immuno-neutralization of somatostatin and its effects on animal production

DOMESTIC ANIMAL ENDOCRINOLOGY Vol. 3(2):55-68, 1986

IMMUNO-NEUTRALIZATION OF SOMATOSTATIN AND ITS EFFECTS ON ANIMAL PRODUCTION

G.S.G. Spencer

Animal and Grassland Research Institute, Shinfield, Reading RG2 9AT.

Received January 6, 1986

INTRODUCTION

Growth is a complex process involving interactions between nutrients, gen- otype, environment and the influence of a number of different hormones on nutrient availability to cells and cell division. Improving the utilization of food (through influencing appetite, digestion and absorption of feedstuffs) and manipulating the endocrine factors involved in growth, are areas holding considerable potential for increasing the efficiency of animal production. The discovery, in recent years, of a number of neural peptides which control the release of hormones and integrate neural inputs (stress, environment, tem- perature, etc.) with hormonal responses, offers a new approach to controlling functions such as growth.

HORMONAL CONTROL OF GROWTH

It is now clear that no single hormone is uniquely responsible for growth. Furthermore, the hormones controlling growth by cell division and those stimulating growth by hypertrophy are interdependent (1). In addition to those hormones having anabolic effects, there are also catabolic influences which often work completely independently of the anabolic hormones. Growth hormone (GH) is of major importance in regulating growth, but this hormone alone has both anabolic and catabolic actions. The catabolic effects are dem- onstrated in the lipolytic effects of GH during malnutrition and lactation, while the anabolic effects are mediated by the somatomedins (2). In addition to being dependent on growth hormone, the release of the somatomedins by the liver seems to require adequate levels of insulin (3). Similarly, the ability of somatomedins to stimulate growth at the tissue level may be dependent on thyroid hormones (1,4). Thus a balance of hormones is required to maximally stimulate growth (Figure 1).

To integrate the balance of these hormones and allow them to act in concert to stimulate growth, it would appear reasonable that there should be a common regulating factor. Growth hormone release inhibiting hormone (somatostatin; SRIF) may be this factor. Apart from its ability to inhibit the release of growth hormone (5), somatostatin also inhibits the release of many other hormones including insulin, (6) and thyroid stimulating hormone (7) although not all workers agree on the effect on TSH (8). It therefore influences the release of the three major positive hormonal influences on somatomedins and growth. Furthermore, SRIF has also been shown to be present in large quantities in the gastro-intestinal tract where it controls the release of many gut hormones including: secretin, motilin, gastrin, gastric acid, vasoactive-intestinal peptide

Copyright © 1986 by DOMENDO, INC. 55 0739-7240/86/$3.00

56 SPENCER

SRIF

J Growth hormone

GRF

j

Oestrogen Androgens

Prolactin

~--- Placental Lactogen

O,.cooor,,co'O, WS "

Free fatty acids

"SM Inhibitor"

v

" O " J

Thyroxine Insulin

¢ Oestrogen ?

Androgen ?

FIGURE 1. Although the growth hormone-somatomedin (SM) axis is the central route for stimulation of growth, a multitude of other factors influence this pathway. These substances may act by interfering with the release of the hormones of this axis, mimicking or inhibiting their actions, or regulating their actions by altering the availability of their receptors. This figure is a simplified scheme of peripheral hormone interactions and does not include the effects of nutrition, stress or the central nervous system (except hypothalamic SRIF and growth hormone releasing hormone (GRF). (From Spencer, GSG. Livestk Prod Sci 12:31, 1985, with permission).

(VIP) , ga s t r i c i n h i b i t o r y p e p t i d e ( G I P ) , a n d p e p s i n ( see 9 ) . S o m a t o s t a t i n seems , t h e r e f o r e , to b e c e n t r a l l y i n v o l v e d in r e g u l a t i n g d i g e s t i o n a n d a b s o r p t i o n o f f o o d as w e l l as t he s u b s e q u e n t d i s t r i b u t i o n o f t he a b s o r b e d n u t r i e n t s in to t i s sues w i t h i n t h e b o d y .

