Immunology 7bday, vol. 6, No. 9, 1985
256 nicely illustrated the remarkable adjustment of protein and ligands to accommodate to each other's structures. A. Allison (Palo Alto) discussed vehicles for antigen administration and pointed out that the immunogenicity of antigens was enhanced by liposomes capable of activating complement. Interestingly, fatty acids are a suitable carrier for poorly immunogenic carbohydrate antigens.
Immunopotentiation The chemistry and biological properties of muramyl dipeptides were reviewed by A. Adam (Orsay). Although the use of muramyl dipeptide derivatives as adjuvants or as stimulators of non-specific resistance appears promising, there are potential hazards in their use as immunomodulators in general. Observations presented by A. Mikhailova (Moscow) indicate that peptides derived from bone-marrow cell culture (myelopeptides) increase specific antibody responses in vitro. Interestingly, these myelopeptides have an opiate-like activity. B. Morein (Uppsala) has constructed an interesting complex, the I S C O M (immunostimulating complex) which enhances the immunogenicity of viral proteins included within it. The I S C O M consists of a matrix of glycoside derived from the bark of the South American tree Saponaria quiloya Molina. Viral proteins (perplomers) are attached to the micelle form of the glycoside by hydrophobic interaction. It was clearly shown that these I S C O M S were very immunogenie and allowed an i m m u n e response to structures poorly exposed in the virus particles. A new class of controlled delivery systems based on composites in which water-soluble glasses are the ratecontrolling component were presented by C. Drake (Harlow). T h e composition of these controlled-release glasses as well as their geometry directly determine the length of the delay time, and the total release period of a given substance contained in these systems. I m m u n i t y at mucosal surfaces has great importance in prevention and protection against several pathogenic microorganisms. Mucosal immunity is characterized by a predominantly IgA i m m u n e response and results from the selective transport of secretory IgA across an epithelial cell. As stressed byJ. Bienenstock (Hamilton) a strategy for stimulating immunity at mucosal surfaces must be devised. This strategy could greatly benefit from new knowledge in several areas such as antigenhandling at the mucosal surface, genetic regulation of the immune response to
antigens presented at the mucosa and identification of adjuvants promoting mucosal immune responses.
Conclusions In the final discussion, Ada pointed out that, traditionally, vaccines have been prepared from the whole infectious agent. Attenuated infectious virus had formed the basis of several highly successful vaccines, such as those against smallpox, poliomyelitis, measles and rubella. Furthermore, the ability to introduce D N A coding for other antigens into, for example, vaccinia virus to form recombinant virus (see p. ??) offered the prospect of preparing cheap, effective and easily administered vaccines' against a variety of diseases against which vaccines were not currently available. They potentially provided a bench mark which peptides in unit protein-based preparations had to reach if they were to be effective as vaccines. This meeting showed that great progress is being made towards the development of adjuvants and delivery systems. There is substantial progress
D o w e n e e d suppressor cells to e x p l a i n tolerance of self?. SIR, Self tolerance has been ascribed to clonal inactivation of self-reactive cells and to inhibition of such cells' activity by suppressor cells. Continuing an interesting discussion on the interrelationship of suppressor (Ts) and helper (TH) T lymphocytes (Immunol. Today, 1984, 5, 61) Matja~ Zwitter suggested that T s cells might convert to T H cells and possibly vice versa. In our view these ideas give an elegant explanation for the control of i m m u n e reactions in which only T s and T n cell types are involved and where 'presentation of T lymphocytes as suppressor or helper cells is closely related to the requirement for an i m m u n e response, that is, to the presence or absence of antigen'. A reduction in the n u m b e r of cell types thought to be involved in immune regulation could perhaps help the network theory of immunity to pass from its present state of uncertainty. K~Shler has suggested that for control purposes a simplified network would be more effective and certainly more 'economical '~. As far as T cells are concerned, one may speculate that T s are derived from cytptoxic (Tc) T lymphocytes not encountering the antigen against which they have been committed. This pos-
towards an understanding of protein structures, such as the delineation of epitopes which will preferentially react with B cells, T-helper ceils ~nd possibly T-suppressor cells. However, there is still a lot to understand about antigen presentation by cells other than macrophages. It is significant that only one peptide-based preparation has reached the stage of approval for phase I vaccine trials in humans. This is directed against a hormone (the fl subunit of h u m a n chorionic gonadotrophin) which is a simpler target than an infectious disease agent (V. Stevens, Columbus). Considerably more research is needed before peptide-based vaccines become generally available against the many diseases which are prevalent in developed and developing countries.
