R e v is ta d a S o c ie d a d e B ra sile ir a de M edic ina Tro pica l 27 (3 ):1 1 9 -1 2 5 , ju l-s e t, 1994.
A R T IG O S
SC H ISTO SO M A M A N S ONI
IN MICE: M ODULATION OF
GRANULOMATOUS RESPONSE AFTER REINFECTION AND
CHEMOTHERAPEUTIC TREATMENT
Paulo M arcos Z . Coelho, Pedro Raso, R6muIo Teixeira de M ello and N ivaldo H . Toppa
M ice p revio usly infected w ith Schistosoma mansoni, and cured by sp ecific treatm ent (400ing/kg oxam niquine, p . o .) in the ch ronic p h a se o f the disease, w ere rein fecte d 20 da ys after treatm en t to assess their ca p a city fo r m odulation o fth e granulom atous response. H istopathologic exam ination o f the anim als ’ liver, a t 60 d a ys after reinfection, eviden ced the p re se n c e o f typ ical g ra nu lo m a s o f the ch ron ic p h a se in m ost anim als. This infer that the capacity f o r m odulation o f the g ra n ulo m atou s re sp on se h a d been m aintained, thus preven tin g a new acute p h a se o f the disease. C onversely, a grou p o f p revio u sly infected m ice, untre ated a n d su b m itted to reinfection, sh o w ed reactivation o f the gran ulom atous response in 50% o f the anim als. The po ssib le im plications o f these fin d in g s in hum an schistosom iasis m ansoni are discussed.
K ey-w ords: Schistosoma mansoni. G ranuloma. C hem otherapeutic treatm ent. M o dulation o f gra nulom atous response.
In i 9 6 4 A n d ra d e & W a rre n 4 de m o n stra ted th at a d e c re a se in th e siz e o f g ra n u lo m a s fo rm ed a ro u n d S c h is to s o m a m a n s o n i e g g s o ccu rs at th e c h ro n ic p h a se o f th e d ise a se, as w e ll as a lte ra tio n s in the c e llu la r a n d n o n - c e llu la r c o n s titu e n ts w h ic h p a rtic ip a te in th is in fla m m a to ry p ro c e ss. T h is p h e n o m e n o n h a s b e e n c o rro b o ra te d by several o th er a u th o rs, as can b e se e n in B o ro s ’ re v ie w 7. T h is state o f im m u n e to le ra n c e in re la tio n to th e a n tig en s ex c re te d b y e g g s re p re se n ts a c o n tro l o v e r th e im m u n o p ath o lo g ical resp o n se, an d this p henom enon is called m o d u la tio n o f the g ra n u lo m a to u s response. C olley e t a l .12, show ed a h ig h e r b lastogénie response in d u c e d b y so lu b le egg an tig e n s in in d iv id u a ls w ith severe clinical form s o f schistosom iasis. C onversely, th e a b se n c e o f th e g ra n u lo m a to u s re a c tiv ity in im m u n o d e p re sse d an im a ls sh o w e d ag g rav a tio n o f th e p a th o lo g ic p ro c e ss9 11 17 24 25 28.
C o n s id e r in g th a t th is m o d u la tio n o f th e
D e p arta m e n to s d e P arasito lo g ia d o Instituto de C iências B iológicas, d e A nálises C lín icas e T o x ico ló g ica s da F aculdade de Farm ácia e de A natom ia Patológica da Faculdade deM edícina, U n iv ersid ad e F ed eral de M inas G erais, Belo H orizonte, MG ; U n iv ersid ad e F ed eral de O u ro P reto , O u ro P reto , M G . T h is w o rk w as supported in p art b y C N P q , F A P E M IG , and F IN E P , B razil, an d b y W H O , Sw itzerland.
A d d r e s s to-. P ro f. Paulo M a rco s Z . C o e lh o . D e p to . de P arasito lo g ia/IC B /U F M G , C aixa Postal 4 8 6 , 30161-970 Belo H o rizo n te, M G .
