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Streptozotocin induced immunosuppression in rats
412
STREPTOZOTOCIN F.B. De Brlto.
INDUCED
Imperial
IMMUNOSUPPRESSION
Chemical
IN
Industries,
18
RATS
Alderley
Park,
Cheshire
UK
T h e i m m u n e s t a t u s of d i a b e t i c rats was e x a m i n e d to shed s o m e l i g h t on the often assumed association of d i a b e t e s w i t h i n c r e a s e d s u s c e p t i b i l i t y to infection. Rats with established hyperglycaemia as a r e s u l t of 6 0 m g / k g i.v. day - 3 S t r e p t o z o t o c i n had thymus:body weight ratios that were markedly l o w e r than that of n o n - d i a b e t i c c o n t r o l rats w h e r e a s s p l e e n : b o d y weight ratios were relatively less a f f e c t e d . The serum agglutin response to iv s h e e p red b l o o d c e l l s was s i m i l a r in b o t h g r o u p s b u t d i a b e t i c r a t s f a i l e d to m o u n t d e l a y e d s k i n r e a c t i o n s to egg a l b u m i n and w e r e e x t r e m e l y susceptible to s y s t e m i c i n j e c t i o n w i t h L i s t e r i a m o n o c y t o ~ e n e s and C a n d i d a albicans. The non-specific acute inflammatory r e a c t i o n to c a r r a g e e n a n in the p a w of d i a b e t i c r a t s w a s h o w e v e r m o r e i n t e n s e as was p a s s i v e a c u t e experimental glomerulonephritis, j u d g e d by the v o l u m e Of u r i n e and t o t a l protein excreted. A l s o if C . a l b i c a n s w a s g i v e n w i t h the a n t i - g l o m e r u l a r b a s e m e n t m e m b r a n e s e r u m t h e r e was a p r o p o r t i o n a t e l y greater reduction in r e n a l c a n d i d a l c o u n t s in d i a b e t i c rats. The d a t a i n d i c a t e s that w h i l e cell-mediated i m m u n e d e f e n c e s in d i a b e t i c rats is h e a v i l y s u p p r e s s e d , nons p e c i f i c and h u m o r a l i m m u n e d e f e n c e s w h i c h a p p e a r i n t a c t m a y a c c o u n t for the p r o l o n g e d s u r v i v a l of t h e s e rats. EFFECT
OF M U R A M Y L P E P T I D E S
ON H U M A N
MONOCYTE-MEDIATED
ANTI-TUMORCYTOTOXICITYS~
H.W.L. Ziegler-Heitbrock a n d G. R i e t h m H l l e r Institut fdr Immunologie, M H n c h e n , F e d e r a l R e p u b l i c of G e r m a n y . Besides their strong in-vivo immunostimulatory e f f e c t in a n i m a l s , muramylp e p t i d e s (MPs) h a v e b e e n s h o w n to s t i m u l a t e human monocyte cytotoxicity invitro. The assay systems for cytotoxic monocytes available thus far have several disadvantages in t h a t t h e y r e q u i r e a) p u r i f i c a t i o n of the e f f e c t o r c e l l s a n d b) l o n g i n c u b a t i o n t i m e s of 2-3 days. Hence, we h a v e d e v e l o p e d an assay circumventing these problems by u s i n g A c t i n o m y c i n D pretreated Wehi 164 c e l l s (JNCI 72:23, 1984). In o r d e r to a s c e r t a i n whether M P s are e f f e c tive also with cytotoxic monocytes detected in t h i s s h o r t t e r m a s s a y , w e have studied the CGP 11637 and 19835 (nor-MDP and MTP-PE, respectively) after preincubation of monocytes w i t h t h e s e d r u g s f o r 2 a n d 16 h. I n c u b a t i o n w i t h C G P 11637 w a s e f f e c t i v e at 100 n g / m l in e n h a n c i n g cell mediated cytotoxicity a g a i n s t W e h i 164 a f t e r 2 h of p r e i n c u b a t i o n . By c o n t r a s t , CGP 19835 w a s o n l y e f f e c t i v e a f t e r 16 h p r e t r e a t m e n t . Further, M P s are a b l e to stimulate the release from human monocytes of a f a c t o r which is h i g h l y cytotoxic to t h e t a r g e t cell used. Thus, MPs are effective agents for enhancement of m o n o c y t e mediated cytotoxicity a l s o in the W e h i 1 6 4 / A c t i n o mycin D system.