I M M U N O - N E U T R A L I Z A T I O N O F S O M A T O S T A T I N

E f f e c t o n h o r m o n e l e v e l s . A d m i n i s t r a t i o n o f a n t i b o d i e s aga ins t SRIF (pas- s ive i m m u n i z a t i o n ) has b e e n s h o w n to i n c r e a s e g r o w t h h o r m o n e l eve l s in rats ( 1 0 ) , s h e e p (1 1) a n d c h i c k e n s ( 1 2 ) . H o w e v e r , t he e f fec t a p p e a r s to b e t r ans i en t , a n d c i r c u l a t i n g G H l eve l s a re n e a r n o r m a l b y 24 h r a f te r a d m i n i s t r a t i o n o f t he a n t i s e r u m ( 1 1 , 1 2 ; F i g u r e 2) , a l t h o u g h the l eve l s r e m a i n s t a t i s t i c a l l y h i g h e r t han in c o n t r o l s . S ince a n t i b o d y t i t r e s r e m a i n p r e s e n t at a h igh l eve l for c o n s i d e r a b l y l o n g e r t han 24 h r (1 1), t he r e t u r n o f GH leve l s to n e a r n o r m a l is p r e s u m a b l y d u e to t he ef fec t o f f e e d b a c k m e c h a n i s m s on GH re l ea se .

IMMUNO-NEUTRALIZATION OF SOMATOSTATIN 57

E

"1'- (...9

3° t 20- . 10- o

' 4 ' 6 2'4 h o u r s

FIGURE 2. Changes in the circulating level of ovine growth hormone (GH) both before, and at various times after the intravenous administration of 12 g of sheep immunoglobulin raised against either somatostatin (O) or human serum globulin (0). Values are means _+ s.e.m.; ' = P <0.05.

It might be e x p e c t e d that active immuniza t ion , not be ing const ra ined by the level of an t ibody adminis tered, may p roduce a sustained e levat ion of GH levels. In only one s tudy (13) has a significant increase in basal g rowth ho rmone levels been found. Most o ther studies have found that a l though basal GH levels were higher in the animals immun ized against somatostat in, they were not significantly increased (14 ,15 ,16 ,17 ,18 ) . On examina t ion of the available ev idence it seems that the immuniza t ion may increase c i rcula t ing GH levels, but that the marked f luctuations in GH levels and the l imitat ions of the assays may obscure the differences. Certainly there is an increased abil i ty of immun ized animals to respond to GH s t imulat ion tests (13 ,15) .

Despi te the marginal effect on measured GH levels, an increase in c i rcula t ing soma tomed in levels has been consis tent ly de tec ted using both bioassay and rad io immunoassay t echn iques of measu remen t (14 ,15,19; Figure 3).

In mammals , no significant effect of act ive immuniza t ion on thyro t rop in or thyroid h o r m o n e levels has been observed, but increased levels of bo th thyroxine and t r i - iodothyronine have been observed in chicks passively immun ized against somatosta t in (20 ,21) .

Plasma insulin levels are not affected by immuno-neu t ra l i za t ion of SRIF using e i ther act ive or passive immuniza t ion . This may reflect the inabil i ty of the an t ibody to pene t ra te the in terce l lu lar space be tween the pancrea t ic islet cells in sufficient quant i ty to effect ively counte rac t the paracr ine effect of SRIF on insulin release (22) . Recent ly it has been shown that SRIF can have marked effects on insulin s t imula t ion of nutr ient up take into cells in v i t ro (23 ,24) . Immuno-neu t ra l i za t ion of SRIF may, therefore, still play a role in regulat ing insulin act ion if not its release.

58 SPENCER

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300"

200-

100

IIII I1~ ~ ~0

i I I

I I

i I

/ / \ I / / o / I %',

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WEEKS

FIGURE 3. Circulating levels (means _+ s.e.m.) of immunoreactive somatomedin-C (IGF-1) in the plasma of sheep immunized against somatostatin (O--O) or control sheep immunized against globulin (0----0). The sheep (nine in each group) were immunized at three weeks of age and every fortnight thereafter. Blood samples were taken by jugular vein puncture each week at the same time of day. Over the period of the study the mean levels of IGF-1 were significantly different (P <0.01) in the two groups. Week 0 = 3 weeks of age.