R eceb id o p a ra p u b licação em 0 6 /0 1 /9 4 .
g ra n u lo m a to u s re sp o n se is fa v o ra b le to th e h o st, a n d th at m illio n s o f p e o p le h a v e been su b m itte d to tre atm en t, a la rg e n u m b e r o f th e m b e in g cu re d , it is im p o rta n t to d e te rm in e w h e th e r m o d u la tio n o f th e im m u n o p a th o lo g y re m a in s a fte r c u re , s in c e m any o f th e in d iv id u a ls tre a te d a n d c u re d w ill c e rta in ly b e rein fected . O n th e o th e r h a n d , it is a m a tte r o f in te re st to k n o w w h e th e r re in fe c tio n o f th e h o st b e a rin g activ e sc h isto so m ia sis can m o d ify th is state o f im m u n e to lera n c e d u e to o th e r im m u n o lo g ic a l stim u li in c o n se q u e n ce o f c erc a rial p e n e tra tio n , m ig ra tio n o f th e p a ra site s fro m th e sk in to th e lu n g s, and fro m th e lu n g s to th e p o rta l s y ste m , le a d in g to an in crease o f th e in itia l p o p u la tio n , as w e ll as o f the n u m b e r o f eggs in th e tissu es.
T h is w o rk aim s a t s tu d y in g in m ic e w h e th e r th e m o d u la tio n o f th e g ra n u lo m a to u s p ro c e ss a ro u n d e g g s rem a in s a fter c u re a n d , on th e o th e r h a n d , if re in fe c tio n ca n a lte r th is state o f c o n tro l in u n tre a te d an im a ls, as far as th e g ra n u lo m a to u s re sp o n se is concerned.
M A T E R IA L S A N D M E T H O D S
F e m a le o u tb re d a lb in o m ic e w e re u se d in th ese e x p e rim e n ts. T h e S c h is to s o m a m a n s o n i s tr a in u tiliz e d w a s th e L E stra in (iso la te d fro m a p a tie n t in B elo H o riz o n te , M G , B ra z il, a n d k e p t fo r m o re
C oelho P M Z, R a so P, M e llo R T , Toppa NH. Schistosom a mansoni in m ice: m o du la tio n o f g ra n u lo m a to u s re sp o n se a fte r re in fe c tio n a n d ch em o th era p eu tic treatm ent. R evista da S o cie da de B ra sile ira de M e d ic in a T ro p ic a l 27:119 -12 5 , ju l- s e t, 1994.
t h a n 3 0 y e a r s a t t h e l a b o r a t o r i e s o f t h e S c h isto so m ia sis R e se a rc h U n it, F e d e ra l U n iv e rsity o f M in a s G e ra is , B ra zil, th e in te rm e d ia te and d e fin itiv e h o sts b e in g B io m p h a la r ia g la b r a ta and h a m s te r, re sp e c tiv e ly ). M ic e w e re in fected in itially w ith 15 S. m a n s o n i c e rc a ria e (L E s tra in ), by su b c u ta n e o u s ro u te , ex cep g ro u p V.
T h e a n im a ls w e re th e n d iv id e d in to fiv e g ro u p s (th e u n in fe c te d g ro u p b ein g k e p t as c o n tro l o f r e in f e c tio n ) , a n d s u b m itte d to th e f o llo w in g p ro c e d u re s:
Group I (n = 11). T h e m ice w e re p re v io u sly in fe c te d a n d tre a te d w ith 4 0 0 m g /k g o x am n iq u in e , s in g le d o se , o ra l ro u te , a t 100 days a fte r infection. T h e y w e r e re in fe c te d w ith 2 0 c e rc a ria e , b y su b c u ta n e o u s ro u te , a t 2 0 d ay s a fter tre a tm e n t, and sa c rific e d a t 6 0 d ay s a fte r re in fe ctio n .
Group II (n = 8). T h e an im a ls p re v io u sly in fe c te d w e re su b m itte d to tre a tm e n t w ith 4 0 0 m g / k g o x a m n iq u in e , o ra l ro u te , a t 100 d a y s a fter in fe c tio n , a n d sa c rific e d a t th e sam e d a te o f group I , th a t is, a t 6 0 d ay s a fte r re in fe c tio n o f g ro u p s I and
III.
Group III (n = 24). T h e a n im als p re v io u sly in fe c ted w e re re in fe c te d an d sac rific e d a t th e sam e d ate s o f g ro u p I.