n-i J. A. Louis is in the Institute ofBiochemistry, University of Lausanne," P. -H. Lambert is in the Department of Pathology, University of Geneva," both authors are in the WHO Immunology Research and Training Centre, Lausanne~Geneva. sibility accords with the well-known sharing of differentiation markers on T c and Ts, for instance O K T 8 in m a n and OX8 in the rat. But what about the term ' antigen' ? We have recently suggested that in an autologous system the cell targets of T lymphocytes are different from the targets of natural killer (NK) or NK-like cells and immunoglobulins (Ig) 2. This idea is supported by the demonstration of distinct determinants for T c and Ig on an antigenic molecule 3. Moreover, to become the target of immune effector cells, the tissue cell should exhibit a particular configuration of cell-surface markers ~. Ther~ are steps in the differentiation of somatic (tissue) cells, which are probably all registered and controlled by the immune system (' self control') but the damage of a tissue cell by the i m m u n e effectors is stimulated only by 'inappropriate' behavior by such a cell ( ' i m m u n e surveillance'). W e have suggested that the differentiation of any tissue cell is under the cellmediated control of a specialized 'tissue control system' consisting of at least two cell types, the Thy-1 ÷ control cells of dendritic type, and Ia + cells of dendritic or reticular type. The former gives to the tissue cell functional ability, the latter influences its expression of surface markers (see Ref. 2 for details). There might be also an involvement of specialized cells of macrophage type in the control of mitotic activity of reserve tissue cells, influencing their ability to express self M H C determinants 4. In
Immunology Today, vol. 6, No. 9, 1985 mouse bone marrow chimeras the decidual cells express in vitro H-2 determinants of bone marrow donor origin 5. As an alternative to the authors' explanation for their origin we have suggested that this could confirm the role of bone marrow-derived cells in the decidual transformation of uterine stromal cells4. This concept could also be of general importance because if T lymphocytes monitor the occurrence of unfavorable variants of tissue cells and if the T cell effect is an MHC-restricted phenomenon 6, the potential targets o f T lymphocytes should be able to express the same M H C antigens as the individual's lymphocytes *. There is also a question about why there are so many lymphocytes in most peripheral non-lymphoid tissues? Their suspected cytotoxic effect, we have found, is rare, taking the form of selective action against some structures (some degenerating ovarian follicles2; regressing 'old uterine lumen' in pregnant uterus4). Cells bearing T-cell or N K markers are, however, present in considerable numbers among some differentiating tissue cells (vaginal epithelium; corpora lutea of the ovary), especially in connection with Ia ÷ cells of dendritic type, the latter sometimes degenerating among differentiating tissue cells such as those in the intermedial cell layer of the vagina (Bukovsk~ et al., unpublished) or Langerhans' Ia ÷ cells in epidermis. There is evidence that N K cells might affect antigen-exposed accessory cells7. For terminal differentiation the tissue cells probably need a signal from lysed Ia + cells. To explain a 'natural' tolerance we suggest that during early ontogeny the i m m u n e system and the 'tissue control system' mutually cooperate in enabling the tissue cells to attain the appropriate differentiation. With the termination of an adaptive period in the development of the i m m u n e and tissue control systems, the pathways of tissue cell differentiation, which are specific for particular tissue, are encoded into both these systems. In adults the tissue cells differing significantly from an 'allowed' (encoded) pathway are rejected, including those that are altered or senescent. In conclusion, we suggest that the immune system could participate in homeostasis by actively supporting some steps in the differentation of tissue cells, according to pathways encoded during ontogeny. The T s cells seem to us not necessarily to be involved in the maintenance of tolerance against self structures. They may, however, terminate the specific i m m u n e reaction after elimination of an antigen, possibly by conversion of developed T c to T s. The term 'antigen' we understand either as the occurrence of an unfamiliar antigenic molecule (alone or in corn-
257 bination with self determinant) or as a 'forbidden' combination of self determinants, not encoded for a given tissue cell type during ontogeny. The self determinant has not been necessarily only individually specific (as is M H C ) but may be represented by a determ i n a n t shared, for instance, within the species (as are tissue-specific antigens or differentiation markers of lymphoid cells). T h u s the restriction of reactivity o f T cells may not be only M H C related. This could account for the unusual reactivity of T cells in allogeneic mixed lymphocyte culturess. Furthermore the essence of the autologous mixed lymphocyte reaction could lie in the expression of a 'forbidden' combination of self determinants on cultured syngeneic lymphocytes.
