48
immunology today, March 1981
in-vitro C F U - c suppressor activity 12- However, upon contact with pokeweed mitogen, T o cells, but not T odepleted cell populations, can efficiently suppress colony formation of both autologous a n d allogeneic marrow cells u'. This activity is mediated by the supernatant of T o cell suspensions cultured overnight, and is abrogated by irradiation 16. However it is still unclear whether T G cells regulate hemopoiesis in normal conditions in vivo. T h e fact that cells capable of suppressing the in-vitro growth of myeloid and erythroid progenitor cells can be easily generated in vitro after mitogen or antigen stimulation suggests that a similar T-cell activation m a y occur in vivo. For example, transient p a n c y t o p e n i a occurring during virus infections ~8 may result as a consequence of hemopoietic suppression by virus-activated T cells. F u r t h e r investigations along this line are clearly needed. Thus, T cells which regulate hemopoiesis should be further characterized by analyzing other Tcell markers 20 In addition, activation of suppressor T cells in vitro should be induced by naturally occurring agents such as bacteria or viruses. ANDREA
BACIGALUPO
LORENZO
MORETTA
Department of Hematology, Oapedale San Martino, 16132 Genova, Italy; and the Ludwig Institute for Cancer Research, Lausanne Branch, 1066 Epalinges , &vitz erland.
References 1 Parkman, R. (1978) C/in. Hematol. 7, 482 2 Trainin, N. and Resnitzky, P. (1969) Nature (London) 221, 1154
3 Speck, B., Gluckman, E., Haak, H. L. and Van Rood, J. L. (1977) Lancet ii, 1145 4 Hoffman, R., Zanjani, E. D., Lutton, J. D., Zalusky, R. and Wasserman, L. R. (1977) New Engl. J. Med. 296, 10 5 Haak, H. L., Goselink, H. M., Sabbi, L., Veenhol, W. F. J., Bogers, A. J. J. C. and Waayer, J. L. M. (1979) Haematot. Btutttransfus. 24, 259 6 Ascensao, J. A., Pahwa, R., Kagan, W., Hansen, J., Moore, M. A. and Good, R. A. (1976) Lancet i, 669 7 Kagan, W. A., Ascensao, J. R., Fialk, M. A., Coleman, M., Valera, E. D., and Good, R. A. (1979) Am.J. Med., 65, 444 8 Faille, A., Barret, J. A., Balitrand, N., Ketels, F., Gluckman, E. and Najean, J. (1979) Brit. J. Haematol. 42, 371 9 Torok-Storb, B., Siffe,C., Storb, R. and Thomas, E. D. (1980) Blood 55, 2l 1 10 Gorski, A., Gaciong, Z., Korzak, G., Skopinska, E., MoscickaWesolowska, M. (1980) Exp. Hematol. 8 (suppl. 7), 90 11 Bacigalupo, A., Podesta', M., Raffo, M. R., Piaggio, G., Van Lint, M. T. and Marmont, A. M. (1980) Exp. Hematol. 8, 795 12 Bacigalupo, A., Podesta', M., Mingari, M. C., Moretta, L., Van Lint, M. T. and Marmont, A. M. (1980)J. Immunol. 125, 1449 13 Bagby, G. C., Goodnight, S. H., Mooney, W. M. and Richter Book, K. (1979) Blood54, 322 14 Bacigalupo, A., Podesta', M., Van Lint, M. T. and Marmont, A. M., (1981) Brit. J. Haematol. (in press) 15 Moretta, L., Webb, S. R., Grossi, C. E., Lydyard, P. M. and Cooper, M. D. (1977)J. Exp. Med. 146, 184 16 Bacigalupo, A., Podesta', M., Mingari, M. C., Moretta, L., Piaggio, G. and Marmont, A. M. (1981) Blood (in press) 17 Banisadre, M., Ascensao, J. L., Kay, N. E., Ash, R. C. and Zanjani, E. D. (1980) Ex)~. Hematol. 8 (suppl. 7) 44 18 Lutton, J. D. and Levere, R. D. (1980) Exp. HematoL 8 (suppl. 7) 127 19 Camitta, B. M. (1980) Haematol. Bluttraansfus. 24, 39 20 Moretta, L., Moretta, A., Canonica, G. W., Bacigalupo, A., Mingari, M. C. and Cerottini, J.-C. (1981) hnmanoL Rev. 56 (in press)
