The MHC: Analyzing allograft rejection patterns in urodele and anuran amphibians

DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY, Vol. 5, pp. 5-14, 1981 0145-305X/81/010005-10502.00/0 Printed in the USA. Copyright (c) 1981 Pergamon Press Ltd. All rights reserved.

~HE MHC: ANALYZING AI~OGRAFT REJECTION PATTERNS IN URODELE AND ANURAN AN~HIBIANS

Barbara P~ytycz Department of Comparative Anatomy, Jagiellonian University, M. Karasla 6, 30-060 Krak6w, Poland

INTRODUCTION One question which ~ a n o b i o l o g i s t s try to answer is when t h e m a j o r h i s t o c o m p a t i b i l i t y complex (MHC) f i r s t a p p e a r e d d u r i n g v e r t e b r a t e e v o l u t i o n ( 1 ). A c c o r d i n g t o a p r i m a r y h y p o t h e s i s , p h y l o g e n e s i s of t h e MHC may r e f l e c t c o n v e r g e n t gene e v o l u t i o n . W e l l - r e c o g n i z e d f u n c t i o n a l m a r k e r s o f t h e MHC ( i . e . , a c u t e g r a f t r e j e c t i o n , l e t h a l @vH, and s t r o n g lV~C r e a c t i o n s ) h a v e b e e n documented i n t e l e o s t s , a n u r a n a m p h i b i a n s , b a r d s , and mammals, t h u s t h e ~ C may have d e v e l o p e d a t l e a s t f o u r s e p a r a t e t i m e s d u r i n g v e r t e b r a t e e v o l u t i o n ( 2 , 3 , 4 ) . For s e v e r a l y e a r s , Cohen and c o - w o r k e r s have p r o p o s e d an alternative hypothesis assnm~ng that a genetic complex, fully or partially homologous with the mammalian ~4C, also exists in other taxonomic groups, particularly in urodele amphibians, where experimental data are more numerous (5,6,7). In addition, some anuran amphibian species (4,8,9,10) have been shown to exhibit a chronic allograft rejection pattern similar to that present in most urodele amphibians tested so far (.11,12,13), and that some urodele amphibians, by contrast, ( 12,14 18 ~ react to skin allografts in a manner characteristic of ranid anurans (19). This review supports the proposition that a division of Amphibia according to rates of reaction against skin allografts does not coincide with the existing division into Urodela and Anura. For this purpose certain results of experiments reported e--1"g~nere on transplantation immunity in several Polish amphibian species are reviewed and discussed (9,10,17-20).

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Do.ujs o~'ter g r o ~ . ~ 9 Figure I Survival of S k l n A l l o g r a f t s in Several A m p h i b i a n Species• Large circles - survival of individual grafts in adult hosts, small circles survival of indlvidual grafts in tadpoles Ctp). x - experiments conducted now.

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STRENGTH OF TRANSPLANTATION ANTIGENS It is generally accepted that the rapidity of graft rejection is related to: I/ number and "strength" of transplantation alloantigens possessed by the donor and not by the recipient and 2/ the 1--.une response capacity of the recipient. Transplantation antigens in all mammals and birds are coded by genes divided into two categories. First, the emaJor" genes code for transplantation antigens evoking acute tissue allograft reactions and are located within the major histocompatibility complex (MHC). Second, the "minor" genes are located outside the MHC and code for cell surface products ("weak" antigens ) which evoke chronic allograft reactions (1,4). It should be stressed, however, that acute reactions can be attributed to synergistic action of certain combinations of multiple "weak" antigens (29). The I m m ~ e response capacity is genetically controlled, and in mammals the genes which code for it belong to the MHC (1,4).

G E ~ T I C CONTROL AND THE LYMPHOID SYSTEM The genetically-controlled ~mmune response capacity of a recipient towards a given panel of alloantigenic disparities has been found in amphibians (12,15). However, I do not exclude that the rate of Immunological reactions may be limited in some amphibians by the structure of their lymphoid organs (30). A recognizable homologue of the MHC has been discovered for the pipid anuran, Xenopus laevis (31). Moreover, experiments on larvae of Rana pipiens (28) also strongly supports the presence of a homologous locus in the genus Rana. Therefore, acute allograft rejection in tadpoles of R.temporaria (25) may be interpreted as resulting from strong antlgenic disparities and strong ~mmunologic potential. Tadpoles of the genus Rana possess a unique lymphoid organ called the lymph g!am-~-~32,33, 34). Consequently, subacute reactions to allografts in adult ~ . ~ is also caused by strong antigenic disparities; proAonga~xon of allograft viability compared with larvae results from an impairment of immunologic reactivity. This impairment in turn may result from rearrangement of the lymphoid system during metamorphosis (32,34) and/or from the u n s o w n suppressor factors C cells and/or antibodies ~ . The same type of transplantation response as in adult individuals of ~.temporaria was found in adults of R.esculenta~19).

