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Differental polymorphism of the amphibian MHC
DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY, Vol. 8, pp. 727-732, 0145-305X/84 $3.00 + .00 Printed in the USA. Copyright (c) 1984 Pergamon Press Ltd. All rights reserved.
1984.
DIFFERENTAL POLYMORPHISMOF THE AMPHIBIAN MHC Barbara P~ytycz Department of Comparative Anatomy, Jagiellonian University, M.Karasia 6, 30-060 Krak6w, POLAND
INTRODUCTION The existence of a homologue for the mammalian and avian MHC in ectothermic vertebrates is s t i l l an open question. The presence of this complex was proved in one anuran species, ×enopus laevis (I) and implicated in another, Rana pipiens (2). Comparative studies of transplantation reactions in adult individuals from ten Polish amphibian species allow presentation of the hypothesis that such complex may exist in all amphibians but that p a r t i cular species d i f f e r in t h e i r degrees of MHC polymorphism (3,4). Recent results on larval individuals from four of these species seem to confirm this hypothesis (5-8). The aim of this paper is to review our data collected to data on this subject under the same experimental conditions. EXPERIMENTAL DESIGN Data concerning a l l o g r a f t v i a b i l i t y in several Polish amphibian species was collected during several successive years under the same laboratory conditions, at temperature 20-24 C. Investigated animals were f i e l d - c o l l e c t e d from several populations, as a rule geographically d i s t a n t . A l l o g r a f t were mutually exchanged between randomly paired adults or larval individuals (Fig.l). In adults orthotopic or heterotopic skin a l l o g r a f t s were performed (Fig.la) adopting the method of Cohen's experiments (9). Total pigment cell destruction was used as a c r i t e r i o n of the end of a l l o g r a f t v i a b i l i t y . In larval individuals heterotopic t a i l - t i p a l l o g r a f t s were performed (Fig.lb) according to the simple procedure described in the previous papers (5-8) and a pigment cell destruction and/or a l l o g r a f t f l a c c i d i t y were used as a c r i t e r i a of a l l o g r a f t r e j e c t i o n . Some long-term viable heterotopic t a i l - t i p a l l o g r a f ~ were, however, resorbed during the host metamorphic climax simultaneously with host t a i l (Anura) or t a i l - t i p (Urodela) resorption, thus observations had to be ended, nu~-nu-Fanlarvae were g ~ a t developmental stages 31-34 (I0) and urodele larvae at developmental stage 52 ( I I ) . 727
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ALLOGRAFTS IN ADULT AMPHIBIANS (large circles on Fig. 2) The fate of allografts exchanged between adult representatives of four urodele and six anuran species proved that there is no difference of a l l o g r a f t rejection patterns between urodele and anuran amphibians (3,4). According to the a l l o g r a f t rejection pattern the investigated species may be divided into three groups: a, b and c (Fig.2). a) Subacute a l l o g r a f t rejection pattern was characteristic for one urodele (Triturus cristatus) and two anuran species (Rana esculenta and Rana temporaria), b) Typically chronic a l l o g r a f t rejection pattern was characteristic for one urodele (Salamandra salamandra) and three anuran species (Bufo bufo, Bombina bombina and Bombina variegata), c) Wide range~of a l l o g r a f t v i a b i l i t y (acute, subacute and chronic a l l o g r a f t rejection patterns) was characteristic for two urodele species (Triturus vulgaris and Triturus alpestris) and one anuran species (Hyla arborea). ALLOGRAFTS IN AMPHIBIAN LARVAE (smal~ circles and empty circles on Fig.2) Ontogeny of transplantation immunity was investigated in representatives of each of three groups (a, b and c) formed according to a l l o g r a f t rejection pattern in adults, a) All but one tadpole of Rana temporaria rejected small heterotopic t a i l - t i p allografts from unrelated donors very promptly, prior to metamorphosis (data from 6). b) No tadpoles of Bufo bufo and Bombina variegata rejected heterotopic t a i l - t i p allografts before metamorphic climax: all ~grafts were resorbed simultaneously with host t a i l resorption (data from 7). c) Some larvae of Triturus alpestris rejected the heterotopic t a i l - t i p allografts very promptly, others rejected the allografts more slowly, and a majority of larvae retained viable heterotopic t a i l - t i p allografts until metamorphic climax (data from 8).
a)
b)
Fig. 1
~
oQ
Pattern of grafting in adult (a) and larval (b) individuals of anuran and urodele amphibians.
