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The immunologic problem of pregnancy
The immunologic The immunologic problem problem of of pregnancy pregnancy V. The V. The effect effect of of estrogen estrogen and and progesterone progesterone on on ollograft ollograft survival survival
RICHARD L. RICHARD L. SIMMONS, SIMMONS, M M .. D.D.ANNE L. ANNE L. PRICE PRICE ARLEENE J. ARLEENE J. OZERKIS OZERKIS ,, N~w
York ,, York
N~w
B .. S B S ..
York York
Th~ administration administration 01 01 r~lativ~ly hh igh igh doses doses 01 01 ~stradiol to to mice mice dela)'s dela)'s the the rejection rejection 01 both 01 both first first -- and and second-set second-set skin skin allografts. allografts. In In contrast. contrast. progesterone progesterone has has no no eOect on on allograft survival. The results are discussed with "fe"nce to the possible in the privileged survival of ovarian, role 01 high local steroid concentrations in testicular, and trophoblastic tissue allografts.
Methods Methods Inbred mice Inbred mice of of the the CRA/J CRA/J and and A/Jax A/Jax strains were strains were used used in in these these experiments. experiments.* * These strains These strains differ differ at at strong strong histocompatihistocompatibility loci bility loci (H-2). (H-2). Donor Donor full full thickness thickness skin skin grafts were grafts were obtained obtained from from A/Jax A/Jax mice mice and and transplanted onto transplanted onto the the dorsal dorsal thorax thorax of of rerecipient adult cipient adult female female CBAl CBAl ll mice mice by by the the method of method of Billingham Billingham and and Medawar.9 Medawar.9 The The grafts were grafts were dressed dressed on on the the sixth sixth postgrafting postgrafting day and day and judged judged for for total total epithelial epithelial death death by by inspection thereafter. inspection thereafter. Recipient Recipient mice mice weigh_ weigh_ ing 20 ing 20 to to 25 25 grams grams were were divided divided into into several several groups as groups as follows: follows: Group Group I, I, no no treatment treatment folfollowing grafting lowing grafting ;; Group Group II, II, 1.0 1.0 mg. mg. estradiol estradiol or estradiol estradiol undecylatet undecylatet injected injected valerate or valerate subcutaneously twice subcutaneously twice weekly; weekly; Group Group III, III, 1.0 1.0 mg. estradiol mg. estradiol subcutaneously subcutaneously three three times times weekly; Group weekly; Group IV, IV, 1.0 1.0 mg. mg. estradiol estradiol subsubcutaneously d<&ily. cutaneously d<&ily. Group Group V V received received 5.0 5.0 mg. mg. progesterone (Proluton) progesterone (Proluton) injected injected subcutane_ subcutane_ ously twice ously twice weekly; weekly; Group Group VI, VI, 5.0 5.0 mg. mg. proprogesterone injected gesterone injected subcutaneously subcutaneously three three times times
THE M THE M E E C C HAN HAN ISM ISM by which by which transtransplanted mouse planted mouse trophoblast trophoblast fails fails to to express express its histocompatibility its histocompatibility antigens antigens is is unclear. unclear. I-a I-a Hulka44 has Hulka has recently recently suggested suggested that that the the proproduction by duction by the the trophoblast trophoblast of of aa high high local local concentration of concentration of steroid steroid hormones hormones may may sucsuccessfully interfere cessfully interfere with with the the immunologic immunologic dedestruction of struction of the the trophoblast. trophoblast. Although Although the the corticosteroids have corticosteroids have long long been been known known to to suppress allograft suppress allograft rejection,5-7 rejection,5-7 other other steroids, steroids, such as such as estradiol, estradiol, testosterone, testosterone, and and progesprogesterone, have terone, have been been found found to to have have no no such such These studies studies have have all all used used relarelaeffect. 55 -- ss These effect. tively small tively small doses doses of of the the compounds compounds tested. tested. If estrogen If estrogen or or progesterone progesterone were were secreted secreted at at the site the site of of trophoblast trophoblast implantation, implantation, aa high high local concentration local concentration might might be be produced. produced. The The present studies present studies were were designed designed to to determine determine the effect the effect of of high high doses doses of of estrogen estrogen and and proprogesterone on gesterone on firstfirst- and and second-set second-set skin skin alloallograft rejection. graft rejection. From the Depar/ment of Surgery, Columb ia University College 0/ 0/ Physicians and Surgeons. Aided by Grant CA"()7466 from the National Institu/es of Health, United Stal,s Public Health Service. • Recipient, Mead-Johnson Award, AmeTlcan Coll,g, of Surgeons.