STREPTOZOTOCIN F.B. De Brlto.
INDUCED
Imperial
IMMUNOSUPPRESSION
Chemical
IN
Industries,
18
RATS
Alderley
Park,
Cheshire
UK
T h e i m m u n e s t a t u s of d i a b e t i c rats was e x a m i n e d to shed s o m e l i g h t on the often assumed association of d i a b e t e s w i t h i n c r e a s e d s u s c e p t i b i l i t y to infection. Rats with established hyperglycaemia as a r e s u l t of 6 0 m g / k g i.v. day - 3 S t r e p t o z o t o c i n had thymus:body weight ratios that were markedly l o w e r than that of n o n - d i a b e t i c c o n t r o l rats w h e r e a s s p l e e n : b o d y weight ratios were relatively less a f f e c t e d . The serum agglutin response to iv s h e e p red b l o o d c e l l s was s i m i l a r in b o t h g r o u p s b u t d i a b e t i c r a t s f a i l e d to m o u n t d e l a y e d s k i n r e a c t i o n s to egg a l b u m i n and w e r e e x t r e m e l y susceptible to s y s t e m i c i n j e c t i o n w i t h L i s t e r i a m o n o c y t o ~ e n e s and C a n d i d a albicans. The non-specific acute inflammatory r e a c t i o n to c a r r a g e e n a n in the p a w of d i a b e t i c r a t s w a s h o w e v e r m o r e i n t e n s e as was p a s s i v e a c u t e experimental glomerulonephritis, j u d g e d by the v o l u m e Of u r i n e and t o t a l protein excreted. A l s o if C . a l b i c a n s w a s g i v e n w i t h the a n t i - g l o m e r u l a r b a s e m e n t m e m b r a n e s e r u m t h e r e was a p r o p o r t i o n a t e l y greater reduction in r e n a l c a n d i d a l c o u n t s in d i a b e t i c rats. The d a t a i n d i c a t e s that w h i l e cell-mediated i m m u n e d e f e n c e s in d i a b e t i c rats is h e a v i l y s u p p r e s s e d , nons p e c i f i c and h u m o r a l i m m u n e d e f e n c e s w h i c h a p p e a r i n t a c t m a y a c c o u n t for the p r o l o n g e d s u r v i v a l of t h e s e rats. EFFECT
OF M U R A M Y L P E P T I D E S
ON H U M A N
MONOCYTE-MEDIATED
ANTI-TUMORCYTOTOXICITYS~
H.W.L. Ziegler-Heitbrock a n d G. R i e t h m H l l e r Institut fdr Immunologie, M H n c h e n , F e d e r a l R e p u b l i c of G e r m a n y . Besides their strong in-vivo immunostimulatory e f f e c t in a n i m a l s , muramylp e p t i d e s (MPs) h a v e b e e n s h o w n to s t i m u l a t e human monocyte cytotoxicity invitro. The assay systems for cytotoxic monocytes available thus far have several disadvantages in t h a t t h e y r e q u i r e a) p u r i f i c a t i o n of the e f f e c t o r c e l l s a n d b) l o n g i n c u b a t i o n t i m e s of 2-3 days. Hence, we h a v e d e v e l o p e d an assay circumventing these problems by u s i n g A c t i n o m y c i n D pretreated Wehi 164 c e l l s (JNCI 72:23, 1984). In o r d e r to a s c e r t a i n whether M P s are e f f e c tive also with cytotoxic monocytes detected in t h i s s h o r t t e r m a s s a y , w e have studied the CGP 11637 and 19835 (nor-MDP and MTP-PE, respectively) after preincubation of monocytes w i t h t h e s e d r u g s f o r 2 a n d 16 h. I n c u b a t i o n w i t h C G P 11637 w a s e f f e c t i v e at 100 n g / m l in e n h a n c i n g cell mediated cytotoxicity a g a i n s t W e h i 164 a f t e r 2 h of p r e i n c u b a t i o n . By c o n t r a s t , CGP 19835 w a s o n l y e f f e c t i v e a f t e r 16 h p r e t r e a t m e n t . Further, M P s are a b l e to stimulate the release from human monocytes of a f a c t o r which is h i g h l y cytotoxic to t h e t a r g e t cell used. Thus, MPs are effective agents for enhancement of m o n o c y t e mediated cytotoxicity a l s o in the W e h i 1 6 4 / A c t i n o mycin D system.