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THE AMPHIBIAN MHC
729
INTERPRETATION OF THE RESULTS In order to i n t e r p r e t the obtained data two s i m p l i f y i n g assumption are made. F i r s t , that a l l o g r a f t rejection rate is mainly dependent upon donorhost antigenic d i s p a r i t i e s . Strong transplantation antigens encoded within the MHC evoke rapid a l l o g r a f t rejection while weak antigens encoded outside t h i s complex evoke slow a l l o g r a f t r e j e c t i o n . And second, that larvae tend to react rapidly to strong transplantation antigens encoded by the MHC while they tend to " t o l e r a t e " weak antigenic s t i m u l i (6,12,13). These assumptions allow consideration of a genetic basis for the a l l o g r a f t rejection reaction in representatives of the three amphibian groups: a, b, and c ( F i g . 2 ) .
0 I a)
U Triturus cristatus Rana A esculenta
A
b)
20 I
40 I
I
4~j~-
60 I
I
80 I
i
100 1
~'-':
-~..'...
Oo° • 0
Rana temporaria
Salamandra U salamandra
.
,'m,", . .
°,
a,',
A Bufo bufo A
Bombina bombina
• •
oeoe%~o
•
oe
%
oo
-
A Bombina variegata c)
o~e~°o"
• .
•
°oOo~oO o o
X
.
oo
oo
U Triturus vulgaris Triturus U alpestris
•
•; ; • , ~ ' , ° s
T,--
:'-..:.: . ~ ° - ° ~ p ~ . ~ o - o o o ~ o o
A Hyla arborea
O• 1
i 20
•
I
•
I 40
L
• 000
|
•
I 60
o •
I
I 80
•
•
I 100
Days after grafting
Fig, 2. Fate of individual a l l o g r a f t s in several urodele (U) and anuran (A) species. • - rejection of one skin a l l o g r a f t in adult host; - - rejection of one t a i l - t i p a l l o g r a f t in larval host; o - resorption of one t a i l - t i p a l l o g r a f t during the larval metamorphic climax; a,b,c - three a l l o g r a f t rejection patterns: a - subacute ; b - chronic; c - wide range of reaction.
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a) Adult amphibians of this group as a rule rejected a l l o g r a f t s in a subacute manner therefore a majority of the grafted skin fragments d i f f e r from the host tissues in that they have d i f f e r e n t strong transplantation antigens encoded by the MHC a l l e l e s . Therefore this genetic region of Rana temporaria, Rana esculenta, and Triturus c r i s t a t u s seem to be highly poyT~morphic. Th~Thypothesis is confirmed by the fate of a l l o g r a f t s in Rana temporaria tadpoles: all but one tadpole rejected the a l l o g r a f t s very promptl y , therefore i t is possible that a l l but one of the t a i l - t i p a l l o g r a f t s differed from the host tissue in MHC a l l e l e s . b) Adult individuals of Bufo bufo, Bombina bombina, Bombina variegata, and Salamandra salamandra reacted to a l l o g r a f t s in a chronic manner. No tadpole rejected the t a i i - t i p a l l o g r a f t . Thus i t seems that the grafted tissues differed from the host tissues exclusively in weak transplantation antigens encoded by minor h i s t o c o m p a t i b i l i t y l o c i . Therefore one can assume that these species do not possess the MHC. However, in the l i g h t of the great biological importance of the MHC (14) I prefer the hypothesis that they possess a MHC homologue which is minimally polymorphic (15) or which contains only one h i s t o c o m p a t i b i l i t y a l l e l e . In the l a t t e r case all animals used for investigations share strong transplantation antigens and react exclusively to weak transplantation antigens. c) Rapid a l l o g r a f t rejection observed in some adult individuals and in some larvae of Triturus a l p e s t r i s might be caused by the presence of strong transplantation antigen(s) encoded by the MHC a l l e l e ( s ) in the grafted tissue which are absent in the host tissue. The a l l o g r a f t s rejected slowly by adult individuals and those resorbed during the larval metamorphic climax possibly shared the hosts strong transplantation antigens (the MHC a l l e l e s ) . Thus i t may be concluded that the MHC polymorphism of Triturus a l p e s t r i s , Triturus vulgaris, and Hyla arborea is moderate.