Prospects for vaccinating against pregnancy Current contraception leaves a lot to be desired. To the growing catalogue of complaints about present measures to reduce fertility has been a d d e d recent concern about the possibly harmful consequences of vasectomyl, 2 T h e r e is thus currently a search for new technology, a sort of third generation contraceptive, to fill the gap. One idea that is theoretically appealing is to vaccinate against pregnancy. Vaccination is a simple procedure with a long history of success in preventing the invasion of foreign organisms into the h u m a n body. W h y not use it to prevent the invasion of the female by sperm and embryQ? The p r o b l e m is to devise a vaccine which combines the potency necessary to ensure an acceptable reduction in fertility, with specificity, i.e. the avoidance of autoimmunity, since sperm a n d embryo do not differ extensively from the host in antigenic terms. Another i m p o r t a n t requirement is that of reversibility, at least where women m a y wish to conceive sometime after receiving the vaccine. ©Elsevier/North-Holland BicJmedicalPress 1981
A variety of antigens are currently under scrutiny as possible targets for vaccination 3,4,s,6. These include: sperm-specific antigens, perhaps the most promising of which, at the moment, is the lactic dehydrogenase isoenzyme which is present only in the sperm; antigens of the zona pellucida that surrounds the egg, which unfortunately have the potential to provoke anti-ovarian autoimmunity; placental antigens; and antigenic components of pregnancy-specific hormones. T h e latter have received the greatest emphasis in terms of publicity a n d funding by the W o r l d Health O r g a n i z a t i o n ' s task force on h u m a n reproduction. At present, the principal hormone target is h u m a n chorionic gonadotropin (HCG). This molecule is produced by cells of the fetally derived trophoblast and its continued presence is crucial for maintaining pregnancy. M u c h effort has been made, therefore, to immunize specifically against this hormone. One difficulty is that H C G shows extensive cross-reactivity with other hormones, such as luteinising hormone,
immunology today, March 1981
which are important for maintaining normal sexual cycling. Some very elegant protein chemistry has been used in an attempt to isolate those areas of the molecule specific to H C G . But the difficulty so far has been in using those peptides to obtain an i m m u n e response potent enough to inhibit fertility3,4,6. This delay in the development of the H C G work has stimulated a search for other potential antigenic targets. A n attractive possibility resides in the socalled oncofetal antigens, of which the murine F9 teratocarcinoma antigen is the prototype. J a c o b and his colleagues have published a long series of papers documenting the presence of F9 antigen in the male germ line, on sperm and in the early embryoL It disappears shortly after i m p l a n t a t i o n and so far it has not been found anywhere in the adult female body. It also cross-reacts extensively with a similar antigen found in humans. It seems to be a rather i m p o r t a n t cell-surface component because xenogeneic antibodies p r o d u c e d against it, and their F a b fragments, can inhibit development at very specific stages, a r o u n d the time of implantation 8. These properties suggest that the antigen could be a candidate for an "antipregnancy vaccine for two reasons. I m m u n i t y against it should not cause a u t o i m m u n i t y in the female, and mouse experiments m a y directly translate into an ultimately effective h u m a n vaccine. F u r t h e r m o r e , work presented at a recent workshop on early embryonic antigens in Lake Placid, New York, indicates that a number of monoclonal antibodies have been p r e p a r e d to this type of antigen~ and that some seem to recognize c a r b o h y d r a t e determinants (to be published). It is therefore interesting that H a m i l t o n el al. 9, and more recently W e b b 1°, have used teratocarcinoma cells in mice to bring about a reduction in fertility by vaccination. Although neither one of these attempts achieved total infertility the fact that they worked at all was rather remarkable as there was no obvious attempt to immunize specifically for the reproductive tract. In