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URODELE AND ANURAN RESPONSES COMPARED In T.vulgaris (17,18) and T.alpestris (18)some first and second-s~t allografts were acutely rejected prior to the tenth postoperative day (Table 1, Fig. I). This rate of reaction was frequent in second-set and subsequent allografts in T.cristatus (17,18,20). In contrast, graft viability of less tha~ ten days did not appear in any adult anuran allografts (8,9,10,19). Thus adult newts C genus Triturus )may be better responders to allografts than adult anurans. Taking into consideration, however, that acute rejection of several first-set allografts in T_.vulgaris (17,18) and T_.alpestris (18) is comparable to acute allograft rejection in immunized individuals of T.cristatus, extremely rapid rejection of some sensitizing skin ~ragments may be caused by prior Immunlzation of these particular hosts with histocompatibility antigens of unknown invaders possessing identical specificities or those cross-reactive with alloantigens. Consequently, I suggest that acute reaction to skin allografts in tadpoles (genus Rana (25) might be caused by pre~,,munization to alloantigens vta--~e intestine since they are frequently cannibalistic. Prolongation of skin allograft viability after oral application of anti-lymphocytic serum has been found in rats (35). It should be stressed that there is no stomach in the larvae of anuran amphibians (36~, thus the lack of acid reaction might favor the passage of glycoprotein material directly into the bloodstream. This supposition may be readily tested in stringently controlled laboratory conditions. Preimmunization usually decreases but in some conditions it can prolong graft survival (37), therefore prolongation of allograft viability during ontogeny (25) or in response to repeated transplantation stimuli ( 13,17,18 ) is not surprising. Because of a great similarity of allograft reactions in .cristatus C 17,18,20 ) and T.alpestris ( 18 ) with those of Rana 1 9 - ~ that in these--two phylogenetically distant genera, subacute allograft rejection is caused by strong antigenic disparities and that these "strong" antigens are coded by the locus homologous to the major histocompatibility complex of Xenopus (31). In T_.vulgaris (13,17,18 ~ I observed all three types of reactions to allografts: acute, subacute and chronic. The chronic reaction, relatively frequent in individuals of this species can increase the MST value (41 days ) in T.vulgaris versus F~Ts of the two remaining species analyze~ using similar conditions. I suppose that long-term survival of grafts in T.vulgaris reflects antigen sharing between tested donors and hosts. However, I do not exclude the possibility that acute rejection of some grafts in T.vulgaris and in T.alpestris, apart from or instead of the reasons mentioned above, might re£1eot differences in major antigens plus the cumulative interaction of some "weak" transplantation antigens.

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I observed a quite different picture of transplantation reactions in three anuran species: Bufo bufo CI0), Bombina variegata and B.bombina (8,9~. The ~ c a - T ~ chronic rejection of all allograJ~ts also may have been due to weak transplantation antigenic disparities and to a consistently deficient immune response capacity. Moreover, "strong" histocompatibility antigens may not exist, but I prefer the hypothesis: a "major" histocompatibility locus does exist in these genera but it is minimally polymorphic, thus in the samples of anlmAls which I studied, individuals only shared "strong" transplantation antigens.

CONCLUSIONS:

AP~HIBIAN MHC

Despite the fact that present speculations are based exclusively on allograft reactions and do not concern the remaining functional markers of MHC (i.e., GvH and MLC reactions~ I think that Cohen's speculations (6) on the hypothetical homologue of the MHC in urodeles are also valid for chronically reacting anuran species. If chronic allograft reactions in some urodele and anuran species reflects the complete absence of the MHC, and if rapid allograft rejection in other urodele and anuran species reflects the presence of an MHC homologue, then the MHC has evolved several times during amphibian evolution, i,e., during the evolutionary processes of ancestors of contemporary amphibian genera or even particular species. I prefer, however, the hypothesis that all amphibians, or even all ectothermic vertebrates, have a complex homologous to the MHC of endothermlc vertebrates, but that this complex can exist in hundreds of forms. There is strong support that genetic organization of the MHC may differ dramatically even in closely related families of mammals (38~. Therefore, one can expect the existence of decidedly stronger differences between decidedly older families, genera or even species of amphibians. The simplest explanation is that these differences concern the degree of polymorphism of the loci which constitute the MHC of particular amphibian species.