"AU lDiee "AU lDiee
w~r.
obtainni IrolD obtainni IrolD the the Jackson Jackson Laboratory, Laboratory,
Bar Harbor. Bar Harbor. Maine. Maine.
tEotraciiol valerate tEotraciiol valerate (Delnt~n) and and .. ..tradial tradial unclecylate unclecylate (Delestrec:) were (Delestrec:) were obUliDrd obUliDrd tbroulh tbroulh tile tile eourt eourt... ...yy 01 01 W. W. H. H. Bold of Bold of Ih. Ih. Squibb Squibb Institute Institute lor lor M.cIical M.cIical ae ae.. ..arch. arch. New New BruNwic:k, New BruNwic:k, New Jeney. Jeney.
908 908
Volume 100 Number 7
Effect of estrogen and progesterone on allograft survival
909
Table I. Effect of estradiol and progesterone on the survival of A skin grafts on eBA female mice Group
I II
Treatment None Estradiol 1.0 Estradiol 1.0 Estradiol 1.0 Progesterone Progesterone Progesterone
III IV V
VI
VII
No . of
No. of
16
0 1 0 4 0 0
animals
10
mg. h i..w. mg. t.i.w. mg. o.d . 5.0 mg. h.i.w. 5.0 mg. t.i.w. 5.0 mg. o.d.
ID 10 10 10 10
deaths
2
IMedian survival time ± standard error 9.9 13.5 12.7 15.0 10.3 9.8 9.6
± 0.2 ± 0.7 ~ 0.5 ± 0.8 ~ 0.4± 0.3 ± 0.3
Table II. Effect of estrogen and progesterone on the survival of second-set A skin grafts on eBA female mice Group
V
VI
VIII
Treatment
No. of animals
Days graft survival
None Estradiol 1.0 mg. daily Progesterone 5.0 mg. daily
10 10 10
6, 6, 6, 6, 6, 6, 6, 6, 7, 7 6, 7, 7, 7, a, a, a, a, a, 9 6, 6, 6, 6, 6, 6, 6, 7, 7, 7
weekly; Group VII, 5.0 mg. progesterone injected subcutaneously daily. eBA females previously sensitized to A skin grafts one week pr~viously were divided into three groups of graft recipients: Group VIII received no treatment; Group IX received 1.0 mg. estradiol subcutaneously daily; and Group X received 5.0 mg. progesterone daily. Injections in all groups were begun on the day of grafting and continued until rejection was complete.
Result. The results are summarized in Tables I and II. Daily doses of 1.0 mg. of estradiol resulted in the death of 40 per cent of the recipient CBA mice in the first 5 days following grafting. One death also occurred in recipients of estradiol twice weekly. No deaths occurred in Group III and all survivors of Groups II and III appeared healthy at the termination of the experiment. The administration of estradiol did not appear to interfere with the healing of the grafts when examined on the sixth postgrafting day. The median survival of first-set A skin grafts on all the CBA recipients of estradiol were significantly (p :5 0.05) prolonged compared with the normal survival
on untreated animals. Almost all of the second-set grafts were rejected by untreated CBA recipients at the time of dressing removal 6 days following graftings. Daily estradiol resulted in a slight delay of the rejection of the second-set grafts. The daily administration of 5.0 mg. of progesterone resulted in the death of 20 per cent of the recipient CBA mice in the first week following grafting. No deaths occurred in other recipient groups. Progesterone had no effect on either first-set or second-set allograft survival in this donor-host combination. Comment
Heterotopic allografts of pure mouse trophoblast are known to survive a high degree of pre-existing immunity in both male and female recipients. I, 10 We have recently shown that this property is not dependent on either an extracellular "fibrinoid" antigenic barrier around the trophoblastic cells 2 , a, 11, 12 or on the invasive and phagocytic properties of trophoblastic growth. 2 • 12,13 The possibility still remains that the failure of the trophoblast to express its histocompatibility antigens is due to its endocrinologic secretion. The problem is even more complex, since the nature and quantity of these secretions have
910 Simmons, Price, and Ozerkis