CONCLUSION The results of comparative studies on d i f f e r e n t i a l a l l o g r a f t v i a b i l i t y in adult amphibians confirmed by the fate of a l l o g r a f t s in larval individuals may be explained by a species-specific polymorphism of the MHC a l l e l e . According to this view, the MHC polymorphism, oligomorphism, or even monomorphism can exist in amphibian species. A d d i t i o n a l l y , recent results showed that natural populations of the r e l a t i v e l y polymorphic anuran species, Rana temporaria, contain a much higher percentage of the MHC homozygous indiv-T~-uals (about 25%), than wild mice populations do (16). The simple transplantation technique does not, however, allow the exclusion of a l t e r n a t i v e hypotheses. I) The chronic rejection reaction in some amphibians may be caused by the lack of the MHC homologues in these species. 2) The acute rejection of some a l l o g r a f t s may be caused by cumulative action of several weak transplantation antigens in the absence of the MHC (17). 3) The rate of a l l o g r a f t rejection may be limited by the a c t i v i t y of the immune response gene(s) (18). 4) The rate of a l l o g r a f t rejection may be modulated by some unspecific factors, e.g. the actual status of the host immune system which seems to be seasonal (19, and unpublished data). The hypothesis presented here is a simple explanation of our experimental results but should be v e r i f i e d by experiments conducted using other immunological techniques.
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THE AMPHIBIAN MHC
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GENERAL REMARKS Most information about MHC structure and function concerns man and some laboratory mammals (mice, r a t s ) . The main discovery of recent immunology is that immunocompetent cells recognize antigenic epitopes in association with products of t h e i r own MHC (20). Since the MHC polymorphism of mice and man is e x t r a o r d i n a r i l y high, most hypotheses postulate that mutant MHC a l l e l e s are favoured by natural selection: the more MHC a l l e l e s are expressed, the more foreign antigenic epitopes are p o t e n t i a l l y recognizable by the host immunocompetent cells (21). I t is also postulated that polymorphic h i s t o compatibility antigens may operate in some colonial invertebrates (sponges, corals) to save the i d e n t i t y of p a r t i c u l a r colonies (22). In recent excellent review (23), REIMANN and MILLER showed, however, that even mammalian species d i f f e r considerably in the degree of t h e i r MHC polymorphism. Known extremies are mice (with e x t r a o r d i n a r i l y polymorphic r~C) and hamster (with oligo- or even monomorphic MHC). Despite this drastic difference, both these rodent species can cope successfully with pathogens or neoplastic diseases. The authors (23) offered a new, very a t t r a c t i v e hypothesis concerning polymorphism and MHC gene function. They emphasize that MHC polymorphism may be not essential for the functional e f f i c i e n c y of membrane glycoproteins encoded by the MHC genes. Instead, an invariant molecule, encoded by MHC, associated with the d i f f e r e n t antigenic epitopes, would constitute the immunogeniccomplex, which would be effective in stimulating immunocompetent c e l l s . According to this view, the MHC polymorphism may be the r e s u l t of random genetic d r i f t and has no adaptive value in i t s e l f . If this assumption is correct the presence or absence of the MHC polymorphism should correlate with the presence or abcense of chances for genetic d r i f t of species in consideration. The authors proved that such correlation exists in the case of mice and hamster, respectively (23). I f future investigation confirm the presence of the MHC homologues in poikilothermic vertebrates, postulated in the present paper, i t would be interesting to look for correlations of species-specific MHC polymorphism and the behaviour of these animals, especially t h e i r reproductive strategies. ACKNOWLEDGEMENTS The expert secretarial work of Mrs Marit BrekkAs in the preparation of this manuscript is g r a t e f u l l y acknowledged. This work was supported by the Polish Academy of Sciences, research project MR.II.6. and by a grant from the Norwegian Cancer Society. REFERENCES I. DU PASQUIER, L., CHARDONNENS, X. and MIGGIANO, V.C. A major histocompatib i l i t y complex in the toad Xenopus laevis (Daudin). Immunogenetics.l,482, 1975. 2. ROUX, K.H. and VOLPE, E.P. Evidence for a major h i s t o c o m p a t i b i l i t y complex in the leopard frog. Immunogenetics, 2,577,1975. 3. P~YTYCZ, B. The MHC:analyzing a l l o g r a f t rejection patterns in urodele and anuran amphibians. Dev.Comp.lmmunol., 5,5,1981. 4. P~YTYCZ, B. Filogeneza odporno~ci transplantacyjnej kregowc6w. (Phylogeny of vertebrate transplantation immunity). Przegl.Zool.,25,15,1981(In Polish). 5. P[YTYCZ, B. Preliminary report on skin a l l o g r a f t rejection in tadpoles and froglets of Rana temporaria. Dev.Com.lmmunol., 4,747,1980.