fact there has been surprisingly little emphasis given to specific attempts to immunize locally for antigens in the reproductive tract. Recent work indicates that IgA precursors originating in the mesenteric lymph nodes can selectively migrate, upon adoptive transfer, to the female reproductive tract, and that this migration is under hormonal controP~,~2, ~3. Although this does not prove that oral i m m u n i z a t i o n will specifically immunize the reproductive tract, work on m a m m a r y - g l a n d i m m u n i t y has p r o v i d e d an elegant precedent for such a prospect. It has long been clear that breast milk is selectively enriched for antibodies directed against enteric antigens ~4. Indeed, an a p p a r e n t l y effective folk remedy, in I n d i a and elsewhere, is the application of breast milk to infected wounds. T h e basis for this seems to be that gutderived IgA producing cells will selectively migrate to the breast under the influence of sex hormones ~5. In
49
the future one might expect to see the results obtained from antifertility research, which is concentrated on finding a proper antigenic target on sperm or embryo, combined with those from research on the specific directing of immunity in the reproductive tract. It is not clear at this point what form an effective h u m a n anti-pregnancy vaccine will take. It could come from a completely unexpected source. For example, Lopo and Vacquier have lately reported that rabbits vaccinated against sea urchin sperm produce anti-sperm antibody which not only reacts with rabbit sperm but also cross-reacts against sperm derived from animals of seven different phyla 16. It also reacts with h u m a n sperm. It is possible that the isolation and characterization of the active component in sea urchin sperm may result in an effective means of controlling our population growth. T h e point to emphasize is that at this stage of development we need a lot more information before we know which p a r t i c u l a r a p p r o a c h will allow us to provide the technical means for effective population control via vaccination. Nevertheless a n u m b e r of reasonable candidates are emerging and u n d o u b t e d l y there will be more before the p r o b l e m is solved. THOMAS G. WEGMANN
Department of Immunology, University of Alberta, Edmonton, Canada T5~ 2H7.
References 1 Clarkson, T. B. and Alexander, N. J. (1980)J. c/in. Invest. 65,
15-25
2 Wegmann, T. G. (1980) lmmunol. Today. 1, 4 3 Stevens, V. C. (1978) Bull. of the World Health Organization 56 (2), 179-192 4 Talwar, G. P. (1979) Int. J. of Gynaecol. and Obstet. 15,410-414 5 Loke, Y. W. (1980) Immunology and lmmunopalhology of the Human Foetal-Maternal Interaction. Elsevier/North Holland Press, Inc. Amsterdam. 6 Dhindsa, D. and .Schumacker, G., eds. (1980) Immunological Aspects of Infertility and Fertihty Regulation. Elsevier/North Holland, Inc., Amsterdam. 7 Jacob, F. (1977) Immunological Rev. 33, 3-32 8 Kemler, R., Babinet, C., Eisen, H. and Jacob, F. (1977) Proc. Nat. Acad. &'i., U.S.A., 74, 4449-4452 9 Hamilton, M. S., Beer, A. E., May, R. D. and Vitetta, E. S. (1979) Transplant. Proc. 11, 1069-1072 10 Webb, C. G. (1980)Biol. of Reproduction 22, 695-704 11 McDermott, M. R. and Bienenstock, J. (1979) J. lmmunol. 122, 1892-1898 12 McDermott, M. R., Clark, D. A., and Bienenstock, J. (1979) j . Immunol. 124, 2536-2539 13 Wira, C. R. and Sandoe, C. P. (1977) JVature (London) 268, 534-536 14 Ahlstedt, S., Carlson, B., Fallstrom, S. P., Hanson, L. A., Holmgren, J., Lidin-Janson, G., Lindblad, B. S., Jodal, U., Kaijer, B., Sohl-Aherlund, A. and Wadsworth, C. (1977) in Immunology of the Gut. Ciba Foundation Symposium 46, 115 Elsevier Press, N. Y. 15 Weisz-Carrington, P., Schrater, A. F., Lamm, M. E. and Thorbecke, G. J. (1979) Cell. lmmunol. 44, 343-351 16 Lopo, A. and Vaequier, V. D. (1980) Nature (London) 288, 397-399