not been clearly defined. Nevertheless, there is a variety of indirect evidence that the trophoblastic giant cells in the placentas of both rats and mice secrete steroid hormones.14 There is also evidence that the local concentration of these hormones may be greater than the systemic concentration ... · III Although the secretion of steroids has not been systematically investigated in ectopic transplants of trophoblast, it is possible that ectopic trophoblast may secrete a high local concentration of steroids in its vicinity without detectable systemic effect. The sophisticated endocrinologic studies of Kirbyt1· I . have definitely proved that transplants possess some degree of endocrinologic activity. Certain other endocrine tissues also are somewhat privileged with respect to allograft survival. lII • 21 The ovary and testis both secrete steroid hormones and are capable of prolonged survival upon transplantation when weak histocompatibility differences are involved. 19 • 20 I t is likely that higher local than systemic concentrations of these hormones are produced by the grafted tissue. In addition, the testis appears to be a relatively privileged site for the survival of implanted allografts of other tissues. 22 Zipper and associates 23 have recently demonstrated that rejection of first-set skin allografts on the endometrium of outbred rats can be delayed by the systemic administration of estrogens. These authors point out that the uterus tends to concentrate such estrogens, 2~ thereby creating a high local concentration at the site of the allograft. No experiments in presensitized recipients are recorded. 2a Lajos and associates 25 have also emphasized the role of estrogens in facilitating prolonged survival of trophoblast transplants in the human. No effect of systemic endocrinologic factors has been detected by other investigators, however.26
REFERENCES
1. Simmons, R. L., and RUDell, P. S.: Ann.
New York Acad. Sc. 129: 35, 1966. 2. Simmons, R. L.: Fed. Proc. 25: 356, 1966. 3. Simmons, R. L., Cruse, V., and McKay, D. G.: AM. J. OUT. & GVNEC. 97: 218, 1967.
April I, 1968
Am. J. Ob.t. I: Gynec:.
Studies of the effect of estrogen on allograft rejection have uniformly concluded that there is no prolongation in the dose ranges studied. ~-I! In fact, estrogens have generally been found to enhance antibody formation. 2H9 The evidence is contradictory and inconclusive with respect to the role of endogenous honnones in the immune capacity of a host. 3n , 31 The present experiments have shown that high systemic levels of estradiol (but not progesterone) will inhibit both first- and secondset skin graft rejection across strong histocompatibility barriers. Since estrogen seems to share this characteristic with corticosteroids and certain synthetic progestational agents,S the possibility that the secretion of high local concentrations of steroid hormones by endocrine grafts may act to interfere with the rejection of such tissue cannot be completely excluded. The hypothesis is more attractive in its potential application to the survival of ovarian or testicular grafts, since such grafts survive only in the face of relatively weak donor-host histocompatibility barriers. lB. 20 However, the hypothesis is less appealing in the case of trophoblast, since the trophoblast survives transplantation into hosts which are highly immune to strong histocompatibility antigens. 1 The mild immunosuppressive influence of steroid honnones would be expected to have little effect under those circumstances. In addition, the presence of healthy trophoblast with its secretory products does not interfere with the intensity of allograft reactions directed against antigenic tissues in its immediate vicinity. 1 Thus, the survival of trophoblast under these highly adverse immunologic conditions is better explained by an alternative hypothesis, namely, an intrinsic deficit of transplantation antigens on the trophoblastic cell surface. 2 , a, 12, la
4. Hulka, J. F.: Penonal communication. S. Billingham. R. E., Krohn, P. L., and Medawar, P. B.: Brit. M. J. 1: 1157, 1951. 6. Krohn, P. L.: J. Endocrinol. 11: 78, 1954. 7. Medawar, P. B., and Sparrow, E. M.: J. Endocrinol. 14: 240, 1956.