Group IV (n = 11). T h e a n im als b e a rin g th e in itia l in fe c tio n w e re sa c rific e d to g e th e r w ith all th e o th e r g ro u p s , i . e . , a t 180 days a fte r in fec tio n o r 6 0 d ay s a fte r re in fe c tio n o f g ro u p s I a n d III.
Group V (n = 19). T h is g ro u p (w ith o u t p re v io u s in fe c tio n ) w a s su b m itte d to in fec tio n w ith 2 0 c e rc a ria e b y su b c u ta n e o u s ro u te , at th e sam e date e s ta b lish e d fo r re in fe c tio n o f g ro u p s I an d III, and sa c rific e d a t 6 0 d a y s a fte r in fe c tio n .
T h e a n im a ls w e re k ille d by cerv ic a l fra c tu re , a n d th e ir liv e rs p re se rv e d in 10 % b u ffe re d fo rm alin . A g ro u p o f 10 tre a te d m ic e w as p e rfu se d fo r w o rm s, a t 3 0 d a y s a fte r ch e m o th e ra p y . N o w o rm s c o u ld be fo u n d , th u s c o n firm in g th e efficacy o f th e treatm ent.
T h e p re s e rv e d liv e rs w e re slic e d in to sm all bits o f 3 .0 m m o f th ic k n e ss each, a n d soak ed in p arafin . T h e slices o f 5/xm th ic k n e ss so o b ta in e d w e re sta in e d w ith h e m a to x y lin an d eo sin .
O n ly th e d ia m e te rs o f th e g ra n u lo m a s a t the n e c ro tic -ex u d a tiv e , ex u d a tiv e an d p ro d u c tiv e phases w e re m e a su re d . T h e o th e r o n es (g ra n u lo m a s in p ro c e ss o f c u re b y fib ro sis) w e re n o t co n sid ered .
T h e av e rag e o f th e d ia m e te r siz e w a s d e te rm in e d by th e m e a n b e tw e e n th e s m a l l e r a n d la r g e s t m easu rem en ts o f th e d ia m e te rs p a ssin g th ro u g h the m ira c id iu m in sid e th e eg g , w h ic h w a s id e n tifie d by th e e o sin o p h ilic sta in in g . T h e re fo re , o n ly re c e n t g ran u lo m as w e re ex a m in e d w ith a s p littin g eyepiece (10X , E m e st-L e itz , W e tz la r, G e rm a n y ) a d a p te d to a Z e iss m icro sco p e.
S ta tis tic a l a n a ly s is . A n a ly sis o f v a ria n c e w a s used to detect differences am o n g the m ean gran u lo m a m easu rem en ts re c o rd e d fo r g ro u p s I, III, IV an d V. G ro u p II w h ic h p re se n te d n o re c e n t g ra n u lo m a s, b u t o n ly g ra n u lo m a s th a t w e re a lrea d y c u re d by fib ro sis, w as n o t taken in to a c c o u n t fo r p u rp o se s o f analysis.
R E S U L T S
H is t o p a t h o lo g ic a l d e s c r ip t io n o f th e anim als’liver used in this experim ent:
Group I (tre a te d a n d re in fe c te d ). M o s t a n im als p re se n te d g ra n u lo m a s a t tw o d iffe re n t e v o lu tiv e p hases: a) so m e a t th e re c e n t e x u d a tiv e p h a se , p ro b a b ly re su ltin g fro m re in fe c tio n ; b ) o th e rs a t th e re p a ira b le p h ase o r in p ro c e ss o f c u re b y fib ro sis, c e rta in ly d e riv e d fro m p rim o in fe c tio n . T h e se g ra n u lo m a s w e re fo u n d to b e m a rk e d ly sm a lle r th an th e o th e rs a t th e e x u d a tiv e p h a se .