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6. P~YTYCZ, B. Ontogeny of transplantation immunity in the common frog, Rana temporaria L. D i f f e r e n t i a t i o n , 20,71,1981. 7. P~YTYCZ, B. Ontogeny of transplantation immunity in three anuran species: Rana temporaria, Bufo bufo and Bombina variegata. Fol.Biol.(Krak6w), 31, 393,1983. S. P[YTYCZ, B., MICHA~EK-ANIKO, D. and ANIKO, K. Ontogeny of transplantation immunity in the newt, Triturus alpestris. Bull.Acad.Polon.Sci.ser.Biol. 29,215,1981. 9. COHEN, N. Tissue transplantation immunity in the adult newt, Diemictylus viridescens. I. The latent phase:healing, restoration of circularion, and pigment cell changes in autografts and a l l o g r a f t s . J.Exp.Zool.163,157,19C#. lO. GOSNER, K.L. A simplified table for staging anuran embryos and larvae with notes on i d e n t i f i c a t i o n . Herpetologica, 16,183,1960. I I . GALLIEN, L. and BIDAUD, O. Table chronologique du d~veloppement chez T r i turus helveticus Razoumowsky. Bull.Soc.Zool.Fr., 84,22,1959. 12. CHARDONNENS, X. and DU PASQUIER, L. Indiction of skin a l l o g r a f t tolerance during metamorphosis of the toad Xenopus laevis: a possible model for studying generation of self tolerance to h istocompatibility antigens. Eur.J.Immunol., 3,569,1973. 13. DI MARZO, S. and COHEN, N. Immunogenetic aspects of in vivo a l l o t o l e rance induction during the ontogeny of Xenopus laevis. Immunogenetics, 16, I03,1982. 14. KLEIN, J. Evolution and function of the major histocompatibility system: facts and speculations. In: The Major Histocompatibility System in Man and Animals. D. G~tze (Ed.) Berlin, Heidelberg, New York: Springer Verlag. 1977, p.339. 15. COHEN, N. Salamanders and the evolution of the major histocompatibility complex. In: Contemporary Topics in Immunobiology. Vol. 9, J.J. Marchalohis and N. Cohen (Ed.). 1980, p.109. 15. P[YTYCZ, B. MHC zygosity in Rana temporaria. Immunogenetics,19,3,1984. 17. GRAFF, R.J., SILVERS, W.K., BILLINGHAM, R.E., HILDEMANN, W.H. and SNELL, G.D. The cumulative effect of histocompatibility antigens. Transplantation, 4,605,1966. 18. COHEN, N. Predictable v a r i a b i l i t y in the response of two newt subspecies (D.v.viridescens and D.v.dorsalis) to f i r s t - s e t a l l o g r a f t s . F o l . b i o l . (Praha), 19,169,1973. 19. P[YTYCZ, B. and BIGAJ, J. Seasonal cyclic changes in the thymus gland of the adult frog, Rana temporaria. Thymus, 5,327,1983. 20. ZINKERNAGEL, R.M., CALLAHAN, C.N., ALTHAGE, A., COOPER, S., KLEIN, P. and KLEIN, J. On the thymus in d i f f e r e n t i a t i o n of "H-K-self-recognition" by T cells: Evidence for dual recognition. J.Exp.Med. 147,882,1978. 2l. KLEIN, J. Generation of diversity of MHC loci: Implications for T-cell receptor repertoire. In: Immunology 80. M. Fougereau and J. Dausset (Eds.) London: Academic Press, 1980, p.239. 22. COHEN, N. Some thoughts about the possible early phylogeny of MHCrestriction. Dev.Comp.lmmunol., 7,775,1983. 23. REIMANN, J. and MILLER, R.G. Polymorphism and MHC gene function. Dev. Comp.lmmunol., 7,403,1983. Received Accepted
: October 1983 : December, 1983
1984.