Effects o n g r o w t h a n d caracass c o m p o s t i o n . The first e x p e r i m e n t show- ing that immun iza t i on against somatos ta t in c o u l d s t imula te growth used twin St Kilda lambs (14) . The t rea ted lambs were i m m u n i z e d wi th somatos ta t in con juga ted to human se rum g lobu l in (see 15) and con t ro l twins wi th g lobu l in a lone. The t rea ted lambs grew at 176% of the rate of the con t ro l lambs (Figure 4) . This p r e l i m i n a r y e x p e r i m e n t was fo l l owed by a more de t a i l ed s tudy using Dutch m o o r s h e e p (15 ,25 ) ; in this e x p e r i m e n t we igh t gain was also increased by immuno-neu t r a l i z a t i on of somatos ta t in (Figure 5). Subsequent s tudies have conf i rmed the effect of this t r ea tment on rate of g rowth ( 1 6 , 1 9 , 2 6 , 2 7 ) .

Since it has been shown that neu t ra l i za t ion of SRIF w o u l d lead to inc reased s o m a t o m e d i n levels, and s ince a major role of soma tomed ins is to s t imula te bone growth, the he igh t gain in animals i m m u n i z e d against SRIF shou ld be increased. The e x p e c t e d increases in s ta ture ( s tanding shou lde r he ight ) were found in these sheep (Figure 6) and the e longa t ion of the l imbs subsequen t ly conf i rmed by pos t -mor t em carcass d i ssec t ion (Table 1). For any pa r t i cu la r bone it was diff icult to show s ta t i s t ica l ly signif icant increases in length because of the small number s in each g roup w h e n separa ted by sex and t rea tment . However , the inc reased sum of the length of c o m p l e m e n t a r y l imb bones (e.g. femur and t ib ia / f ibu la ) a p p a r e n t l y c o n t r i b u t e d to the increased s tature i n v i v o .


20-

15- A 0

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@

,,J 5-

.O / /

/ f

d.O

/ /

() 1 2 3 ~, 5 6 "l 8 9 1'0 1'1 1'2 1'3 Weeks

FIGURE 4. The mean weights of four St Kilda lambs immunized against somatostatin at three weeks of age and fortnightly thereafter (O- - -O), and four other St Kilda lambs which were similarly immunized against globulin ( 0 - - 0 ) . (From Spencer, GSG, J. Roy Soc Med 77:496, 1984, with permission).

v

.E cg

=

2 0 -

12

/

, , o 7 "

' ' l b ' '

Weeks

FIGURE 5. Weight velocity curves (weight gain over initial weight at week 0) for lambs immunized against somatostatin (O- -O) and those immunized against globulin (O---Q). Values are mean ___ s.e.m, of nine animals in each group. The mean weights became significantly different (P <0.05) by five weeks and the overall regression was significantly different (P <0.001). (From Spencer, GSG et al, Livestk Prod Sci 10:25, 1983, with permission).

60 SPENCER

E 0

@

0 _c

-I-

20"

15"

10-

5"

s" J

+ ' + ' 1'o ' '

Weeks

FIGURE 6. Height velocity curves (height increase over initial height at week 0) for lambs immunized against somatostatin (O- -O) and those immunized against globulin (0---0). Values are means _+ s.e.m, of nine animals in each group. The standing height of the treated animals was significantly different (P <0.05) after five weeks and the overall regression and final heights were different (P <0.01). (From Spencer, GSG et al, Livestk. Prod. Sci. 10:25, 1983, with permission).

In sheep, c o m p l e t e carcass d issect ion has shown that there was no al terat ion in the p ropor t ions of muscle , fat and bone as a resul t of t rea tment w h e n lambs were s laughtered at the same age (Table 2). Growth had, therefore , been s t imula ted propor t iona l ly . However , there is some ev idence that w h e n slaugh- te red at the same we igh t (36 kg), lambs i m m u n i z e d against somatosta t in are l e a n e r than c o n t r o l s ( 2 6 ) - p r o b a b l y b e c a u s e t h e y r e a c h s l a u g h t e r w e i g h t at a

y o u n g e r age. As yet , t h e r e are no p u b l i s h e d s tud ies on the e f fec t o f i m m u n i z a t i o n

aga ins t SRIF on carcass c o m p o s i t i o n in o t h e r spec i e s .

