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Prevention of autoimmune hemolytic anemia in NZB mice treated with monoclonal nonspecific suppressor factor (MNSF)
WS12-12 P R E V E N T I O N OF A U T O I M M U N E H E M O L Y T I C A N E M I A IN NZB M I C E T R E A T E D WITH M O N O C L O N A L N O N S P E C I F I C S U P P R E S S O R F A C T O R (MNSF) H. Ogawa, M. N a k a m u r a & T. T s u n e m a t s u 3rd D i v i s i o n of Internal Medicine, Shimane M e d i c a l University, Izumo, Japan M o n o c l o n a l n o n s p e c i f i c s u p p r e s s o r factor (MNSF) is a m u r i n e T-T h y b r i d o m a derived lymphokine. MNSF n o n s p e c i f i c a l l y s u p p r e s s e s IgG production, in vitro. We a d m i n i s t e r e d i n t r a p e r i t o n e a l l y 20 ug of MNSF into i0 m o n t h - o l d NZB mice, once w e e k l y for i0 weeks. With this a d m i n i s t r a t i o n , MNSF significantly l o w e r e d the levels of serum IgG and a n t i - e r y t h r o c y t e a u t o a n t i b o d y , c om p a r e d with findings in control mice. H e m a t o c r i t levels in treated mice were m a i n t a i n e d h i g h e r than levels in the controls. E i g h t of nine t r e a t e d mice were still alive at the end of o b s e r v a t i o n stage, 15 months, w h i l e only one out of nine in the c o n t r o l s were alive. We also studied T cell subsets (Thy-l, Lyt-l, Lyt-2 & L3T4) and b l a s t o g e n e s i s (Con A, PHA & LPS) of spleen cells in 13 month old mice, after about 2 weeks from the last i n j e c t i o n (4ug MNSF x i0 times). The u n t r e a t e d NZB mice showed d e c r e a s e d p e r c e n t a g e s of Thy-i and L3T4 p o s i t i v e cells and d e c r e a s e d r e s p o n s e s against Con A and PHA, c o m p a r e d with findings in normal control BALB/c mice. The r e s p o n s e s in the treated NZB mice were p r a c t i c a l l y w i t h i n normal. Thus, the a d m i n i s t r a t i o n of M N S F to NZB mice prevents the progression of h e m o l y t i c anemia and p r e s e r v e s normal l y m p h o c y t e functions.
WS12-13 A D O P T I V E I M M U N O T H E R A P Y OF M A L I G N A N T D I S E A S E S WITH A L L O G E N E I C LAK CELLS. Y. Kimoto, Y. Tanji, T. Tanaka, A. F u j iw a r a and T. Taguchi. D e p a r t m e n t of O n c o l o g i c Surgery, R e s e a r c h Institute for M i c r o b i a l D i s e a s e s Osaka University, Osaka, Japan P e r i p h e r a l blood l y m p h o c y t e s o b t a i n e d from normal donors were m i x - c u l t u r e d and p r o l i f e r a t e d in m e d i a c o n t a i n i n g 10% of normal human plasma and r e c o m b i n a n t i n t e r l e u k i n 2 (TGP-3). The cells grown after 10-14 days incub a t i o n increased 2-50 fold in number and p o s s e s s e d greater c y t o t o x i c i t y a g a i n s t several c u l t u r e d tumor cell lines. Eighty to ninty percent of the cells showed OKIal p o s i t i v e and were seemed to be l y m p h o b l a s t o i d cells. Then, they were c o n s i d e r e d as a l l o - r e a c t i v e l y m p h o k i n e - a c t i v a t e d killer cells. The c o m b i n e d use of anti-CD3 m o n o c l o n a i a n t i b o d y OKT3 induced up to 250- f o l d increase in cell number after 3-week incubation. These LAK cells could be i n j e c t e d into p a t i e n t s with m a l i g n a n t diseases, and no i m m u n o l o g i c a l side effects such as a n a p h y l a x i s or graft versus host r e a c t i o n were experienced. The n u m b e r of i n j e c t e d LAK cells was i-15x109 per body and frequent i n j e c t i o n such as three times a week could be carried out safely. Several p u l m o n a r y m e t a s t a s e s of b r e a s t a d e n o c a r c i n o m a and l a r y n g e a l squamous cell c a r c i n o m a showed partial or c o m p l e t e regression. No new lesion has a p p e a r e d in two p a t i e n t s who have r e c e i v e d more than 50 times i n j e c t i o n of these a l l o - r e a c t i v e LAK cells.