DIFFERENTAL POLYMORPHISMOF THE AMPHIBIAN MHC Barbara P~ytycz Department of Comparative Anatomy, Jagiellonian University, M.Karasia 6, 30-060 Krak6w, POLAND
INTRODUCTION The existence of a homologue for the mammalian and avian MHC in ectothermic vertebrates is s t i l l an open question. The presence of this complex was proved in one anuran species, ×enopus laevis (I) and implicated in another, Rana pipiens (2). Comparative studies of transplantation reactions in adult individuals from ten Polish amphibian species allow presentation of the hypothesis that such complex may exist in all amphibians but that p a r t i cular species d i f f e r in t h e i r degrees of MHC polymorphism (3,4). Recent results on larval individuals from four of these species seem to confirm this hypothesis (5-8). The aim of this paper is to review our data collected to data on this subject under the same experimental conditions. EXPERIMENTAL DESIGN Data concerning a l l o g r a f t v i a b i l i t y in several Polish amphibian species was collected during several successive years under the same laboratory conditions, at temperature 20-24 C. Investigated animals were f i e l d - c o l l e c t e d from several populations, as a rule geographically d i s t a n t . A l l o g r a f t were mutually exchanged between randomly paired adults or larval individuals (Fig.l). In adults orthotopic or heterotopic skin a l l o g r a f t s were performed (Fig.la) adopting the method of Cohen's experiments (9). Total pigment cell destruction was used as a c r i t e r i o n of the end of a l l o g r a f t v i a b i l i t y . In larval individuals heterotopic t a i l - t i p a l l o g r a f t s were performed (Fig.lb) according to the simple procedure described in the previous papers (5-8) and a pigment cell destruction and/or a l l o g r a f t f l a c c i d i t y were used as a c r i t e r i a of a l l o g r a f t r e j e c t i o n . Some long-term viable heterotopic t a i l - t i p a l l o g r a f ~ were, however, resorbed during the host metamorphic climax simultaneously with host t a i l (Anura) or t a i l - t i p (Urodela) resorption, thus observations had to be ended, nu~-nu-Fanlarvae were g ~ a t developmental stages 31-34 (I0) and urodele larvae at developmental stage 52 ( I I ) . 727
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ALLOGRAFTS IN ADULT AMPHIBIANS (large circles on Fig. 2) The fate of allografts exchanged between adult representatives of four urodele and six anuran species proved that there is no difference of a l l o g r a f t rejection patterns between urodele and anuran amphibians (3,4). According to the a l l o g r a f t rejection pattern the investigated species may be divided into three groups: a, b and c (Fig.2). a) Subacute a l l o g r a f t rejection pattern was characteristic for one urodele (Triturus cristatus) and two anuran species (Rana esculenta and Rana temporaria), b) Typically chronic a l l o g r a f t rejection pattern was characteristic for one urodele (Salamandra salamandra) and three anuran species (Bufo bufo, Bombina bombina and Bombina variegata), c) Wide range~of a l l o g r a f t v i a b i l i t y (acute, subacute and chronic a l l o g r a f t rejection patterns) was characteristic for two urodele species (Triturus vulgaris and Triturus alpestris) and one anuran species (Hyla arborea). ALLOGRAFTS IN AMPHIBIAN LARVAE (smal~ circles and empty circles on Fig.2) Ontogeny of transplantation immunity was investigated in representatives of each of three groups (a, b and c) formed according to a l l o g r a f t rejection pattern in adults, a) All but one tadpole of Rana temporaria rejected small heterotopic t a i l - t i p allografts from unrelated donors very promptly, prior to metamorphosis (data from 6). b) No tadpoles of Bufo bufo and Bombina variegata rejected heterotopic t a i l - t i p allografts before metamorphic climax: all ~grafts were resorbed simultaneously with host t a i l resorption (data from 7). c) Some larvae of Triturus alpestris rejected the heterotopic t a i l - t i p allografts very promptly, others rejected the allografts more slowly, and a majority of larvae retained viable heterotopic t a i l - t i p allografts until metamorphic climax (data from 8).
a)
b)
Fig. 1
~
oQ
Pattern of grafting in adult (a) and larval (b) individuals of anuran and urodele amphibians.