F o r th e m o st p a rt, th e g ra n u lo m a s w e re fo u n d a t th e p o rta l tracts; so m e tim e s th ey w e re c o n flu e n t an d , in so m e an im a ls, th e y w e re p erm e ate d by intense inflam m atory in filtrate. T h is w as resp o n sib le fo r cu ffin g o n th e o th e r p o rta l tra c ts. M o re o v e r, d u c ta l p r o lif e r a tio n a s s o c ia te d to a c c e n tu a te d re g re ssiv e p h e n o m e n a o f th e e p ith e lia l c e lls w ith a c id o p h ilic h o m o g e n e o u s c y to p la sm a n d n u c le i th at w e re e ith e r p ic n o tic o r a b se n t c o u ld b e seen.
T h e h ep ato c y te s sh o w e d re g re s s iv e p h e n o m e n a a n d re c e n t n e c ro tic a re a s o f d iffe re n t sizes, w ith scarce in fla m m a to ry re a c tio n , i f a n y , as w e ll as o ld e r n e c ro tic a re a s, p a rtia lly su b stitu te d b y y o u n g c o n ju n c tiv e tis s u e . F u r t h e r m o r e , a n in te n s e p o ly p lo id y c o u ld b e seen.
C oelh o P M Z , R a so P, M ello R T , Toppa NH. Schistosom a m ansoni itim ic e : m o d u la tio n o f g ra n u lo m a to u s resp on se a fte r re in fe c tio n a n d ch e m o th e ra p e u tic treatm en t. R ev ista da S o c ie d a d e B ra sile ira d e M e d ic in a T ro p ic a l 27 :1 1 9 -125, ju l- s e t, 1994.
h y p e rp la stic . In ta c t a n d s tu n t w o rm s c o u ld also b e o b s e rv e d in s id e th e p o rta l b ra n c h e s, w ith little o r no in fla m m a to ry re a c tio n a ro u n d them .
G r o u p I I (tre a ted an d n o n -re in fe c ted ). In this g ro u p , n e a rly a ll g ra n u lo m a s w e re co eta n e o u s, a t th e sam e e v o lu tiv e p h a s e o f c u re by fib ro sis, fe w o f th e m to t a l l y h y a lin iz e d . T h e r e w a s d is c r e te in fla m m a to ry in filtra te in th e p o rta l tra c ts. In sp ite o f th e ir p re se n c e , th e d e g e n e ra tiv e p h e n o m e n a o f c ells in th e d u c ta l e p ith e liu m w e re n o t so as intense as th o se o b s e rv e d in g ro u p I. M o re o v e r, n e c ro sis o f th e h e p a to c y te s w a s n o t so as fre q u e n t an d in ten se a s th a t d e te c te d in g ro u p I. S m all a m o u n ts o f sc h isto so m e p ig m e n t w e re also seen in sid e the p o rta l m a c ro p h a g e s a n d K u p ffe r cells.
G r o u p I I I (in fe cte d a n d rein fe c ted ). T h is g ro u p w a s c o m p o se d o f n u m e ro u s g ra n u lo m a s, w h ic h w e re d e tec te d b o th a t ex u d a tiv e p h a se (w ith o r w ith o u t n e c ro sis) a n d a t th e p h ase o f c u re by fib ro s is . G ra n u lo m a s c u re d b y fib ro sis w e re found to b e p re d o m in a n t. T h e m o st im p o rta n t d ifferen ce b e tw e e n th is gro u p a n d gro u p I w a s th e in te n sity o f th e d iffu s e e x u d a tiv e p h e n o m e n a th a t o c c u rre d at th e p o rta l h e p a tic sp aces, an d so m etim es in the in n e r p a rt o f th e h e p a tic lo b e s. H e p a tic n e cro sis s h o w e d le ss in te n sity a n d e x te n sio n . L e sio n s caused b y d e a d w o rm s w e re u n fre q u e n t. T h e re w a s a cle a r p re d o m in a n c e o f p rim o in fe c tio n o v e r th e recent o n es, d u e to a la rg e r n u m b e r o f g ra n u lo m a s and cu re b y fib ro sis.