ACKNOWI~DGEMENTS I would like to thank Prof. Dr. A. Skowron-Cendrzak and Prof. Dr. H. Szarskl for invaluable discussion and critical revision of the manuscript.

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REFERENCES

I. KLEIN,J. Evolution and function of the major histocompatlbility system: facts and speculations. In: The Major Histocompatibility System in ~ n and Animals. D.GStze (Ed.). Berlin, Heidelberg, New York: Sprlnger-Verlag. 1977, P.339. 2. COHEN,N. and BORYSENKO,M. Acute and chronic graft rejection: possible phylogeny of transplantation antigens. Transplantation Proc., 2, 333, 1970. 3. CO.HEN,N. Immunologic diversity within the class ~ . In. Comparative Tmmunology. J.J.Marchalonis ~ E d . ~ 3 ~ e l l , London, 1976, p.209. 4. COHEN,N. and COLLINS,N.H. Major and minor histocompatlbility systems of ectothermic vertebrates. In:The Major His~compatibility System in Man and Animals. D.GStze (Ed.). Berlin, Heidelberg, New York: Springer-Verlag. 1977, p.313. 5. COHEN,N. Phylogeny of the major histocompatibility complex: theoretical implications of studies with urodele amphibians. In: Phylogeny of Thymus and Bone Marrow - Bursa Cells. R.K. Wright and E.L.0ooper (Eds.). North-Holland Publishing Company, Amsterdam, New York, Oxford. 1976, p. 169. 6. COHEN,N. Evolution of the major histocompatibility complex in vertebrates: a saga of convergent gone evolution? Transplantation Proc., 11, 1118, 1979. 7. COHEN,N. Salamanders and the evolution of the major histocompatibility complex. In: Contemporary Topics in Tmm~tnobiology. Vol.9. J.J.Marchalonis and N.Cohen (Eds.). 1980, p. I09. 8. P&YTYCZ,B., BARA~ZIEJ,A. and KOSNO,A. 0hronic rejection of skin grafts in the fire-bellied toads, Bomblna ~omblna ~ L.~ and B.variegata (L.). Acta Biol.Cracov.,Zool., 21,193,1978. 9. P&YTYCZ,B. Rejection of skin allo- and xenografts in the fire-bellied toads, Bombina bombina(Z.) and B.variegata (~.) Folia Biol. Krakdw ~ , 19~O. 10. P&YTYCZ,B. Rejection of skin allografts in the common toad, Bufo bufo L. Bull.Acad.Polon.Sci.,ser.Biol.,27,879,1979. 11. COHEN,N. Chronic skin graft rejection in the Urodela. I. A comparative study of first- and second-set allograft reactions. J.Exp.Zool., 167, 37, 1968. 12. COHEN,N. Tissue transplantation Immunity and immunologic memory in Urodela and Apoda. Transplantation Proc., 2, 275, 1970.

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13. P~YTYCZ,B. The rejection of skin allografts in three populations of Trlturus vulgaris (L.). Folla Biol. (Krak6w), 22, 405, 1974. 14. COHEN,N. and HILDEMANN,W.H. Population studies on allograft rejection in the newt, Diemict21us viridescens. Transplantation, 6, 208, 1968. 15. COHEN,N. Predictable variability in the response of two newt subspecies ( D.v.viridescens and D.v.dorsalis to first-set allografts. ~oT.biol. (Praha), I ~ , - I ~ - ' ~ . ) 16. P~YTYCZ,B. Strong histocompatibility antigens in Urodele amphibians. Folla biol. (Praha), 23, 72, 1977. 17. P&YTYCZ,B., MAKIEL,K., SKOWRONSKA,A. and ROSZAK A. Rejection of skin allografts in two geographically distant populations of Triturus vul~aris (L.] and T.cristatus (Laurentl). Bull. Acad.Polon.Sci.,ser.Biol., 26,-431, 1978. 18. P~YTYCZ,B. Odrzucanie przeszczepdw sk6rnych u trzech gatunkdw traszek: Triturus vulgaris, ~.alpestris i T.cristatus (Amphibia, Ur0dela). Immunologia Polska, 5 ~ ~ . 19. P&YTYCZ,B. and SEMIK,D. Rejection of skin allo- and xericgrafts in the grass frog, Rana temporarla and the edible frog, R.esculenta. Arch.Im~un.Therap.Exp., 28, 625, 1980. 20. PLYTYCZ,B. The fate of ten successive skin allografts in Triturus cristatus CLaur.). Bull.Acad.Polon.Scl. ,set.Biol., 1979.