WS12-14 A N T I M E T A S T A T I C E F F E C T BY SYSTEMIC A D M I N I S T R A T I O N OF M O U S E R E C O M B I N A N T IFN- 7 A G A I N S T P U L M O N A R Y M E T A S T A S E S IN MICE J. Murata, I. Saiki, S. Saito, N. Higashi* and I. Azuma Institute of I m m u n o l o g i c a l Science, H o k k a i d o University, Sapporo, and *Suntory Limited, Tokyo, Japan The t h e r a p e u t i c effects of IFN-y given by m a i n l y i.v. or i.m. a d m i n i s t r a t i o n have been e x t e n s i v e l y studied with the c o n t r a d i c t o r y reports on the evaluations of therapy and v a r i o u s b i o l o g i c a l a c t i v i t i e s of r e c o m b i n a n t IFN-]'. Therefore, in oreder to r e - e v a l u a t e and e s t a b i s h the o p t i m i z e d t r e a t m e n t regimen, we e x a m i n e d the a d m i n i s t r t i o n m o d a l i t i e s and doses of IFN-7 in s p o n t a n e o u s m e t a s t a s e s model using two m u r i n e m e t a s t a t i c tumors. Multiple treatments with IFN-y s i g n i f i c a n t l y reduced the i n c i d e n c e of lung m e t a s t a ses. R e p e a t e d 4 c o n s e c u t i v e treatment m o d a l i t i e s with low dose of IFN-f, particularly, showed r e m a r k a b l e r e d u c t i o n of m e t a s t a s e s , and also rendered alv e o l a r m a c r o p h a g e s (AM) more cytotoxic to tumor cells than those of high dose. In contrast, 14 c o n s e c u t i v e i n j e c t i o n s of IFN-y at any doses (i0-I03 U) could not a c t i v a t e AM, but was e f f e c t i v e in r e g r e s s i n g metastases. We c o n c l u d e d that even low doses of IFN-7 in a p p r o p r i a t e m u l t i p l e treatment m o d a l i t i e s results in the r e d u c t i o n of lung m e t a s t a s e s following the activation of AM and direct a n t i p r o l i f e r a t i v e action.
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WS12-13 A D O P T I V E I M M U N O T H E R A P Y OF M A L I G N A N T D I S E A S E S WITH A L L O G E N E I C LAK CELLS. Y. Kimoto, Y. Tanji, T. Tanaka, A. F u j iw a r a and T. Taguchi. D e p a r t m e n t of O n c o l o g i c Surgery, R e s e a r c h Institute for M i c r o b i a l D i s e a s e s Osaka University, Osaka, Japan P e r i p h e r a l blood l y m p h o c y t e s o b t a i n e d from normal donors were m i x - c u l t u r e d and p r o l i f e r a t e d in m e d i a c o n t a i n i n g 10% of normal human plasma and r e c o m b i n a n t i n t e r l e u k i n 2 (TGP-3). The cells grown after 10-14 days incub a t i o n increased 2-50 fold in number and p o s s e s s e d greater c y t o t o x i c i t y a g a i n s t several c u l t u r e d tumor cell lines. Eighty to ninty percent of the cells showed OKIal p o s i t i v e and were seemed to be l y m p h o b l a s t o i d cells. Then, they were c o n s i d e r e d as a l l o - r e a c t i v e l y m p h o k i n e - a c t i v a t e d killer cells. The c o m b i n e d use of anti-CD3 m o n o c l o n a i a n t i b o d y OKT3 induced up to 250- f o l d increase in cell number after 3-week incubation. These LAK cells could be i n j e c t e d into p a t i e n t s with m a l i g n a n t diseases, and no i m m u n o l o g i c a l side effects such as a n a p h y l a x i s or graft versus host r e a c t i o n were experienced. The n u m b e r of i n j e c t e d LAK cells was i-15x109 per body and frequent i n j e c t i o n such as three times a week could be carried out safely. Several p u l m o n a r y m e t a s t a s e s of b r e a s t a d e n o c a r c i n o m a and l a r y n g e a l squamous cell c a r c i n o m a showed partial or c o m p l e t e regression. No new lesion has a p p e a r e d in two p a t i e n t s who have r e c e i v e d more than 50 times i n j e c t i o n of these a l l o - r e a c t i v e LAK cells.
WS12-14 A N T I M E T A S T A T I C E F F E C T BY SYSTEMIC A D M I N I S T R A T I O N OF M O U S E R E C O M B I N A N T IFN- 7 A G A I N S T P U L M O N A R Y M E T A S T A S E S IN MICE J. Murata, I. Saiki, S. Saito, N. Higashi* and I. Azuma Institute of I m m u n o l o g i c a l Science, H o k k a i d o University, Sapporo, and *Suntory Limited, Tokyo, Japan The t h e r a p e u t i c effects of IFN-y given by m a i n l y i.v. or i.m. a d m i n i s t r a t i o n have been e x t e n s i v e l y studied with the c o n t r a d i c t o r y reports on the evaluations of therapy and v a r i o u s b i o l o g i c a l a c t i v i t i e s of r e c o m b i n a n t IFN-]'. Therefore, in oreder to r e - e v a l u a t e and e s t a b i s h the o p t i m i z e d t r e a t m e n t regimen, we e x a m i n e d the a d m i n i s t r t i o n m o d a l i t i e s and doses of IFN-7 in s p o n t a n e o u s m e t a s t a s e s model using two m u r i n e m e t a s t a t i c tumors. Multiple treatments with IFN-y s i g n i f i c a n t l y reduced the i n c i d e n c e of lung m e t a s t a ses. R e p e a t e d 4 c o n s e c u t i v e treatment m o d a l i t i e s with low dose of IFN-f, particularly, showed r e m a r k a b l e r e d u c t i o n of m e t a s t a s e s , and also rendered alv e o l a r m a c r o p h a g e s (AM) more cytotoxic to tumor cells than those of high dose. In contrast, 14 c o n s e c u t i v e i n j e c t i o n s of IFN-y at any doses (i0-I03 U) could not a c t i v a t e AM, but was e f f e c t i v e in r e g r e s s i n g metastases. We c o n c l u d e d that even low doses of IFN-7 in a p p r o p r i a t e m u l t i p l e treatment m o d a l i t i e s results in the r e d u c t i o n of lung m e t a s t a s e s following the activation of AM and direct a n t i p r o l i f e r a t i v e action.
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