E f f e c t s o n f o o d c o n v e r s i o n e f f i c i e n c y . Apar t f r o m m o r e r ap id w e i g h t

gain, an i m p o r t a n t p r a c t i c a l a s p e c t o f g r o w t h in d o m e s t i c an ima l s is f e e d i n g

costs . In m a n y p r a c t i c a l s i t ua t i ons it is d e s i r a b l e tha t i nc reases in g r o w t h are

no t b o u g h t at the cos t o f i n c r e a s e d f o o d in take. S ince the gas t ro - in te s t ina l t rac t

c o n t a i n s m o s t o f the b o d y ' s soma tos t a t in , and as s o m a t o s t a t i n c o n t r o l s the

r e l ea se o f m a n y gu t h o r m o n e s , it is l i ke ly that s o m a t o s t a t i n may have effects

on the e f f i c i ency o f d i g e s t i o n and a b s o r p t i o n o f food .

TABLE 1. LENGTH OF LONG BONES OF LAMBS IMMUNIZED AGAINST SOMATOSTATIN (TREATED) OR GLOBULIN (CON~OL).

Male Female Bone Length (cm) Treated Control Treated Control

Humerus 14.3 13.5 13.5 12.8' Ulna 18.1 17.4 17.2 16.6 Femur 16.9 16.4 16.1 15.6 Tibia/Fibula 19.3 18.4 18.3 17.2" Humerus + Ulna 32.4 29.4" 30.8 29.3" Femur + Tibia 36.2 34.8 34.4 32.8" N=5 in both male groups. N=4 in both female groups. Values are means.

= P<O.05), treated vs control.


TASL~ 2. POP, PORTIONS OF MUSCLE, FAT AND BONE IN THE CARCA~ES OF LAMBS IMMUNIZED AGAINST SOMATOSTAT1N (TREATED) AND CONTROL LAMBS IMMUNIZED AGAINST GLOBULIN (CONTROL).

Control Treated

Carcass weight (kg) 14.42 _+ 0.95 17.08 _+ 0.82" Side weight (g) 6738 + 453 7931 + 390" Muscle weight (g) 3588 + 209 4181 + 266' Bone weight (g) 980 _+ 64 1093 -+ 63 Fat weight (g) 1987 -+ 196 2453 + 148"

% Muscle 54 53 % Bone 15 14 % Fat 29 31

All lambs were slaughtered at 20 weeks of age. ' = P<O.05

In lambs which were weaned at one day of age and fed indoors on milk replacer , hay and concentra tes ad libitum, those lambs immunized against somatostat in f rom three weeks of age showed advantages in efficiency over cont ro l lambs (25) . Immunized lambs showed a 10% decrease in relative appet i te ( food intake/kg live weight ) and a 14% improvement in food uti l ization efficiency (Table 3). As a consequence of their increased growth rate the t reated lambs reached the slaughter weight of the control lambs (30 kg) in 16 weeks rather than the 20 weeks taken by the controls. There was, therefore, a saving of 20% in the t ime taken to reach slaughter weight .

In pract ical animal p roduc t ion terms, especial ly for animals fed concentrates , it is perhaps more informative to compare the efficiency of the t reatment to st imulate growth to the same weight rather than age. As a result of the decreased maintenance costs associated wi th the quicker growth, the lambs immunized against SRIF showed a 27% increase in food uti l izat ion efficiency for the same weight gain as the controls (Table 3). Similar studies wi th o ther breeds of sheep (for example , Suffolk x Clun) show similar, though less dramatic, changes in response to this treatment; a 10% increase in growth rate and an 11% increase in efficiency during the per iod to weaning (26; Table 4).