Volume 100 Number 7
Effect of estrogen and progesterone on allograft survival
8. Hulka, J. F., Mohr, K, and Lieberman, 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
M. W.: Endocrinology 77: 897, 1965. Billingham, R. E., and Medawar, P. B.: Brit. J. Exper. Bio!. 28: 385, 1951. Kirby, D. R. S., Billington, W. D., and James, D. A.: Transplantation 4: 713, 1966. Kirby, D. R. S., Billington, W. D., Bradbury, S., and Goldstein, D. S.: Nature 204: 548, 1964. Simmons, R. L., and Russell, P. S.: Transplantation 5: 85, 1967. Simmons, R. L., and Ozerkis, A. J.: AM. J. OBST. & GVNEC. 99: 271, 1967. Deane, H. W., Rubin, B. L., Dirks, E. C., Lobel, B. L., and Leipsner, G.: Endocrinology 70: 407, 1962. Csapo, A.: Am. J. Anat. 98: 273, 1956. Zarrow, M. X., Wilson, E. D., Caldwell, A. L., Jr., Yochim, J., and Sawin, P. B.: Ferti!. & Steri!. 11: 370, 1960. Kirby, D. R. S.: J. Reprod. & Ferti!. 10: 403, 1965. Kirby, D. R. S.: J. Endocrino!. 36: 85, 1966. Cock, A. G.: Transplantation Bull. 29: 96, 1962. Linder, O. E. A.: J. Nat. Cancer Inst. 27: 351, 1961.
911
21. Russell, P. S., and Gittes, R. F.: j. Exper. Med. 109: 571,1959. 22. Russell, P. S., and Monaco, A. P.: The Biology of Tissue Transplantation, Boston, 1965, Little, Brown & Company. 23. Zipper, J., Ferrando, G., Siez, G., and Tchernitchin, A.: AM. J. OBST. & GVNEC. 94: 1056, 1966. 24. Roy, S., Mahesh, V. B., and Greenblatt, R. B.: Acta endocrino!. 47: 669, 1964. 25. Lajos, L., Gores, J., Szekely, J., Csaba, I., and Dominy, S.: AM. J. OBST. & GVNEC. 89: 595, 1964. 26. Simmons, R. L., and Russell, P. S.: Transplantation 2: 551, 1964. 27. Von Haam, E., and Rosenfeld, I.: J. Immuno!' 43: 109, 1942. 28. Stem, K., and Davidsohn, I.: J. Immuno!. 74: 479, 1955. 29. Broome, A. W. J, and Lamming, G. E.: J Endocrino!. 18: 229, 1959. 30. Graff, R. j., Hildemann, W. H., and Snell, G. D.: Transplantation 4: 425, 1966. 31. Weintraub, R. M., Churchill, W. H., Jr., Crisler, C., Rapp, H. J., and Borsos, T.: Science 152: 783, 1966.
RICHARD L. RICHARD L. SIMMONS, SIMMONS, M M .. D.D.ANNE L. ANNE L. PRICE PRICE ARLEENE J. ARLEENE J. OZERKIS OZERKIS ,, N~w
York ,, York
N~w
B .. S B S ..
York York
Th~ administration administration 01 01 r~lativ~ly hh igh igh doses doses 01 01 ~stradiol to to mice mice dela)'s dela)'s the the rejection rejection 01 both 01 both first first -- and and second-set second-set skin skin allografts. allografts. In In contrast. contrast. progesterone progesterone has has no no eOect on on allograft survival. The results are discussed with "fe"nce to the possible in the privileged survival of ovarian, role 01 high local steroid concentrations in testicular, and trophoblastic tissue allografts.