21. HILDEFiiNN,W.H. and HAAS,W. Homotransplantatlon Immunity and tolerance in the bullfrog. J.Ymmunol., 83,478, 1959. 22. COHEN,N.TIssue transplantation immunity in the adult newt, Diemictylus viridescens. I. The latent phase: healing, restoration of circulation, and pigment cell changes in autografts and allografts. J.Exp.Zool., 163,157, 1966. 23. FOLPE,E.P. Fate of neural crest homotransplantatlon in pattern mutants of the leopard frog. J.Exp.Zool., 157, 179, 1964. 24. OOHEN,N. Tissue transplantation immunity in the adult newt, Diemictylus viridescens. II. The rejection phase: firstand second-set allograft reactions and lack of sexual dlmorphism. J.Exp.Zool., 163, 173, 1966. 25. P~YTYCZ,B. Preliminary report on skin a11ograft rejection in tadpoles and froglets of Rana temperaria. Develcp.Oomp. Immunol., 4, 747, 1980.

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26. LITCHFIELD,J.T. A method for rapid graphic solution of tlme-per cent effect curves. J.Pharmacol.Exp.Ther., 98, 399, 1949. 27. BOVBJERG,A.M. Rejection of skin homografts in larvae of Rana pipiens. J.Exp.Zool., 162, 69, 1966. 28. ROUX,K.H. and VOLPE,E.P. Evidence for a major histocompatibillty complex in the leopard frog. Tmmunogenetics, 2, 577, 1975. 29. GRAFF,R.J., SILVERS,W.K., BILLINGHAM,R.E., HILDEF~%NN,W.H. and SNELL,G.D. The cumulative effect of histocompatibility antigens. Transplantation, 4, 605, 1966. 30. P~YTYCZ,B. Filogeneza ukladu odpornosciowego kr~gowc6w. Post~py Biologii Komdrki, in press. 31. DU PASQUIER,L., CHARDONI~NS,X. and MIGGIANO,V.C. A major histocompatibility complex in the toad Xenopus laevis (Daudin). Tmmunogenetics, I, 482, 1975. 32. SZARSKI,H. Corpus lymphaticum subdermale in the frogs: Rana esculenta, R.temporaria and R.terrestris. Bull.de l'AcaS~m'fe Polonaise d~s Sciences et de~ Lettres. Ser.B. 2, 79, 1938. 33. COOPER,E.L., BROWN,B.A. and WRIGHT,R.K. New ideas on amphibian ~mmunity: the lymph gland: a generator of both T and B cells. Amer.Zool., 15, 85, 1975. 34. COOPER,E.L. Tmmunlty mechanisms. In: Physiology of the Amphibia. Vol.3. B.Lofts (Ed.~. New York, San Francisco, London. Academic Press, 1976, p.467. 35. SEIFERT,J., RING,J. and BRENDEL, W. Prolongation of skin allograft after oral application of ALS in rats. Nature, 249, 776, 1974. 36. GRIFFITHS,J. The form and function of the fore-gut in anuran larvae (Amphibia, Sallentia~ with particular reference to the manlcotto glandulare. Proc.Zool.Soc. London, 137, 249, 1961. 37. JONKER,M., PERSIJN,G.G., PARLEVLIET,J., FREDERIKS,E. and VAN ROOD,J.J. Influence of previous ~mmunization on skin graft survival. Transplantation, 27, 250, 1979. 38. CLARK,E.A. and HARMON,R.C. The phylogeny of m~-,,alian histocompatibility Immunogens. Transplantation Proc., 11, 1113, 1979.