Vol. 8, No. 3
THE AMPHIBIAN MHC
729
INTERPRETATION OF THE RESULTS In order to i n t e r p r e t the obtained data two s i m p l i f y i n g assumption are made. F i r s t , that a l l o g r a f t rejection rate is mainly dependent upon donorhost antigenic d i s p a r i t i e s . Strong transplantation antigens encoded within the MHC evoke rapid a l l o g r a f t rejection while weak antigens encoded outside t h i s complex evoke slow a l l o g r a f t r e j e c t i o n . And second, that larvae tend to react rapidly to strong transplantation antigens encoded by the MHC while they tend to " t o l e r a t e " weak antigenic s t i m u l i (6,12,13). These assumptions allow consideration of a genetic basis for the a l l o g r a f t rejection reaction in representatives of the three amphibian groups: a, b, and c ( F i g . 2 ) .
0 I a)
U Triturus cristatus Rana A esculenta
A
b)
20 I
40 I
I
4~j~-
60 I
I
80 I
i
100 1
~'-':
-~..'...
Oo° • 0
Rana temporaria
Salamandra U salamandra
.
,'m,", . .
°,
a,',
A Bufo bufo A
Bombina bombina
• •
oeoe%~o
•
oe
%
oo
-
A Bombina variegata c)
o~e~°o"
• .
•
°oOo~oO o o
X
.
oo
oo
U Triturus vulgaris Triturus U alpestris
•
•; ; • , ~ ' , ° s
T,--
:'-..:.: . ~ ° - ° ~ p ~ . ~ o - o o o ~ o o
A Hyla arborea
O• 1
i 20
•
I
•
I 40
L
• 000
|
•
I 60
o •
I
I 80
•
•
I 100
Days after grafting
Fig, 2. Fate of individual a l l o g r a f t s in several urodele (U) and anuran (A) species. • - rejection of one skin a l l o g r a f t in adult host; - - rejection of one t a i l - t i p a l l o g r a f t in larval host; o - resorption of one t a i l - t i p a l l o g r a f t during the larval metamorphic climax; a,b,c - three a l l o g r a f t rejection patterns: a - subacute ; b - chronic; c - wide range of reaction.
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Vol. 8, No. 3
a) Adult amphibians of this group as a rule rejected a l l o g r a f t s in a subacute manner therefore a majority of the grafted skin fragments d i f f e r from the host tissues in that they have d i f f e r e n t strong transplantation antigens encoded by the MHC a l l e l e s . Therefore this genetic region of Rana temporaria, Rana esculenta, and Triturus c r i s t a t u s seem to be highly poyT~morphic. Th~Thypothesis is confirmed by the fate of a l l o g r a f t s in Rana temporaria tadpoles: all but one tadpole rejected the a l l o g r a f t s very promptl y , therefore i t is possible that a l l but one of the t a i l - t i p a l l o g r a f t s differed from the host tissue in MHC a l l e l e s . b) Adult individuals of Bufo bufo, Bombina bombina, Bombina variegata, and Salamandra salamandra reacted to a l l o g r a f t s in a chronic manner. No tadpole rejected the t a i i - t i p a l l o g r a f t . Thus i t seems that the grafted tissues differed from the host tissues exclusively in weak transplantation antigens encoded by minor h i s t o c o m p a t i b i l i t y l o c i . Therefore one can assume that these species do not possess the MHC. However, in the l i g h t of the great biological importance of the MHC (14) I prefer the hypothesis that they possess a MHC homologue which is minimally polymorphic (15) or which contains only one h i s t o c o m p a t i b i l i t y a l l e l e . In the l a t t e r case all animals used for investigations share strong transplantation antigens and react exclusively to weak transplantation antigens. c) Rapid a l l o g r a f t rejection observed in some adult individuals and in some larvae of Triturus a l p e s t r i s might be caused by the presence of strong transplantation antigen(s) encoded by the MHC a l l e l e ( s ) in the grafted tissue which are absent in the host tissue. The a l l o g r a f t s rejected slowly by adult individuals and those resorbed during the larval metamorphic climax possibly shared the hosts strong transplantation antigens (the MHC a l l e l e s ) . Thus i t may be concluded that the MHC polymorphism of Triturus a l p e s t r i s , Triturus vulgaris, and Hyla arborea is moderate.
