IN ONCHOCERCIASIS: ACTIVATION

IVERMECTIN-FACILITATED IMMUNITY IN ONCHOCERCIASIS: ACTIVATION OF PARASITE-SPECIFIC T H 1 TYPE RESPONSES WITH SUBCLINICAL ONCHOCERCA VOLVULUS INFECTION

SOBOSLAY P.T.*, LÜDER, C.G.K.*, HOFFMANN W.H.*, MICHAELIS I.*, DREWECK CM.*, PRITZE S**, WOLF H.*, BANLA M.*** AND SCHULZ-KEY H.*

KEYWORDS : onchocerciasis, ivermectin treatment, cellular responses, cytokines, antibody production.

T he severity of chronic disease produced by the parasitic nematode Onchocerca volvulus varies widely, ranging from asymptomatic infection to cutaneous involvement to, most severely, opthalmologic pathology which may finally cause blindness (WHO, 1987). Humans chronically infected with O. volvulus not only demonstrate a prominent produc­

tion of all subclasses of parasite-specific immunoglobulins (Karam and Weiss 1985 ; Dafa'alla et al, 1992), but also a depressed cellular reactivity in vitro and a deficient produc­

tion of II.-2 in response to O. volvulus-specific antigenic (OvAg) stimulation (Greene et al., 1983 ; Gallin et al., 1988 ; Ward et al., 1988).

Recent reports suggest that ivermectin, the drug of choice for treatment o f onchocerciasis, temporarily eliminates microfilariae (mf) from the skin and also facilitates cellular immunity in treated patients (Steel et al, 1991 ; Freedman

sitivity (DTH) reactions and circulating lymphocyte subpo- pulations normalized after a single dose o f ivermectin, leading to improved in vitro cellular reactivity to mitogenic stimulation and to augmented cellular production of several cytokines by PBMC (Soboslay et al, 1992). These changes appeared rather gradually, and ivermectin-facilitated immune responses controlling microfilaridermia in infected individuals may only reach critical importance after several treatments with ivermectin.

In the present study we have examined the quantitative and qualitative changes registered in the parasite-specific antibody response, cellular reactivity and cytokine produc­

tion profile in onchocerciasis patients repeatedly treated with ivermectin over a period of 7 years. Our results sug­

gest that parasite-specific cellular immunity of onchocercia­

sis patients underwent further substantial alterations following repeated treatment ; and therefore therapy may be expected to synergistically contribute to effective control of microfilaridermia in already infected individuals and to increase resistance to re-infection.

The density o f O. volvulus microfilariae (mf) in treated patients remained significantly reduced, whereas the num­

ber o f amicrofilaremic patients (subclinical infection) increased with repeated treatments. In vitro cellular res­

ponses to O. volvulus antigen (OvAg) were highest (p <

0.01) in untreated control individuals exposed to infection

* I n s t i t u t e o f T r o p i c a l M e d i a n e . U n i v e r s i t y o f T ü b i n g e n , Wilhelmstr. 2 7 , 7 2 0 7 4 Tübingen, Germany.

** Deutsche Gesellschaft für Technische Zusammenarbeit (gtz), Eschborn, Germany.

*** Centre Hospitalier de Région, Sokodé, Togo.

but n e g a t i v e for m f ( e n d e m i c n o r m a l s ) . Cellular reactivity in r e p e a t e d l y t r e a t e d p a t i e n t s w a s h i g h e r at 8 4 t h a n at 3 6 m o n t h s post initial t r e a t m e n t (p.i.t.) ; furthermore, t h e proli­

ferative r e s p o n s e s to O v A g , m y c o b a c t e r i a l P P D a n d strepto­

c o c c a l SL-O w e r e g r e a t e r ( p < 0 . 0 5 ) at 8 4 m o n t h s p.i.t. in amicrofilaremic than in microfilaria-positive o n c h o c e r c i a s i s patients. In a m i c r o f i l a r e m i c patients s u c h reactivity a p p r o a ­ c h e d t h e m a g n i t u d e o b s e r v e d in e n d e m i c n o r m a l s .

Peripheral b l o o d m o n o n u c l e a r cells ( P B M C ) from patients a n d e n d e m i c n o r m a l s p r o d u c e d e q u i v a l e n t a m o u n t s o f IL-2, IL-4 a n d I F N - g a m m a in r e s p o n s e t o m i t o g e n i c stimulation w i t h P H A ; in r e s p o n s e t o O v A g , h o w e v e r , s i g n i f i c a n t l y m o r e IL-2 a n d I F N - g a m m a w e r e p r o d u c e d b y P B M C from amicrofilaremic patients o r e n d e m i c n o r m a l s than b y m i c r o ­ filaria-positive patients. OvAg-specific p r o d u c t i o n o f IL-4 b y P B M C from t r e a t e d p a t i e n t s w a s l o w e r at 8 4 t h a n at 3 6 m o n t h s p.i.t.

At t h r e e m o n t h s p.i.t. t h e titers o f circulating OvAg-specific I g G i _ 3 h^{a c}* i n c r e a s e d ( p < 0 . 0 5 ) , but t h e y t h e n c o n t i n u o u s l y d e c l i n e d with r e p e a t e d t r e a t m e n t s . O n l y I g G j a n d I g G 4 b o u n d to O v A g o f Mr 2 - 1 2 k at 1 m o n t h p.i.t., w h i l e r e c o ­ gnition o f O v A g o f Mr 1 0 - 2 0 0 k b y I g G i , I g G 2 a n d I g G 4 rea­

c h e d a m a x i m u m i n t e n s i t y at 3 - 6 m o n t h s p.i.t., with t h e overall intensity o f b i n d i n g to O v A g gradually w e a k e n i n g thereafter.

T h e s e results suggest that o n c h o c e r c i a s i s - a s s o c i a t e d immu­

n o s u p p r e s s i o n is r e v e r s i b l e f o l l o w i n g i n v e r m e c t i n - i n d u c e d p e r m a n e n t c l e a r a n c e o f microfilariae from t h e s k i n ; a n d that a v i g o r o u s parasite-specific cellular reactivity a n d a sus­

tained p r o d u c t i o n o f IL-2 a n d I F N - g a m m a in amicrofilare­

mic individuals m a y c o n t r i b u t e to c o n t r o l l i n g O. volvulus infection.

R E F E R E N C E S

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GREENH B.M. el al. Clin. Exp. Immunol, 1 9 8 3 , 52, 2 5 9 - 2 6 5 . KARAM M . , WEISS N . Am.]. Trop. Med. Hyg., 1 9 8 5 , 34, 9 0 7 - 9 1 7 . SOBOSLAY P.T. el al. Clin. Exp. Immunol.. 1 9 9 2 , 89, 4 0 7 - 4 1 3 . STEEL C. etal.J. Infect. Dis., 1 9 9 1 , IM, 5 8 1 - 5 8 7 .

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Parasite, 1994, I , I S

IMMUNOLOGY O F HUMAN FILARIASIS Article available athttp://www.parasite-journal.orgorhttp://dx.doi.org/10.1051/parasite/199401s1015