G r o u p IV (c o n tro l o f th e ch ro n ic phase). G ra n u lo m a s re la tin g to th is g ro u p w e re coetan eo u s, a t th e p h a s e o f c u re b y fib ro sis; v e ry few o f them w e re a t th e e x u d a tiv e o r p ro d u c tiv e -e x u d a tiv e p h a se s. M o d e ra te in fla m m a to ry in filtra te w as also fo u n d in th e p o rta l d u c ts, as w ell as a d isc re te h y p e rp la sia in th e h e p a tic d u c ts. T h e h ep ato cy tes w e re fo u n d to b e p o ly p lo id , an d th e reg re ssiv e p h e n o m e n a , a lth o u g h b e in g c le a rly d e tec te d , w e re n o t as in te n s e as th o se p re v io u s ly o b serv ed .
G r o u p V (c o n tro l o f th e a c u te phase). T h is g ro u p d iffe rre d fro m th e o th e rs b eca u se it p resen ted a la rg e r n u m b e r o f g ra n u lo m a s. T h e se g ran u lo m as w e re la rg e r-siz e d a n d m o re co n flu e n t, a n d w ere fo u n d to b e a t th e e x u d a tiv e a n d n e c ro tic -ex u d a tiv e p h a se s, v e ry few o f th e m b e in g at th e p h a s e o f c u re b y fib ro s is . T h e in fla m m a to ry p o rta l in filtra te w as
fo u n d to b e in d e p e n d e n t o f th e g ra n u lo m a to u s le sio n , a n d less in te n siv e as it. A p o in t o f in tere st w as co n stitu te d b y th e e x te n siv e a re a s o f n e c ro sis b y co ag u la tio n o f th e h e p a to c y te s, w h ic h w e re g en e ra lly n e a r to th e site o f e g g la y in g , a n d in v o lv e d b y a n a ccen tu ated in fla m m a to ry e x u d a te.
A s s e ss m e n t o f t h e a v e r a g e siz e o f th e h e p a tic g r a n u lo m a s a t t h e p r o d u c tiv e p h a s e in a ll th e m ic e f r o m d if f e r e n t g r o u p s :
T h e a n aly sis o f v a ria n c e w as u sed to d e te rm in e statistic a lly sig n ific a n t d iffe re n c e s a m o n g th e m ean diam eters o f recen t g ranulom as fro m d iffe re n t g ro u p s (p < 0 .0 1 ). In th is m a n n e r, g ro u p IV (p a tte rn o f the c h ro n ic p h a se ) sh o w e d s ta tis tic a lly s ig n ific a n t diffe re n c es in re la tio n to g ro u p s III (re in fe c te d a t th e c h ro n ic p h ase) an d V (c o n tro l o f th e acu te p h ase) (T ab les 1 an d 2).
O n th e o th e r h a n d , g ro u p s V (c o n tro l o f the a cu te p h ase) a n d III (re in fe c te d at th e c h ro n ic p h a se ) sh o w ed sta tistic a lly s ig n ific a n t d iffe re n c e s, w h e n com pared w ith th e o th e r g ro u p s. C o n v e rse ly , g ro u p s I (cu re d a t th e c h ro n ic p h a se an d re in fe c te d ) a n d IV (control o f the chronic phase) d id n o t sh o w significant d ifferen ces am o n g th em se lv e s in c o n n e c tio n w ith th e av era g e siz e o f th e g ra n u lo m a s (T a b le 1). T h e
Table 1 - M ean d ia m ete rs o f liver g ra n u lo m a s in diffe rent gro u p s o f m ice with schistosomiasis mansoni.
Groups Number
of mice
Mean and standard error deviation of granulom a diameters
I * 11 222.96 ± 22.43
II ** 8 142.00 ± 13.31
III * 24 237.77 ± 22.26
IV * 11 220.97 + 17.09
v * 19 275.51 + 27.28
I = infected, treated with oxamniquine and reinfected II = infected and treated
III = infected and reinfected IV = infected (primo infection)
V = in fe cted atth esam ed ateo frein fectio n o fth eo th er groups (control o f reifection)
* granulomas at the productive phase ** granulomas at the phase o f cure by fibrosis
C oe lh o P M Z, R a so P, M e llo R T , Toppa NH. Schistosom a mansoni in m ice: m o du la tio n o f g ra n u lo m a to u s resp o n se a fte r re in fe c tio n a n d ch em o th era p eu tic treatm ent. R evista da S oc ie d a de B ra sile ira d e M e d ic in a T ro p ic a l 27:11 9-1 2 5 , ju l- s e t, 9-1994.