CONCLUSION The results of comparative studies on d i f f e r e n t i a l a l l o g r a f t v i a b i l i t y in adult amphibians confirmed by the fate of a l l o g r a f t s in larval individuals may be explained by a species-specific polymorphism of the MHC a l l e l e . According to this view, the MHC polymorphism, oligomorphism, or even monomorphism can exist in amphibian species. A d d i t i o n a l l y , recent results showed that natural populations of the r e l a t i v e l y polymorphic anuran species, Rana temporaria, contain a much higher percentage of the MHC homozygous indiv-T~-uals (about 25%), than wild mice populations do (16). The simple transplantation technique does not, however, allow the exclusion of a l t e r n a t i v e hypotheses. I) The chronic rejection reaction in some amphibians may be caused by the lack of the MHC homologues in these species. 2) The acute rejection of some a l l o g r a f t s may be caused by cumulative action of several weak transplantation antigens in the absence of the MHC (17). 3) The rate of a l l o g r a f t rejection may be limited by the a c t i v i t y of the immune response gene(s) (18). 4) The rate of a l l o g r a f t rejection may be modulated by some unspecific factors, e.g. the actual status of the host immune system which seems to be seasonal (19, and unpublished data). The hypothesis presented here is a simple explanation of our experimental results but should be v e r i f i e d by experiments conducted using other immunological techniques.
Vol. 8, No. 3
THE AMPHIBIAN MHC
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GENERAL REMARKS Most information about MHC structure and function concerns man and some laboratory mammals (mice, r a t s ) . The main discovery of recent immunology is that immunocompetent cells recognize antigenic epitopes in association with products of t h e i r own MHC (20). Since the MHC polymorphism of mice and man is e x t r a o r d i n a r i l y high, most hypotheses postulate that mutant MHC a l l e l e s are favoured by natural selection: the more MHC a l l e l e s are expressed, the more foreign antigenic epitopes are p o t e n t i a l l y recognizable by the host immunocompetent cells (21). I t is also postulated that polymorphic h i s t o compatibility antigens may operate in some colonial invertebrates (sponges, corals) to save the i d e n t i t y of p a r t i c u l a r colonies (22). In recent excellent review (23), REIMANN and MILLER showed, however, that even mammalian species d i f f e r considerably in the degree of t h e i r MHC polymorphism. Known extremies are mice (with e x t r a o r d i n a r i l y polymorphic r~C) and hamster (with oligo- or even monomorphic MHC). Despite this drastic difference, both these rodent species can cope successfully with pathogens or neoplastic diseases. The authors (23) offered a new, very a t t r a c t i v e hypothesis concerning polymorphism and MHC gene function. They emphasize that MHC polymorphism may be not essential for the functional e f f i c i e n c y of membrane glycoproteins encoded by the MHC genes. Instead, an invariant molecule, encoded by MHC, associated with the d i f f e r e n t antigenic epitopes, would constitute the immunogeniccomplex, which would be effective in stimulating immunocompetent c e l l s . According to this view, the MHC polymorphism may be the r e s u l t of random genetic d r i f t and has no adaptive value in i t s e l f . If this assumption is correct the presence or absence of the MHC polymorphism should correlate with the presence or abcense of chances for genetic d r i f t of species in consideration. The authors proved that such correlation exists in the case of mice and hamster, respectively (23). I f future investigation confirm the presence of the MHC homologues in poikilothermic vertebrates, postulated in the present paper, i t would be interesting to look for correlations of species-specific MHC polymorphism and the behaviour of these animals, especially t h e i r reproductive strategies. ACKNOWLEDGEMENTS The expert secretarial work of Mrs Marit BrekkAs in the preparation of this manuscript is g r a t e f u l l y acknowledged. This work was supported by the Polish Academy of Sciences, research project MR.II.6. and by a grant from the Norwegian Cancer Society. REFERENCES I. DU PASQUIER, L., CHARDONNENS, X. and MIGGIANO, V.C. A major histocompatib i l i t y complex in the toad Xenopus laevis (Daudin). Immunogenetics.l,482, 1975. 2. ROUX, K.H. and VOLPE, E.P. Evidence for a major h i s t o c o m p a t i b i l i t y complex in the leopard frog. Immunogenetics, 2,577,1975. 3. P~YTYCZ, B. The MHC:analyzing a l l o g r a f t rejection patterns in urodele and anuran amphibians. Dev.Comp.lmmunol., 5,5,1981. 4. P~YTYCZ, B. Filogeneza odporno~ci transplantacyjnej kregowc6w. (Phylogeny of vertebrate transplantation immunity). Przegl.Zool.,25,15,1981(In Polish). 5. P[YTYCZ, B. Preliminary report on skin a l l o g r a f t rejection in tadpoles and froglets of Rana temporaria. Dev.Com.lmmunol., 4,747,1980.