Methods Methods Inbred mice Inbred mice of of the the CRA/J CRA/J and and A/Jax A/Jax strains were strains were used used in in these these experiments. experiments.* * These strains These strains differ differ at at strong strong histocompatihistocompatibility loci bility loci (H-2). (H-2). Donor Donor full full thickness thickness skin skin grafts were grafts were obtained obtained from from A/Jax A/Jax mice mice and and transplanted onto transplanted onto the the dorsal dorsal thorax thorax of of rerecipient adult cipient adult female female CBAl CBAl ll mice mice by by the the method of method of Billingham Billingham and and Medawar.9 Medawar.9 The The grafts were grafts were dressed dressed on on the the sixth sixth postgrafting postgrafting day and day and judged judged for for total total epithelial epithelial death death by by inspection thereafter. inspection thereafter. Recipient Recipient mice mice weigh_ weigh_ ing 20 ing 20 to to 25 25 grams grams were were divided divided into into several several groups as groups as follows: follows: Group Group I, I, no no treatment treatment folfollowing grafting lowing grafting ;; Group Group II, II, 1.0 1.0 mg. mg. estradiol estradiol or estradiol estradiol undecylatet undecylatet injected injected valerate or valerate subcutaneously twice subcutaneously twice weekly; weekly; Group Group III, III, 1.0 1.0 mg. estradiol mg. estradiol subcutaneously subcutaneously three three times times weekly; Group weekly; Group IV, IV, 1.0 1.0 mg. mg. estradiol estradiol subsubcutaneously d<&ily. cutaneously d<&ily. Group Group V V received received 5.0 5.0 mg. mg. progesterone (Proluton) progesterone (Proluton) injected injected subcutane_ subcutane_ ously twice ously twice weekly; weekly; Group Group VI, VI, 5.0 5.0 mg. mg. proprogesterone injected gesterone injected subcutaneously subcutaneously three three times times
THE M THE M E E C C HAN HAN ISM ISM by which by which transtransplanted mouse planted mouse trophoblast trophoblast fails fails to to express express its histocompatibility its histocompatibility antigens antigens is is unclear. unclear. I-a I-a Hulka44 has Hulka has recently recently suggested suggested that that the the proproduction by duction by the the trophoblast trophoblast of of aa high high local local concentration of concentration of steroid steroid hormones hormones may may sucsuccessfully interfere cessfully interfere with with the the immunologic immunologic dedestruction of struction of the the trophoblast. trophoblast. Although Although the the corticosteroids have corticosteroids have long long been been known known to to suppress allograft suppress allograft rejection,5-7 rejection,5-7 other other steroids, steroids, such as such as estradiol, estradiol, testosterone, testosterone, and and progesprogesterone, have terone, have been been found found to to have have no no such such These studies studies have have all all used used relarelaeffect. 55 -- ss These effect. tively small tively small doses doses of of the the compounds compounds tested. tested. If estrogen If estrogen or or progesterone progesterone were were secreted secreted at at the site the site of of trophoblast trophoblast implantation, implantation, aa high high local concentration local concentration might might be be produced. produced. The The present studies present studies were were designed designed to to determine determine the effect the effect of of high high doses doses of of estrogen estrogen and and proprogesterone on gesterone on firstfirst- and and second-set second-set skin skin alloallograft rejection. graft rejection. From the Depar/ment of Surgery, Columb ia University College 0/ 0/ Physicians and Surgeons. Aided by Grant CA"()7466 from the National Institu/es of Health, United Stal,s Public Health Service. • Recipient, Mead-Johnson Award, AmeTlcan Coll,g, of Surgeons.
"AU lDiee "AU lDiee
w~r.
obtainni IrolD obtainni IrolD the the Jackson Jackson Laboratory, Laboratory,
Bar Harbor. Bar Harbor. Maine. Maine.
tEotraciiol valerate tEotraciiol valerate (Delnt~n) and and .. ..tradial tradial unclecylate unclecylate (Delestrec:) were (Delestrec:) were obUliDrd obUliDrd tbroulh tbroulh tile tile eourt eourt... ...yy 01 01 W. W. H. H. Bold of Bold of Ih. Ih. Squibb Squibb Institute Institute lor lor M.cIical M.cIical ae ae.. ..arch. arch. New New BruNwic:k, New BruNwic:k, New Jeney. Jeney.
908 908
Volume 100 Number 7
Effect of estrogen and progesterone on allograft survival
909
Table I. Effect of estradiol and progesterone on the survival of A skin grafts on eBA female mice Group
I II
Treatment None Estradiol 1.0 Estradiol 1.0 Estradiol 1.0 Progesterone Progesterone Progesterone
III IV V
VI
VII
No . of
No. of
16
0 1 0 4 0 0
animals
10
mg. h i..w. mg. t.i.w. mg. o.d . 5.0 mg. h.i.w. 5.0 mg. t.i.w. 5.0 mg. o.d.
ID 10 10 10 10
deaths
2
IMedian survival time ± standard error 9.9 13.5 12.7 15.0 10.3 9.8 9.6
± 0.2 ± 0.7 ~ 0.5 ± 0.8 ~ 0.4± 0.3 ± 0.3
Table II. Effect of estrogen and progesterone on the survival of second-set A skin grafts on eBA female mice Group
V
VI
VIII
Treatment
No. of animals
Days graft survival
None Estradiol 1.0 mg. daily Progesterone 5.0 mg. daily
10 10 10
6, 6, 6, 6, 6, 6, 6, 6, 7, 7 6, 7, 7, 7, a, a, a, a, a, 9 6, 6, 6, 6, 6, 6, 6, 7, 7, 7
weekly; Group VII, 5.0 mg. progesterone injected subcutaneously daily. eBA females previously sensitized to A skin grafts one week pr~viously were divided into three groups of graft recipients: Group VIII received no treatment; Group IX received 1.0 mg. estradiol subcutaneously daily; and Group X received 5.0 mg. progesterone daily. Injections in all groups were begun on the day of grafting and continued until rejection was complete.