References
Lymph nodes, accessory cells and the staging of AIDS
antigen presentation and regulatory functions ~. This could partly account for the occurrence of both opportunistic infections and unusual malignant tumors in AIDS. Histopathologic studies, the determination of T4/T8 ratios, the demonstration of proliferation antigens as well as the analysis of accessory cells such as macrophages, FD cells and natural killer cells in lymph nodes of patients with LAS or AIDS, should eventually facilitate a morphologic and functional classification of the disease process. This in turn could serve as a basis for an exact immunologic staging of LAS and AIDS. Such a staging would, in analogy to, for instance, Hodgkin's lymphoma, not only be valuable with regard to prognosis but would also guide the development of stagespecific controlled therapeutic protocols. With respect to therapeutic trials involving substances with considerable side-effects such as suramine, interleukin 2 or interferons a reliable classification and staging could allow predictions of the affected individuals' response to therapy. In addition, appropriate studies of lymphatic tissue utilizing ultrastructural and immunohistochemical techniques should further our understanding of the disease process and of the role of the different cell types involved. We therefore advocate despite their invasive nature - lymph node biopsies in patients with LAS and AIDS and their careful evaluation by a pathologist experienced with the special problems related to this complex disease. []
SIR,
Describing ultrastmctural evidence for retrovirus infection of follicular dendritic (FD) cells in lymph nodes from AIDS patients, J. A. Armstrong and coworkers (Immunol. Today, 1985, 6, 122-122) emphasize the possible role of accessory cells in the pathogenesis of AIDS. We recently studied lymph nodes from four patients with the lymphadenopathy syndrome (LAS) and four others with AIDS, all of whom were serologically positive for H T L V III virus. T4+, T8 ÷ and B lymphocytes, macrophages and FD cells were identified; sections were also stained for H L A - D R , proliferation antigens and interleukin-2 receptors (our unpublished results). All LAS patients exhibited a marked increase in the n u m b e r of FD cells and B lymphocytes, whereas in AIDS patients, all cell types were depleted. In comparison with LAS patients T4/T8 ratios in lymph nodes of AIDS patients were further reduced but in both groups lymph nodes stained strongly positive for H L A - D R , reflecting a high degree of activation. These results support the conclusion of Armstrong a n d co-workers that FD cells are probably involved in the pathogenesis of AIDS, since the numerical increase in FD cells parallels that of B lymphocytes and the development of generalized persistent lymphadenopathy in LAS. Conversely, in full blown AIDS the n u m b e r of FD cells is reduced, and the lymph nodes appear lymphocyte-depleted although some activated T4 lymphocytes are still present. Apart from their possible role in the transmission of H T L V III to lymphocytes, FD cells damaged by direct cytopathic effects of the virus could be responsible for a disturbance of
1 K6hler, H. (1984) In: Idiotypy in Biology and Medicine H. Kohler, J. Urbain and P. A. Gazenave, eds. AcademicPress, New York, pp. 3-14 2 Bukovsk~, A., Presl, J. and Holub, M. (1984) Cell Tissue Res. 236, 717-724 3 Russo, C., Flomberg, N., Dupont, B. etal. (1984) CellularImmunol. 88, 228-232 4 Bukovsk~, A., Presl, J. and Zidovsk~, J. (1984) Immunology 52, 631-640 5 Kearns, M. and Lala, P. K. (1982).]'. Exp. Med. 155, 1537-1554 6 Zinkernagel, R. M. and Doherty, P. C. (1974) Nature(London) 248, 701-703 7 Abruzzo, L. V. and Rowley, D. A. (1984) Science 222, 581-585 8 Bukovsk~, A. and Presl, J. (1985) Med. Hypotheses 16, 241-252 ANTON~N BUKOVSK~r and JI~[ PRESL Institute for the Care ofMother and Child, Prague, CS147, 10 Czechoslovakia
References
1 Klaus, G. G. B., Humphrey, J. H., KunkI, A. and Dongworth, D. W. (1980) Immunol. Rev. 53, 3-28 H. MULLER S. FALK H.J. STUTTE Department of Pathology, University of Frankfurt, D-6OO Frankfurt, FR G
256 nicely illustrated the remarkable adjustment of protein and ligands to accommodate to each other's structures. A. Allison (Palo Alto) discussed vehicles for antigen administration and pointed out that the immunogenicity of antigens was enhanced by liposomes capable of activating complement. Interestingly, fatty acids are a suitable carrier for poorly immunogenic carbohydrate antigens.