Ef fec t s o n gu t f u n c t i o n . The marked increase in food convers ion efficiency raises the ques t ion of the mechanism of action of the treatment. Immuno- neutral izat ion of SRIF clearly increased SM levels and bone growth, but this does not adequate ly explain the effect on efficiency. The many actions of SRIF on gut hormones may be involved in this aspect of the treatment. SRIF affects gastric emptying and duodenal moti l i ty (28 ,29) and administrat ion of somatostatin has been shown to increase the passage of food through the gut (30) . The effect of immuno-neutra l iza t ion of SRIF on gut funct ion has also been investigated. Passive immunizat ion, by intravenous administrat ion of ant ibodies to SRIF (31) caused a marked (40%) increase in marker re tent ion t ime of Cr203 marker in the gut (P<0.O 1) whi le similar adminstrat ion of antisera raised against g lobul in had no effect (Figure 7a,b). This increase in re tent ion t ime could, potential ly, influence digestion and absorpt ion of food from the gastro- intestinal tract. Initial studies have been made using sheep with rumen and

TABLE 3. FOOD INTAKE (MJ), RELATIVE APPETITE (MJ/kg), AND FOOD UTILIZATION EFFICIENCY (M~//Xkg) IN LAMBS IMMUNIZED AGAINST GLOBULIN (CONTROL) AND LAMBS IMMUNIZED AGAINST SOMATOSTATIN

(TREATED) FOR THE SAME WEIGHT GAIN AND FOR THE SAME LENGTH OF TIME (TO SLAUGHTER)

Control Treated (Slaughter) (Slaughter) (To 30kg)

Change body weight (kg) 24.34 29.61 24.60 Food intake (MJ/lamb) 1383.3 1470.3 1018.1 Appetite (MJ/lamb/kg) 78.6 71.6 56.5 Efficiency (MJ/,~ wt) 56.83 49.66 41.39

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TABLE 4. WEIGHT GAiN (KG), APPETITE (MJ INTAKE/KG BODY WEIGHT/DAY) AND EFFICIENCY OF FOOD UTILIZATION (MJ INTAKE/WEIGHT GAiN) IN LAMBS IMMUNIZED AGAiNST SOMATOSTATIN (TREATED) OR

GLOBULIN (CONTROL) FROM START OF TREATMENT (THREE WEEKS OF AGE) THROUGH UNTIL WEANING (NINE WEEKS OF AGE).

Treated Control Weight gain (kg) 9.25 _+ 0.79 8.39 - 0.58 10% Appetite (MJ/kg/d) 051 +_ 0.02 0.55 _+ 0.02 9% Efficiency (MJ/A kg) 28.1 _+ 1.1 31.2 _+ 2.4 11%

i lea l f is tulae in an a t t e m p t to i nves t i ga t e the ef fec t o f n e u t r a l i z a t i o n o f SRIF in

d i f fe ren t s e g m e n t s o f the gut. No ma jo r c h a n g e s w e r e o b s e r v e d in these s tudies ,

w h i c h sugges t s that the p r i n c i p a l e f fec t o c c u r s in the large i n t e s t i ne (1 1); a

c o n c l u s i o n s u p p o r t e d by the f ind ing that SRIF in fus ion c o u l d r e d u c e r e t e n t i o n

t i m e in the la rge i n t e s t i n e bu t no t in the fo re -gu t ( 3 0 ) .

E f f e c t s o f i m m u n o - n e u t r a l i z a t i o n d u r i n g p r e g n a n c y . In a d d i t i o n to its

effects on g r o w t h s t i m u l a t i o n , soma tos t a t i n c o n t r o l s the r e l ease o f the t w o

ma jo r s t i m u l a t o r s o f l ac ta t ion : GH and t h y r o x i n e . To inves t iga t e this fu r the r ,

the e f fec t o f i m m u n i z a t i o n aga ins t s o m a t o s t a t i n d u r i n g p r e g n a n c y on m i l k y i e ld

in goats has b e e n s t u d i e d (32 ) . In th is e x p e r i m e n t t he r e was a s igni f icant

CONtrOL periO~

5 0 IOO

1OO

7 r e d t m q m t Der t(>O

C ~ t r t~l p e w m

2 5

Tlmethouts)

b

FIGURE 7. Cumulative percentage excretion of Cr203 marker in the feces of sheep during an untreated control period (O) or following iv administration of 12 g of immunoglobulin (~) against (a) somatostatin and (b) Human serum globulin. Marker was given orally at the same time as the appropriate infusion. The results shown are from a representative sheep. (From Fadlalla et al, J Anim Sci 61:234, 1985, with permission).