Table 2 - D istribution o f m ice fr o m G roups I, 111 an d V, rela ted to m ean diam eter o f gran ulo m as, in connection with the m ean diam eter ± sta n d a rd erro r deviation o f the gra nulom as o f G roup IV.
I (n = l l )
Groups III (n= 24)
V (n = 19)
3 12 18
(27.3%) (50.0% ) (94.7%)
4 6 1
SD + 17.09 (36.3%) (25.0% ) (5.3% )
G lV :M = 220.97^m
( n = l l ) 2 6
-SD - 17.09 (18.2%) (25.0%)
-2
_
(18.2%)
-I = infected, treated with oxamniquine and reinfected III = infected and reinfected
IV = infected (primo infection) - pattern o f the chronic phase
V = infected at the same date o f the other groups (control o f reifection)
re s u lts o f th e m ean d ia m e te rs o f th e g ra n u lo m a s at th e p ro d u c tiv e p h a s e in d iffe re n t g ro u p s (g ro u p II e x c e p t e d , b e c a u s e i t c o m p r is e s t r e a t e d a n d u n c h a lle n g e d a n im a ls, th e re fo re w ith o u t recen t g ra n u lo m a s), in re la tio n to th e ty p ic a l g ra n u lo m a s o f th e c h ro n ic p h a se (g ro u p IV ), re p re se n te d b y th e m e a n a n d s ta n d a rd e r r o r d e v ia tio n (- a n d + ) , a re s h o w n in T a b le 2.
D IS C U S S IO N
T h e a p p ro a c h o f th e p re s e n t stu d y is b a se d on th e fa c t th a t sc h isto so m ia sis p re se n ts tw o d iffe re n t p h a se s, i .e ., th e a c u te p h a se a n d th e c h ro n ic one. T h e f o r m e r i s r e p r e s e n t e d b y an in te n s iv e in fla m m a to ry re a c tiv ity a ro u n d e g g s , c a u sin g e x te n siv e le sio n s, w h e re a s a t th e ch ro n ic p h ase the h o st ’ s o rg a n ism m od u lates o r regulates this response, r e s u l t i n g in g r a n u lo m a f o r m a tio n o f m in o r d im e n sio n s, a n d co m p o se d o f p e c u lia r c e llu la r in filtra te , c a u sin g le sse r in ju ry to th e tissu es4 7 8. T h e a b se n ce o f th is cap a c ity fo r m o d u la tio n o r c o n tro l o f th e im m u n e c e llu la r re s p o n s e c a n b e o n e o f th e re a so n s fo r th e m a n ife sta tio n o f sev ere
ana to m o clin ica l fo rm s o f th e d ise a se 12. T h e re s u lts d e scrib ed h e re a llo w u s to a ffirm th a t re in fe c tio n o f m ic e d id n o t b rin g a b o u t th e a p p e a ra n c e o f a n ew a c u te p h a se fo r m o st a n im a ls. T h is sig n ific a n t n u m b e r o f an im a ls p re se n te d ty p ic a l g ra n u lo m a s o f th e c h ro n ic p h a se . T h e c ap acity fo r m o d u la tio n o f th e g ra n u lo m a to u s re sp o n se w a s m a in ta in e d in m o st c u re d an im a ls (8 o u t o f 11 m ic e in g ro u p I - T a b le 2 ).
C oelho P M Z, R a so P, M ello R T, Toppa NH. Schistosom a mansoni in m ice: m o d u la tio n o f g ra n u lo m a to u s re sp o n se a fte r re in fe c tio n a n d ch e m o th e ra p e u tic treatm ent. R e v ista da S o cied a d e B ra sile ira d e M e d ic in a T ro p ic a l 27:1 19-1 2 5 ,ju l- s e i, 19-1994.