Immunopotentiation The chemistry and biological properties of muramyl dipeptides were reviewed by A. Adam (Orsay). Although the use of muramyl dipeptide derivatives as adjuvants or as stimulators of non-specific resistance appears promising, there are potential hazards in their use as immunomodulators in general. Observations presented by A. Mikhailova (Moscow) indicate that peptides derived from bone-marrow cell culture (myelopeptides) increase specific antibody responses in vitro. Interestingly, these myelopeptides have an opiate-like activity. B. Morein (Uppsala) has constructed an interesting complex, the I S C O M (immunostimulating complex) which enhances the immunogenicity of viral proteins included within it. The I S C O M consists of a matrix of glycoside derived from the bark of the South American tree Saponaria quiloya Molina. Viral proteins (perplomers) are attached to the micelle form of the glycoside by hydrophobic interaction. It was clearly shown that these I S C O M S were very immunogenie and allowed an i m m u n e response to structures poorly exposed in the virus particles. A new class of controlled delivery systems based on composites in which water-soluble glasses are the ratecontrolling component were presented by C. Drake (Harlow). T h e composition of these controlled-release glasses as well as their geometry directly determine the length of the delay time, and the total release period of a given substance contained in these systems. I m m u n i t y at mucosal surfaces has great importance in prevention and protection against several pathogenic microorganisms. Mucosal immunity is characterized by a predominantly IgA i m m u n e response and results from the selective transport of secretory IgA across an epithelial cell. As stressed byJ. Bienenstock (Hamilton) a strategy for stimulating immunity at mucosal surfaces must be devised. This strategy could greatly benefit from new knowledge in several areas such as antigenhandling at the mucosal surface, genetic regulation of the immune response to
antigens presented at the mucosa and identification of adjuvants promoting mucosal immune responses.
Conclusions In the final discussion, Ada pointed out that, traditionally, vaccines have been prepared from the whole infectious agent. Attenuated infectious virus had formed the basis of several highly successful vaccines, such as those against smallpox, poliomyelitis, measles and rubella. Furthermore, the ability to introduce D N A coding for other antigens into, for example, vaccinia virus to form recombinant virus (see p. ??) offered the prospect of preparing cheap, effective and easily administered vaccines' against a variety of diseases against which vaccines were not currently available. They potentially provided a bench mark which peptides in unit protein-based preparations had to reach if they were to be effective as vaccines. This meeting showed that great progress is being made towards the development of adjuvants and delivery systems. There is substantial progress
D o w e n e e d suppressor cells to e x p l a i n tolerance of self?. SIR, Self tolerance has been ascribed to clonal inactivation of self-reactive cells and to inhibition of such cells' activity by suppressor cells. Continuing an interesting discussion on the interrelationship of suppressor (Ts) and helper (TH) T lymphocytes (Immunol. Today, 1984, 5, 61) Matja~ Zwitter suggested that T s cells might convert to T H cells and possibly vice versa. In our view these ideas give an elegant explanation for the control of i m m u n e reactions in which only T s and T n cell types are involved and where 'presentation of T lymphocytes as suppressor or helper cells is closely related to the requirement for an i m m u n e response, that is, to the presence or absence of antigen'. A reduction in the n u m b e r of cell types thought to be involved in immune regulation could perhaps help the network theory of immunity to pass from its present state of uncertainty. K~Shler has suggested that for control purposes a simplified network would be more effective and certainly more 'economical '~. As far as T cells are concerned, one may speculate that T s are derived from cytptoxic (Tc) T lymphocytes not encountering the antigen against which they have been committed. This pos-
towards an understanding of protein structures, such as the delineation of epitopes which will preferentially react with B cells, T-helper ceils ~nd possibly T-suppressor cells. However, there is still a lot to understand about antigen presentation by cells other than macrophages. It is significant that only one peptide-based preparation has reached the stage of approval for phase I vaccine trials in humans. This is directed against a hormone (the fl subunit of h u m a n chorionic gonadotrophin) which is a simpler target than an infectious disease agent (V. Stevens, Columbus). Considerably more research is needed before peptide-based vaccines become generally available against the many diseases which are prevalent in developed and developing countries.