immunology today, March 1981
in-vitro C F U - c suppressor activity 12- However, upon contact with pokeweed mitogen, T o cells, but not T odepleted cell populations, can efficiently suppress colony formation of both autologous a n d allogeneic marrow cells u'. This activity is mediated by the supernatant of T o cell suspensions cultured overnight, and is abrogated by irradiation 16. However it is still unclear whether T G cells regulate hemopoiesis in normal conditions in vivo. T h e fact that cells capable of suppressing the in-vitro growth of myeloid and erythroid progenitor cells can be easily generated in vitro after mitogen or antigen stimulation suggests that a similar T-cell activation m a y occur in vivo. For example, transient p a n c y t o p e n i a occurring during virus infections ~8 may result as a consequence of hemopoietic suppression by virus-activated T cells. F u r t h e r investigations along this line are clearly needed. Thus, T cells which regulate hemopoiesis should be further characterized by analyzing other Tcell markers 20 In addition, activation of suppressor T cells in vitro should be induced by naturally occurring agents such as bacteria or viruses. ANDREA
BACIGALUPO
LORENZO
MORETTA
Department of Hematology, Oapedale San Martino, 16132 Genova, Italy; and the Ludwig Institute for Cancer Research, Lausanne Branch, 1066 Epalinges , &vitz erland.
References 1 Parkman, R. (1978) C/in. Hematol. 7, 482 2 Trainin, N. and Resnitzky, P. (1969) Nature (London) 221, 1154
3 Speck, B., Gluckman, E., Haak, H. L. and Van Rood, J. L. (1977) Lancet ii, 1145 4 Hoffman, R., Zanjani, E. D., Lutton, J. D., Zalusky, R. and Wasserman, L. R. (1977) New Engl. J. Med. 296, 10 5 Haak, H. L., Goselink, H. M., Sabbi, L., Veenhol, W. F. J., Bogers, A. J. J. C. and Waayer, J. L. M. (1979) Haematot. Btutttransfus. 24, 259 6 Ascensao, J. A., Pahwa, R., Kagan, W., Hansen, J., Moore, M. A. and Good, R. A. (1976) Lancet i, 669 7 Kagan, W. A., Ascensao, J. R., Fialk, M. A., Coleman, M., Valera, E. D., and Good, R. A. (1979) Am.J. Med., 65, 444 8 Faille, A., Barret, J. A., Balitrand, N., Ketels, F., Gluckman, E. and Najean, J. (1979) Brit. J. Haematol. 42, 371 9 Torok-Storb, B., Siffe,C., Storb, R. and Thomas, E. D. (1980) Blood 55, 2l 1 10 Gorski, A., Gaciong, Z., Korzak, G., Skopinska, E., MoscickaWesolowska, M. (1980) Exp. Hematol. 8 (suppl. 7), 90 11 Bacigalupo, A., Podesta', M., Raffo, M. R., Piaggio, G., Van Lint, M. T. and Marmont, A. M. (1980) Exp. Hematol. 8, 795 12 Bacigalupo, A., Podesta', M., Mingari, M. C., Moretta, L., Van Lint, M. T. and Marmont, A. M. (1980)J. Immunol. 125, 1449 13 Bagby, G. C., Goodnight, S. H., Mooney, W. M. and Richter Book, K. (1979) Blood54, 322 14 Bacigalupo, A., Podesta', M., Van Lint, M. T. and Marmont, A. M., (1981) Brit. J. Haematol. (in press) 15 Moretta, L., Webb, S. R., Grossi, C. E., Lydyard, P. M. and Cooper, M. D. (1977)J. Exp. Med. 146, 184 16 Bacigalupo, A., Podesta', M., Mingari, M. C., Moretta, L., Piaggio, G. and Marmont, A. M. (1981) Blood (in press) 17 Banisadre, M., Ascensao, J. L., Kay, N. E., Ash, R. C. and Zanjani, E. D. (1980) Ex)~. Hematol. 8 (suppl. 7) 44 18 Lutton, J. D. and Levere, R. D. (1980) Exp. HematoL 8 (suppl. 7) 127 19 Camitta, B. M. (1980) Haematol. Bluttraansfus. 24, 39 20 Moretta, L., Moretta, A., Canonica, G. W., Bacigalupo, A., Mingari, M. C. and Cerottini, J.-C. (1981) hnmanoL Rev. 56 (in press)