A lth o u g h G az z in e lli et a l . 19, d e m o n strate d that in d iv id u a ls tre a te d w ith c h em o th era p y tw o years a g o , liv in g in n o n -e n d e m ic a re a s, seem ed to hav e l o s t t h e i r c a p a c i t y f o r m o d u l a t i o n o f th e g ra n u lo m a to u s in fla m m a to ry resp o n se, it is w o rth to e m p h asiz e th a t th e p ro c e ss o f tra n sm issio n o f the d ise a se p e rsists in en d e m ic areas su b m itte d to m ass tre a tm e n t. In th is m a n n e r, it is o f fundam ental im p o r ta n c e to p ro c e e d th e e v a lu a tio n o f th e p e rsiste n c e o f th e cap acity fo r m o d u la tio n o f th e g ra n u lo m a to u s in fla m m a to ry resp o n se im m ediately a fte r tre a tm e n t, in o rd e r to p re v e n t th e p o ssib ility o f n e w a c u te p h a se s o f th e d isease re su ltin g from re in fe c tio n .
T h e p re s e n t re s u lts sh o w in g th e p e rm an en ce o f th e c a p a c ity fo r m o d u la tio n o f th e g ra n u lo m a to u s re sp o n se in m o st o f th e tre a te d a n d rein fe cted m ice, a d d e d to re su lts o b ta in e d b y A n d ra d e & B rito 3 and B e z e rra e t a l.5 d e m o n stra tin g th a t th e acq u ired im m u n ity in m ice re m a in s a fte r p a ra sito lo g ic a l cu re f o r a ce rta in p e rio d o f tim e, c o rro b o ra te the p ertin en t o b s e rv a tio n s o f th e c o n fe re n c e re a d b y P rata 26 on S c h is to s o m ia s is , th a t s u m m a riz e d th e re s u lts o b t a i n e d b y h i m a n d o t h e r i n v e s t i g a t o r s d e m o n stra tin g th a t th e m a jo rity o f th e in d iv id u a ls tre a te d a n d c u re d , b u t liv in g in en d em ic areas, p o s te rio rly w e re fo u n d to b e re in fe c ted w ith a lo w er w o rm b u rd e n , sh o w in g a lso lo w e r m o rb id ity .
It is a lso a p o in t o f in te re st in th is study th e im p o rta n t o b se rv a tio n th a t re in fe c tio n can a lte r the im m u n e re g u la tio n s ta te o f th e g ran u lo m a, in sig n ific a n t n u m b e rs, in m ice c a rry in g a p rim a ry c h ro n ic in fe c tio n (1 2 o u t o f 2 4 m ice in g ro u p III - T a b le 2).
F u rth e rm o re , th e re su lts o f th e p re se n t study stre n g th e n th e n e e d to c o n sid e r th e d iffe re n tia l re sp o n siv e n e ss in th e im m u n o p a th o lo g ica l process. T h u s , th e u s e o f o u tb re d m ic e ( w ith o u t th e h o m o g e n e o u s g e n e tic p a tte rn th a t o c cu rs in w ell d e fin e d b re e d s) in th e p re se n t ex p e rim e n ts allow ed th e id e n tificatio n o f d iversity in im m unopathological re sp o n se . F o r e x a m p le , in an e x p e rim e n t w ith c h a lle n g e d a n im a ls p re v io u sly cu red b y specific c h e m o th e ra p y , p re s e rv a tio n o f th e cap ac ity o f g ra n u lo m a to u s r e s p o n s e m o d u la tio n c o u ld b e o b se rv e d in v a rio u s, b u t n e v e r in a ll, in d iv id u als. O n th e o th e r h a n d , th e a lte ra tio n in th e c o n tro l o f im m u n o p a th o lo g y , th a t can b e o b se rv e d in the g ro u p c o m p risin g u n tre a te d an im als a t th e c h ro n ic
p h ase o f th e d ise a se an d la te r re in fe c te d (g ro u p III), a lth o u g h o c c u rrin g in 12 a n im a ls (5 0 % ), sh o w s th a t th e re m a in in g 12 m ice w e re a b le to k e e p m o d u la tio n o f th e re sp o n se (T a b le 2).