Result. The results are summarized in Tables I and II. Daily doses of 1.0 mg. of estradiol resulted in the death of 40 per cent of the recipient CBA mice in the first 5 days following grafting. One death also occurred in recipients of estradiol twice weekly. No deaths occurred in Group III and all survivors of Groups II and III appeared healthy at the termination of the experiment. The administration of estradiol did not appear to interfere with the healing of the grafts when examined on the sixth postgrafting day. The median survival of first-set A skin grafts on all the CBA recipients of estradiol were significantly (p :5 0.05) prolonged compared with the normal survival
on untreated animals. Almost all of the second-set grafts were rejected by untreated CBA recipients at the time of dressing removal 6 days following graftings. Daily estradiol resulted in a slight delay of the rejection of the second-set grafts. The daily administration of 5.0 mg. of progesterone resulted in the death of 20 per cent of the recipient CBA mice in the first week following grafting. No deaths occurred in other recipient groups. Progesterone had no effect on either first-set or second-set allograft survival in this donor-host combination. Comment
Heterotopic allografts of pure mouse trophoblast are known to survive a high degree of pre-existing immunity in both male and female recipients. I, 10 We have recently shown that this property is not dependent on either an extracellular "fibrinoid" antigenic barrier around the trophoblastic cells 2 , a, 11, 12 or on the invasive and phagocytic properties of trophoblastic growth. 2 • 12,13 The possibility still remains that the failure of the trophoblast to express its histocompatibility antigens is due to its endocrinologic secretion. The problem is even more complex, since the nature and quantity of these secretions have
910 Simmons, Price, and Ozerkis
not been clearly defined. Nevertheless, there is a variety of indirect evidence that the trophoblastic giant cells in the placentas of both rats and mice secrete steroid hormones.14 There is also evidence that the local concentration of these hormones may be greater than the systemic concentration ... · III Although the secretion of steroids has not been systematically investigated in ectopic transplants of trophoblast, it is possible that ectopic trophoblast may secrete a high local concentration of steroids in its vicinity without detectable systemic effect. The sophisticated endocrinologic studies of Kirbyt1· I . have definitely proved that transplants possess some degree of endocrinologic activity. Certain other endocrine tissues also are somewhat privileged with respect to allograft survival. lII • 21 The ovary and testis both secrete steroid hormones and are capable of prolonged survival upon transplantation when weak histocompatibility differences are involved. 19 • 20 I t is likely that higher local than systemic concentrations of these hormones are produced by the grafted tissue. In addition, the testis appears to be a relatively privileged site for the survival of implanted allografts of other tissues. 22 Zipper and associates 23 have recently demonstrated that rejection of first-set skin allografts on the endometrium of outbred rats can be delayed by the systemic administration of estrogens. These authors point out that the uterus tends to concentrate such estrogens, 2~ thereby creating a high local concentration at the site of the allograft. No experiments in presensitized recipients are recorded. 2a Lajos and associates 25 have also emphasized the role of estrogens in facilitating prolonged survival of trophoblast transplants in the human. No effect of systemic endocrinologic factors has been detected by other investigators, however.26
REFERENCES
1. Simmons, R. L., and RUDell, P. S.: Ann.
New York Acad. Sc. 129: 35, 1966. 2. Simmons, R. L.: Fed. Proc. 25: 356, 1966. 3. Simmons, R. L., Cruse, V., and McKay, D. G.: AM. J. OUT. & GVNEC. 97: 218, 1967.
April I, 1968
Am. J. Ob.t. I: Gynec:.