Prospects for vaccinating against pregnancy Current contraception leaves a lot to be desired. To the growing catalogue of complaints about present measures to reduce fertility has been a d d e d recent concern about the possibly harmful consequences of vasectomyl, 2 T h e r e is thus currently a search for new technology, a sort of third generation contraceptive, to fill the gap. One idea that is theoretically appealing is to vaccinate against pregnancy. Vaccination is a simple procedure with a long history of success in preventing the invasion of foreign organisms into the h u m a n body. W h y not use it to prevent the invasion of the female by sperm and embryQ? The p r o b l e m is to devise a vaccine which combines the potency necessary to ensure an acceptable reduction in fertility, with specificity, i.e. the avoidance of autoimmunity, since sperm a n d embryo do not differ extensively from the host in antigenic terms. Another i m p o r t a n t requirement is that of reversibility, at least where women m a y wish to conceive sometime after receiving the vaccine. ©Elsevier/North-Holland BicJmedicalPress 1981
A variety of antigens are currently under scrutiny as possible targets for vaccination 3,4,s,6. These include: sperm-specific antigens, perhaps the most promising of which, at the moment, is the lactic dehydrogenase isoenzyme which is present only in the sperm; antigens of the zona pellucida that surrounds the egg, which unfortunately have the potential to provoke anti-ovarian autoimmunity; placental antigens; and antigenic components of pregnancy-specific hormones. T h e latter have received the greatest emphasis in terms of publicity a n d funding by the W o r l d Health O r g a n i z a t i o n ' s task force on h u m a n reproduction. At present, the principal hormone target is h u m a n chorionic gonadotropin (HCG). This molecule is produced by cells of the fetally derived trophoblast and its continued presence is crucial for maintaining pregnancy. M u c h effort has been made, therefore, to immunize specifically against this hormone. One difficulty is that H C G shows extensive cross-reactivity with other hormones, such as luteinising hormone,
immunology today, March 1981
which are important for maintaining normal sexual cycling. Some very elegant protein chemistry has been used in an attempt to isolate those areas of the molecule specific to H C G . But the difficulty so far has been in using those peptides to obtain an i m m u n e response potent enough to inhibit fertility3,4,6. This delay in the development of the H C G work has stimulated a search for other potential antigenic targets. A n attractive possibility resides in the socalled oncofetal antigens, of which the murine F9 teratocarcinoma antigen is the prototype. J a c o b and his colleagues have published a long series of papers documenting the presence of F9 antigen in the male germ line, on sperm and in the early embryoL It disappears shortly after i m p l a n t a t i o n and so far it has not been found anywhere in the adult female body. It also cross-reacts extensively with a similar antigen found in humans. It seems to be a rather i m p o r t a n t cell-surface component because xenogeneic antibodies p r o d u c e d against it, and their F a b fragments, can inhibit development at very specific stages, a r o u n d the time of implantation 8. These properties suggest that the antigen could be a candidate for an "antipregnancy vaccine for two reasons. I m m u n i t y against it should not cause a u t o i m m u n i t y in the female, and mouse experiments m a y directly translate into an ultimately effective h u m a n vaccine. F u r t h e r m o r e , work presented at a recent workshop on early embryonic antigens in Lake Placid, New York, indicates that a number of monoclonal antibodies have been p r e p a r e d to this type of antigen~ and that some seem to recognize c a r b o h y d r a t e determinants (to be published). It is therefore interesting that H a m i l t o n el al. 9, and more recently W e b b 1°, have used teratocarcinoma cells in mice to bring about a reduction in fertility by vaccination. Although neither one of these attempts achieved total infertility the fact that they worked at all was rather remarkable as there was no obvious attempt to immunize specifically for the reproductive tract. In