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6. P~YTYCZ, B. Ontogeny of transplantation immunity in the common frog, Rana temporaria L. D i f f e r e n t i a t i o n , 20,71,1981. 7. P~YTYCZ, B. Ontogeny of transplantation immunity in three anuran species: Rana temporaria, Bufo bufo and Bombina variegata. Fol.Biol.(Krak6w), 31, 393,1983. S. P[YTYCZ, B., MICHA~EK-ANIKO, D. and ANIKO, K. Ontogeny of transplantation immunity in the newt, Triturus alpestris. Bull.Acad.Polon.Sci.ser.Biol. 29,215,1981. 9. COHEN, N. Tissue transplantation immunity in the adult newt, Diemictylus viridescens. I. The latent phase:healing, restoration of circularion, and pigment cell changes in autografts and a l l o g r a f t s . J.Exp.Zool.163,157,19C#. lO. GOSNER, K.L. A simplified table for staging anuran embryos and larvae with notes on i d e n t i f i c a t i o n . Herpetologica, 16,183,1960. I I . GALLIEN, L. and BIDAUD, O. Table chronologique du d~veloppement chez T r i turus helveticus Razoumowsky. Bull.Soc.Zool.Fr., 84,22,1959. 12. CHARDONNENS, X. and DU PASQUIER, L. Indiction of skin a l l o g r a f t tolerance during metamorphosis of the toad Xenopus laevis: a possible model for studying generation of self tolerance to h istocompatibility antigens. Eur.J.Immunol., 3,569,1973. 13. DI MARZO, S. and COHEN, N. Immunogenetic aspects of in vivo a l l o t o l e rance induction during the ontogeny of Xenopus laevis. Immunogenetics, 16, I03,1982. 14. KLEIN, J. Evolution and function of the major histocompatibility system: facts and speculations. In: The Major Histocompatibility System in Man and Animals. D. G~tze (Ed.) Berlin, Heidelberg, New York: Springer Verlag. 1977, p.339. 15. COHEN, N. Salamanders and the evolution of the major histocompatibility complex. In: Contemporary Topics in Immunobiology. Vol. 9, J.J. Marchalohis and N. Cohen (Ed.). 1980, p.109. 15. P[YTYCZ, B. MHC zygosity in Rana temporaria. Immunogenetics,19,3,1984. 17. GRAFF, R.J., SILVERS, W.K., BILLINGHAM, R.E., HILDEMANN, W.H. and SNELL, G.D. The cumulative effect of histocompatibility antigens. Transplantation, 4,605,1966. 18. COHEN, N. Predictable v a r i a b i l i t y in the response of two newt subspecies (D.v.viridescens and D.v.dorsalis) to f i r s t - s e t a l l o g r a f t s . F o l . b i o l . (Praha), 19,169,1973. 19. P[YTYCZ, B. and BIGAJ, J. Seasonal cyclic changes in the thymus gland of the adult frog, Rana temporaria. Thymus, 5,327,1983. 20. ZINKERNAGEL, R.M., CALLAHAN, C.N., ALTHAGE, A., COOPER, S., KLEIN, P. and KLEIN, J. On the thymus in d i f f e r e n t i a t i o n of "H-K-self-recognition" by T cells: Evidence for dual recognition. J.Exp.Med. 147,882,1978. 2l. KLEIN, J. Generation of diversity of MHC loci: Implications for T-cell receptor repertoire. In: Immunology 80. M. Fougereau and J. Dausset (Eds.) London: Academic Press, 1980, p.239. 22. COHEN, N. Some thoughts about the possible early phylogeny of MHCrestriction. Dev.Comp.lmmunol., 7,775,1983. 23. REIMANN, J. and MILLER, R.G. Polymorphism and MHC gene function. Dev. Comp.lmmunol., 7,403,1983. Received Accepted
: October 1983 : December, 1983