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~g ' - 3 0 E

o~ v,

25

20

t , , / / /

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FIGURE 8. Mean milk yield (+ s.e.m.) from six goats immunized against somatostatin ( I - - -B) and from six other goats immunized against globulin (Q---~). Primary immunization was made at ten weeks of gestation. Over the whole of the study period there was a significant (P <0.05) stimulation of milk yield in the treated group. ' = P <0.05)

(P<0 .05) increase in milk yield during the early part of lactation (Figure 8). The effect did not cont inue th roughout the whole of lactation and there was no difference in milk composi t ion be tween treated and control goats. However, the early increase in lactation may be of practical importance since early post- natal nutr i t ion has a large effect on growth potential.

As well as early post-natal nutrit ion, size at birth is also a major determinant of the subsequent growth of an animal (33) and the effects of immunizat ion during pregnancy on deve lopment and post-natal growth has been investigated. A number of studies in sheep and goats have failed to show any significant effect of such treatment during pregnancy on birth weights, a l though the mean birth weights of the offspring from treated mothers is 10% greater than the mean weight of the young from control mothers (32; Table 5).

Immunizat ion against SRIF during pregnancy may, potentially, increase growth through a number of mechanisms. By consequence of nutrit ional advantages in the mother there may be an increase in birth size; youn I may acquire passive immunizat ion either transplacentally or via the colost rum and such treatment may enhance milk availability to the neonate. In a prel iminary observation the

TABLE 5. BIRTH WEIGHT (G) OF KIDS BORN OF GOATS IMMUNIZED AGAINST SOMATOSTATIN (TREATED) OR GLOBULIN (CONTROL) DURING PREGNANCY.

Females (n) Males (n) Treated 3451 + 160 (6) 3949 + 163 (7) Control 3128 _+ 344 (5) 3432 -+ 121 (6) Blank 3109 _+ 69 (39) 3528 - 80 (55) Blanks are kids from goats in the same herd not on experiment.

64 SPENCER

,!g

o W

12.

9'

6

~ o

Y / /

/

o / /

ii °

ii//

WEEKS

FIGURE 9. Liveweight gains in lambs immunized against globulin (O--O), at three weeks of age and in two lambs (born of ewes immunized during pregnancy) receiving transfer (passive) immunization (0----0).

growth of two lambs, born of mothers immunized against SRIF before concep t ion and th roughout pregnancy, was fol lowed. These two lambs showed a marked advantage in growth over lambs born of non- immunized mothers (Figure 9). However, in a subsequent fol low-up study on twins born of Masham ewes immunized against SRIF, there was no significant difference be tween the growth rates of lambs from treated or control mothers. Thus the effect of immunizat ion against SRIF during pregnancy is still not clear and needs to be further investigated.

From these studies in sheep and goats it is clear that immunizat ion against SRIF can have marked effects on growth and efficiency and may be a valuable t echnique in sheep product ion. However, SRIF is present in all vertebrates so far studied and so the technique should be equal ly applicable to other farm species. Preliminary investigations have shown that the method works in rabbits, poul t ry and pigs (Figures 10 & 11) and so may eventually prove to be part icularly valuable in reducing feeding costs for animals being fed concentrates. However, there are certainly species differences to be taken into account . For example, there are differences in the maturation of the SRIF-GH axis and in hormone changes. Active immunizat ion against SRIF did not lead to increases in circulat ing thyroid hormones in sheep (Spencer, Hallett & Fadlalla, submit ted for publ ica t ion) but passive immunizat ion of chicks resulted in marked increases (P<0 .001 ) in both T4 and T 3 levels (20,21) . Another species difference is in ant ibody response. However within species, and even within breeds, there can be marked variations in the magnitude and speed of ant ibody response (16) .