O th e r w o rk s d ea lin g w ith p o p u la tio n s fro m endem ic areas sh o w a lo w e r fre q u e n c y o f sev ere cases o f th e d isease in th e A fric a n ra c e 1014 23 25 273°. M o re o v e r, th e in flu e n c e o f b lo o d g ro u p s o n th e d e te rm in ism o f sev e re a n a to m o -c lin ic al fo rm s bears fu rth er evidence o f th e g enetic facto r in th e p athogeny o f th e disease25. T h e A l a n d B 5 a n tig e n s fro m th e h isto c o m p a tib ility sy ste m h a v e b e e n a lso c o rre la te d w ith h e p a to sp le n ic fo rm s o f th e d ise a s e 1 2. T o th is a rg u m e n ta tio n , w e sh o u ld a d d th e o c c u rre n c e o f a h ig h e r in c id e n c e o f h e p a to s p le n ic f o r m s , in in d iv id u als p e rta in in g to th e sam e fa m ilia r g ro u p 13 21 29. It has also b e e n d e m o n stra te d th e racial i n f l u e n c e o n t h e m o d u l a t i o n o f t h e im m u n o p a th o lo g ic a l re s p o n s e , as w e ll as th e ap p earan ce o f h e p a to sp len ic fo rm s o f th e d ise a se in m ice18. T aking all th ese c o n sid e ra tio n s in to acc o u n t, th e ro le o f th e g enetic fac to r in the im m u n o p ath o lo g y o f sch isto so m ia sis seem s to b e c le a r. O u r re s u lts, sh o w in g th e in d iv id u a l v a ria b ility o f th e m o d u la tio n capacity in o u tb re d m ice, an d c o rro b o ra tin g th e re su lts o b ta in e d b y F a n n in g e t a l .18 re in fo rc e th at v ie w p o in t. T h e se c o n c lu sio n s se e m to b e m o re re le v a n t w h e n th e y a r e e x tr a p o l a t e d to th e e p id em io lo g ical co n te x t o f h u m a n sc h isto so m ia sis, co n sid erin g th a t in so m e c o u n trie s su c h as B razil an in ten se in te rrac ial c ro ssin g o c c u rre d in th e p a s t, a n d is o cc u rin g yet.
F in a lly , th e m a in te n a n c e o f th e m o d u la tio n c ap acity fo r im m u n o p a th o lo g ic a l re sp o n se in th e m a jo rity o f th e c u re d a n d re in fe c te d a n im a ls re in fo rc e s so m e e p id e m io lo g ic a l fin d in g s sh o w in g th at c h e m o th e ra p eu tic m ass tre a tm e n t lead s to a decrease in th e se v e re fo rm s o f th e d ise a se in a reas su b m itte d to tre a tm e n t.
R E S U M O
P ara verificar a cap acida de de m od ula çã o da resposta gran ulo m a tosa na esq uistossom ose m urina, após cura quim ioterápica, ca m und on gos p re via m en te infecta do sfo ra m curado s com o xa m niqu in a (400m g/kg, p . o .) e reinfectados 20 dias após tratam ento. O exam e histopatológico d o fíg a d o d o s anim ais, a o s 60 d ia s ap ós reinfecção, m ostrou, na m aioria de les, a p r e s e n ç a de gran ulom as n a fa s e p ro du tiv a , típic os d a f a s e crôn ica d a
C o elho P M Z, R a s o P, M e llo R T , Toppa NH . Schistosom a mansoni in m ic e : m o d u la tio n o f g ra n u lo m a to u s re sp o n se a fte r re in fe c tio n an d ch e m o th e ra p e u tic trea tm en t. R ev ista d a S o c ie d a d e B ra sile ira d e M e d ic in a T ro p ic a l 27:1 19-12 5 , ju l- s e t, 1994.
d o en ça , pertn itind o a inferência d e qu e a capa cidad e de m od ula çã o d a respo sta granu lom a tosa f o i m antida, p re v e n in d o assim um a o u tra fa s e aguda d a doença. P or ou tro lado, um gru p o de ca m undongos previa m en te in fe c ta d o s e su b m e tid o s a r e in fe c ç ã o m o stro u a reag udizaç ão da resposta gra nulom atosa em 50% dos anim ais. A s p o ssív e is im plicações deste s achados na esq uistosso m ose m ansoni hum ana sã o discutidas.
P alavras chaves: Sçhistosoma mansoni. Granuloma. Tratam ento quim ioterápico. M odulação da resposta granulo m a tosa.
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