fact there has been surprisingly little emphasis given to specific attempts to immunize locally for antigens in the reproductive tract. Recent work indicates that IgA precursors originating in the mesenteric lymph nodes can selectively migrate, upon adoptive transfer, to the female reproductive tract, and that this migration is under hormonal controP~,~2, ~3. Although this does not prove that oral i m m u n i z a t i o n will specifically immunize the reproductive tract, work on m a m m a r y - g l a n d i m m u n i t y has p r o v i d e d an elegant precedent for such a prospect. It has long been clear that breast milk is selectively enriched for antibodies directed against enteric antigens ~4. Indeed, an a p p a r e n t l y effective folk remedy, in I n d i a and elsewhere, is the application of breast milk to infected wounds. T h e basis for this seems to be that gutderived IgA producing cells will selectively migrate to the breast under the influence of sex hormones ~5. In
49
the future one might expect to see the results obtained from antifertility research, which is concentrated on finding a proper antigenic target on sperm or embryo, combined with those from research on the specific directing of immunity in the reproductive tract. It is not clear at this point what form an effective h u m a n anti-pregnancy vaccine will take. It could come from a completely unexpected source. For example, Lopo and Vacquier have lately reported that rabbits vaccinated against sea urchin sperm produce anti-sperm antibody which not only reacts with rabbit sperm but also cross-reacts against sperm derived from animals of seven different phyla 16. It also reacts with h u m a n sperm. It is possible that the isolation and characterization of the active component in sea urchin sperm may result in an effective means of controlling our population growth. T h e point to emphasize is that at this stage of development we need a lot more information before we know which p a r t i c u l a r a p p r o a c h will allow us to provide the technical means for effective population control via vaccination. Nevertheless a n u m b e r of reasonable candidates are emerging and u n d o u b t e d l y there will be more before the p r o b l e m is solved. THOMAS G. WEGMANN
Department of Immunology, University of Alberta, Edmonton, Canada T5~ 2H7.
References 1 Clarkson, T. B. and Alexander, N. J. (1980)J. c/in. Invest. 65,
15-25
2 Wegmann, T. G. (1980) lmmunol. Today. 1, 4 3 Stevens, V. C. (1978) Bull. of the World Health Organization 56 (2), 179-192 4 Talwar, G. P. (1979) Int. J. of Gynaecol. and Obstet. 15,410-414 5 Loke, Y. W. (1980) Immunology and lmmunopalhology of the Human Foetal-Maternal Interaction. Elsevier/North Holland Press, Inc. Amsterdam. 6 Dhindsa, D. and .Schumacker, G., eds. (1980) Immunological Aspects of Infertility and Fertihty Regulation. Elsevier/North Holland, Inc., Amsterdam. 7 Jacob, F. (1977) Immunological Rev. 33, 3-32 8 Kemler, R., Babinet, C., Eisen, H. and Jacob, F. (1977) Proc. Nat. Acad. &'i., U.S.A., 74, 4449-4452 9 Hamilton, M. S., Beer, A. E., May, R. D. and Vitetta, E. S. (1979) Transplant. Proc. 11, 1069-1072 10 Webb, C. G. (1980)Biol. of Reproduction 22, 695-704 11 McDermott, M. R. and Bienenstock, J. (1979) J. lmmunol. 122, 1892-1898 12 McDermott, M. R., Clark, D. A., and Bienenstock, J. (1979) j . Immunol. 124, 2536-2539 13 Wira, C. R. and Sandoe, C. P. (1977) JVature (London) 268, 534-536 14 Ahlstedt, S., Carlson, B., Fallstrom, S. P., Hanson, L. A., Holmgren, J., Lidin-Janson, G., Lindblad, B. S., Jodal, U., Kaijer, B., Sohl-Aherlund, A. and Wadsworth, C. (1977) in Immunology of the Gut. Ciba Foundation Symposium 46, 115 Elsevier Press, N. Y. 15 Weisz-Carrington, P., Schrater, A. F., Lamm, M. E. and Thorbecke, G. J. (1979) Cell. lmmunol. 44, 343-351 16 Lopo, A. and Vaequier, V. D. (1980) Nature (London) 288, 397-399