Poor, or slow, ant ibody response may well be responsible for much of the difficulty occasional ly encoun te red in obtaining consistent effects with this treatment. When the animals are slow to respond with high ant ibody levels it reduces the time available for the effect to be reflected in growth rate. In some studies the exper imenters have recorded considerable differences in the mean weight gain be tween treated and control groups but have been unable to show


60- I ,,"T ,,/" j L

48 , , " ~

° Z J N 36 I-" /'~/" 0 24- / / / /

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FIGURE l 0. Weight gain (over weight at the start of treatment) in Large White pigs immunized against somatostatin (O- - -O) or against androstenone (O----O). The pigs had a mean liveweight of 35 kg at the start of treatment. Over the period of study the growth curves were significantly different (P <0 .05 ) .

A 3 - O~ v '

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2 -

i+ I

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W E E K S

FIGURE 11. Change in weight (means _+ s . e . m . ) o f b r o i l e r c h i c k s with age. There were eleven untreated c o n t r o l s (O) and thirteen following active immunization against somatostatin at 8 days o f age ( O ) . " = P < 0 . 0 5 ; "" = P < 0 . 0 1 .

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statistical significance. This may be at tr ibutable to the variations in immune response leading to large variations in gains (16) . Clearly, animals that fail to respond to immuniza t ion wi th p roduc t ion of ant ibodies cannot be expec ted to be different from contro l animals. To date, however , the results from these animals have invariably been inc luded in the t reated group. From the practical, animal p roduc t ion , s tand-point it is more appropr ia te to include all t reated animals in the analysis since this reflects the l ikely benefit to the producer . However , f rom the physiological poin t of view, including non-responders in the t reated group analysis obscures our unders tanding of the physiological mechanisms associated with, or resul t ing from, the treatment.

Poor responders ( those animals which are slow to p roduce a titre or only achieve a low titre of ant ibody) provide an even more difficult p rob lem since it is, as yet, unc lear what re la t ionship there is be tween titre and biological response. This is because most est imations of ant ibody titre ( recording the serum di lu t ion capable of b inding 50% of an arbitrary amount of radio-ligand) are essentially meaningless. A bet te r est imate of titre is recording the amount of ligand (in molar terms) bound by a uni t vo lume of the antiserum. Although physical ly more precise, this latter me thod still has disadvantages in the area of biological effect. Ability to b ind the ligand does not mean that the ant ibody has a biological neutral iz ing effect; if cell receptors have a higher affinity for the ligand than does the ant ibody then it will prefent ia l ly sequester the hormone and p roduc e a biological effect. Such factors need to be borne in mind when assessing the efficacy of this kind of t reatment.

Despite the large and wide-ranging effects of this t reatment, and its advantages over convent iona l ho rmone treatments such as its f reedom from the p rob lem of harmful residues (34) , the p rob lem of variabili ty in response is a major drawback. This may be overcome by passive immunizat ion, but this approach is not free of at tendant problems: anaphylaxis, immuno-response to the im- munoglobul in , variable c learance rates, and the need for repea ted treatments. Fur thermore , in no s tudy to date has passive immuniza t ion against SRIF been shown to st imulate growth (35; Spencer, unpub l i shed observations).

Although most work involving immuno-neutra l iza t ion as a means of enhancing growth or al ter ing physiological states has cen te red around SRIF or sex steroids (36) , the t e chn ique may be useful ly appl ied in o ther ways. One such area is in the field of regulat ing body composi t ion , where immunizat ion against fat cell membranes leads to a reduc t ion in the amount of body fat in chickens (unpub l i shed observat ions) . Similarly, many other aspects of animal p roduc t ion may benefit f rom this sort of approach (for example: appet i te , stress and maturat ion) . However , because of a general lack of practical immunologica l knowledge as re la ted to such applicat ions, fur ther work (par t icular ly as regards re l iably inducing neutral iz ing ant ibody response) should be under taken before this me thod can be wide ly appl ied in pract ice.