Studies of the effect of estrogen on allograft rejection have uniformly concluded that there is no prolongation in the dose ranges studied. ~-I! In fact, estrogens have generally been found to enhance antibody formation. 2H9 The evidence is contradictory and inconclusive with respect to the role of endogenous honnones in the immune capacity of a host. 3n , 31 The present experiments have shown that high systemic levels of estradiol (but not progesterone) will inhibit both first- and secondset skin graft rejection across strong histocompatibility barriers. Since estrogen seems to share this characteristic with corticosteroids and certain synthetic progestational agents,S the possibility that the secretion of high local concentrations of steroid hormones by endocrine grafts may act to interfere with the rejection of such tissue cannot be completely excluded. The hypothesis is more attractive in its potential application to the survival of ovarian or testicular grafts, since such grafts survive only in the face of relatively weak donor-host histocompatibility barriers. lB. 20 However, the hypothesis is less appealing in the case of trophoblast, since the trophoblast survives transplantation into hosts which are highly immune to strong histocompatibility antigens. 1 The mild immunosuppressive influence of steroid honnones would be expected to have little effect under those circumstances. In addition, the presence of healthy trophoblast with its secretory products does not interfere with the intensity of allograft reactions directed against antigenic tissues in its immediate vicinity. 1 Thus, the survival of trophoblast under these highly adverse immunologic conditions is better explained by an alternative hypothesis, namely, an intrinsic deficit of transplantation antigens on the trophoblastic cell surface. 2 , a, 12, la
4. Hulka, J. F.: Penonal communication. S. Billingham. R. E., Krohn, P. L., and Medawar, P. B.: Brit. M. J. 1: 1157, 1951. 6. Krohn, P. L.: J. Endocrinol. 11: 78, 1954. 7. Medawar, P. B., and Sparrow, E. M.: J. Endocrinol. 14: 240, 1956.
Volume 100 Number 7
Effect of estrogen and progesterone on allograft survival
8. Hulka, J. F., Mohr, K, and Lieberman, 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
M. W.: Endocrinology 77: 897, 1965. Billingham, R. E., and Medawar, P. B.: Brit. J. Exper. Bio!. 28: 385, 1951. Kirby, D. R. S., Billington, W. D., and James, D. A.: Transplantation 4: 713, 1966. Kirby, D. R. S., Billington, W. D., Bradbury, S., and Goldstein, D. S.: Nature 204: 548, 1964. Simmons, R. L., and Russell, P. S.: Transplantation 5: 85, 1967. Simmons, R. L., and Ozerkis, A. J.: AM. J. OBST. & GVNEC. 99: 271, 1967. Deane, H. W., Rubin, B. L., Dirks, E. C., Lobel, B. L., and Leipsner, G.: Endocrinology 70: 407, 1962. Csapo, A.: Am. J. Anat. 98: 273, 1956. Zarrow, M. X., Wilson, E. D., Caldwell, A. L., Jr., Yochim, J., and Sawin, P. B.: Ferti!. & Steri!. 11: 370, 1960. Kirby, D. R. S.: J. Reprod. & Ferti!. 10: 403, 1965. Kirby, D. R. S.: J. Endocrino!. 36: 85, 1966. Cock, A. G.: Transplantation Bull. 29: 96, 1962. Linder, O. E. A.: J. Nat. Cancer Inst. 27: 351, 1961.
911
21. Russell, P. S., and Gittes, R. F.: j. Exper. Med. 109: 571,1959. 22. Russell, P. S., and Monaco, A. P.: The Biology of Tissue Transplantation, Boston, 1965, Little, Brown & Company. 23. Zipper, J., Ferrando, G., Siez, G., and Tchernitchin, A.: AM. J. OBST. & GVNEC. 94: 1056, 1966. 24. Roy, S., Mahesh, V. B., and Greenblatt, R. B.: Acta endocrino!. 47: 669, 1964. 25. Lajos, L., Gores, J., Szekely, J., Csaba, I., and Dominy, S.: AM. J. OBST. & GVNEC. 89: 595, 1964. 26. Simmons, R. L., and Russell, P. S.: Transplantation 2: 551, 1964. 27. Von Haam, E., and Rosenfeld, I.: J. Immuno!' 43: 109, 1942. 28. Stem, K., and Davidsohn, I.: J. Immuno!. 74: 479, 1955. 29. Broome, A. W. J, and Lamming, G. E.: J Endocrino!. 18: 229, 1959. 30. Graff, R. j., Hildemann, W. H., and Snell, G. D.: Transplantation 4: 425, 1966. 31. Weintraub, R. M., Churchill, W. H., Jr., Crisler, C., Rapp, H. J., and Borsos, T.: Science 152: 783, 1966.