t r a x a n o x was c a p a b l e of i n d u c i n g s u p p r e s s o r T (Ts) cells and of p o t e n t i a t i n g Ts cells i n d u c t i o n by ConA to SRBC in vivo. The t r a n s f e r of T cells or a d h e r e n t s p l e e n cells (ASC) o b t a i n e d from the B A L B / c mice i m m u n i z e d w i t h SRBC and t r e a t e d w i t h t r a x a n o x to the s y n g e n e i c m i c e r e s u l t e d in s u p p r e s s i o n of s p l e e n PFC p r o d u c t i o n to SRBC. The s p l e e n PFC p r o d u c t i o n to SRBC was also s u p p r e s s e d by t r a n s f e r of A S C t r e a t e d w i t h t r a x a n o x and SRBC in vitro. T he s e results suggest that the i n d u c t i o n of Ts cells by t r a x a n o x may be m e d i a t e d by ASC, and that this drug may be useful for the t r e a t m e n t of p a t i e n t s w i t h Ts cell function deficiency.
17
ADJUVANT EFFECT OF PURIFIED PROTEIN DERIVATIVES OF TUBERCULIN (PPD) ON THE INDUCTION OF CLASSICAL DELAYEDTYPE HYPERSENSITIVITY AGAINST PROTEIN ANTIGEN IN GUINEA PIG S.Kuwajima, A.Kitano, K. Okawa, S.Oka, Y. Tanaka, K.Kobayashi, S. Yama~oto and M.Masui The 3rd Department of Internal Medicine, Department of Bacteriology, Osaka City University Medical School, 1-5-7, Asahi-Machi, Abeno-Ku, Osaka, 545 Japan. In the previous reports, we have already mentioned that T-independent B-cell mitogens in mice, namely lipopolysaccharide(LPS) and dextran(MW;40,000, Pharmacia, Sweden), are able to induce classical delayed type hypersensitivity(DTH) against T-dependent protein antigen(ovalbumin, OVA, grade V,Sigma, USA) in guinea pig, as well as that of waxD of M~dob~zcte~,iz4w ~ul~6I,duZos48 Aoyama B. In this study, PPD(Parke Davis Co., USA) was examined whether it could show the DTH-inducing activity, because PPD has been known to be T-independent B-antigen. (Materials & method) I00 ~g of PPD was injected to i~unize into hind footpad uf randomly bred Haxtley strain of guinea pig together with 1.0 mg of OVA, 0.I ml of Freund incomplete adjuvant(Difco,USA) and 0.i ml of saline per animal in the form of water in oil emulsion. 3 wks later, skin and corneal reaction(48 h) against OVA which was filtered through to sterilize(pore size;0.45 ~m,millipore Co., USA) before use. (Result &conclusion) DTH responses of animals immunized with PPD were positive and well comparable to that of waxD, killed tubercular bacilli, dextran. 12S or MDP(GIRPI,France). Thus, PPD was demonstrafed to have a DTH-inducing activity against protein antigen in guinea pig.
18
A NOVEL
QUINOLINECARBOXAMIDE
WITH
INTERESTING
[MMUNOMODULATORY
ACTIVITY
Torbj~rn StAlhandske, Edgar Eriksoo and Britt-Marle Sandber~ AB Leo, Research Laboratories, Box 9~I 5251 09 Helsin.~borg, Sweden A series of quinolinecarboxamldes screened in a conventional antiinflammatorv program demonstrated marked enhancement of the carra~eenan induced inflammatory response. One of these compounds, LS 2616, was further evaluated. Oral treatment with L5 2616 increased in a wide range of doses (0.65 mq/k~ to 80 m~/k~) the delayed type hypersensitivity (DTH) response to B. pertussis in the pleural cavitv of rats. A significant increase in the volume of exudate and number of macrophages was shown. The effect was evident both after treatment around the period of sensitization and challenge. The DTH response depressed in rats bearin~ D M B A induced m a m m a r y turnouts was restored after 10 m R/k~/day for four days. The growth of the turnouts was inhibited and the mitogenic response of spleen cells to ConA and PHA was increased. A 50% reduction in the number of metastasis produced by the Lewis lung carcinoma was also found after oral treatment with [S 2616. LS 2616 is relatively nontoxic since rats tolerated 960 mg/k,R/day for fourteen days without clinical signs of toxicity. LD50 for rats and mice was found to be approx|mately 1500 mg/kg. LS 2616 possesses an interestinR antitumour and immunomodulatory profile and we are currently investigating its mode of action.