In conclus ion, there is considerable ev idence that immuno-manipula t ion is a potent ia l ly powerfu l tool in animal product ion . Neutral izat ion of inhibi tory influences on growth may be an impor tant new way of p romot ing growth in animals and among these immuno-neut ra l iza t ion of SRIF may be part icular ly impor tant by vir tue of its demonst ra ted effects on growth and efficiency.


A C K N O W I E D G E M E N T S

I am very grateful to Dr. G.J. Garssen, Dr. A.M. Fadlalla and Mieke Well ing for their contr ibut ion to many of the studies reported; to the authors who shared their unpubl ished data with me and those who provided me with information in press. I am also par t icular ly grateful to Kathy Hallett for her invaluable he lp thoughout many of these studies.

Present address of author is: Centre de recherches agricoles, CH 1566, St Aubin (FR), Switzerland.

REFERENCES

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18. Galbraith H, Wigzell S, Scaife JR, Henderson GD. Growth and metabol ic response of rapidly growing male castrate lambs to immunizat ion against somatostatin. Anim Prod 40:523, 1985.

19. Bass JM, Gluckman PD, Fairclough RJ, Peterson AJ, Davis SR. Effect of immunisat ion against somatostatin and feed quali ty on growth control l ing hormones and body composi t ion. Proc Endocr Soc Australia 1983.

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20. Harvey S, Lain S-K, Spencer GSG. Somatostatin inhibi t ion of thyroid function in fowl. Proc lOth Int Symp on Comp Endocr, Colorado 21-26, July, 1985.

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22. Taniguchi H, Utsumi M, Hasegawa M, Kabayashi T, Watambe Y, Murakami K, Seki M, Tsutou A, Makimura H, Sakoda M, Baba S. Physiological role of somatostatin: Insulin release from rat islets t reated by somatostatin antiserum. Diabetes 26:700- 702, 1977.

23. Hill DJ, Spencer GSG. Inhibi t ion of insul in-dependent amino-acid uptake into myoblasts by somatostatin. J Endocrin 102 (Suppl) 16. 1984.

24. Pullen L, Spencer GSG, Hallett KG, Will iams JPG, Garssen GJ, Hill DJ. Somatostatin inhibits the insulin s t imulated glucose uptake into adipocytes in vitro. IRCS Med Sci 13:1094, 1985

25. Spencer GSG, Garssen GJ, Bergstrom PL. A novel approach to growth promotion using auto- immunizat ion against somatostatin. II. Effects on appeti te , carcass composi t ion and food ut i l izat ion in lambs. Livestk Prod Sci 10:469-477, 1983.

26. Spencer GSG, Hallett KG. Immunizat ion against somatostatin in a commercial breed of sheep and its effect on growth and efficiency. Anim Prod 40:523, 1985.

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30. Faichney GJ, Barry TN. Intravenous somatostatin infusion affects gastro-intestinal tract function in sheep. Can J Anim Sci 64: (Suppl) 93-94, 1984.

31. Fadlalla AM, Spencer GSG, Lister D. The effect of passive immunizat ion against somatostatin on marker re tent ion time in lambs. J Anim Sci 61:234-239, 1985.

32. Spencer GSG, Garssen GJ, Well ing AMAW. Increased milk product ion by goats fol lowing immunizat ion against somatostatin. Anim Prod 40:572-573, 1985.

33. McKeown T, Record RG. Observations on foetal growth in mul t ip le pregnancy in man. J Endocrinol 8:386-401, 1952.

34. Lister D. Endocrine systems and immunology, ln: Immunological Approaches to the Regulation of Growth and Reproduct ion in Animals. Ed. D. Lister & J.C. Tayler. ARC. London. pp 2-7, 1983.

35. Lawrence ME, Schell ing GT, Welsh TH, Byers FM, Greene LW. Effect of passive immunizat ion against somatostatin on plasma growth hormone and performance of growing rats. J Anim Sci 61: (Suppl 1) Abstr 111, 1985.

36. Crighton DB. Immunologica l Aspects of Reproduct ion in Mammals. Butterworths. London. 1984.

immuno-neutralization of somatostatin and its effects on animal production

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