n-i J. A. Louis is in the Institute ofBiochemistry, University of Lausanne," P. -H. Lambert is in the Department of Pathology, University of Geneva," both authors are in the WHO Immunology Research and Training Centre, Lausanne~Geneva. sibility accords with the well-known sharing of differentiation markers on T c and Ts, for instance O K T 8 in m a n and OX8 in the rat. But what about the term ' antigen' ? We have recently suggested that in an autologous system the cell targets of T lymphocytes are different from the targets of natural killer (NK) or NK-like cells and immunoglobulins (Ig) 2. This idea is supported by the demonstration of distinct determinants for T c and Ig on an antigenic molecule 3. Moreover, to become the target of immune effector cells, the tissue cell should exhibit a particular configuration of cell-surface markers ~. Ther~ are steps in the differentiation of somatic (tissue) cells, which are probably all registered and controlled by the immune system (' self control') but the damage of a tissue cell by the i m m u n e effectors is stimulated only by 'inappropriate' behavior by such a cell ( ' i m m u n e surveillance'). W e have suggested that the differentiation of any tissue cell is under the cellmediated control of a specialized 'tissue control system' consisting of at least two cell types, the Thy-1 ÷ control cells of dendritic type, and Ia + cells of dendritic or reticular type. The former gives to the tissue cell functional ability, the latter influences its expression of surface markers (see Ref. 2 for details). There might be also an involvement of specialized cells of macrophage type in the control of mitotic activity of reserve tissue cells, influencing their ability to express self M H C determinants 4. In
Immunology Today, vol. 6, No. 9, 1985 mouse bone marrow chimeras the decidual cells express in vitro H-2 determinants of bone marrow donor origin 5. As an alternative to the authors' explanation for their origin we have suggested that this could confirm the role of bone marrow-derived cells in the decidual transformation of uterine stromal cells4. This concept could also be of general importance because if T lymphocytes monitor the occurrence of unfavorable variants of tissue cells and if the T cell effect is an MHC-restricted phenomenon 6, the potential targets o f T lymphocytes should be able to express the same M H C antigens as the individual's lymphocytes *. There is also a question about why there are so many lymphocytes in most peripheral non-lymphoid tissues? Their suspected cytotoxic effect, we have found, is rare, taking the form of selective action against some structures (some degenerating ovarian follicles2; regressing 'old uterine lumen' in pregnant uterus4). Cells bearing T-cell or N K markers are, however, present in considerable numbers among some differentiating tissue cells (vaginal epithelium; corpora lutea of the ovary), especially in connection with Ia ÷ cells of dendritic type, the latter sometimes degenerating among differentiating tissue cells such as those in the intermedial cell layer of the vagina (Bukovsk~ et al., unpublished) or Langerhans' Ia ÷ cells in epidermis. There is evidence that N K cells might affect antigen-exposed accessory cells7. For terminal differentiation the tissue cells probably need a signal from lysed Ia + cells. To explain a 'natural' tolerance we suggest that during early ontogeny the i m m u n e system and the 'tissue control system' mutually cooperate in enabling the tissue cells to attain the appropriate differentiation. With the termination of an adaptive period in the development of the i m m u n e and tissue control systems, the pathways of tissue cell differentiation, which are specific for particular tissue, are encoded into both these systems. In adults the tissue cells differing significantly from an 'allowed' (encoded) pathway are rejected, including those that are altered or senescent. In conclusion, we suggest that the immune system could participate in homeostasis by actively supporting some steps in the differentation of tissue cells, according to pathways encoded during ontogeny. The T s cells seem to us not necessarily to be involved in the maintenance of tolerance against self structures. They may, however, terminate the specific i m m u n e reaction after elimination of an antigen, possibly by conversion of developed T c to T s. The term 'antigen' we understand either as the occurrence of an unfamiliar antigenic molecule (alone or in corn-
257 bination with self determinant) or as a 'forbidden' combination of self determinants, not encoded for a given tissue cell type during ontogeny. The self determinant has not been necessarily only individually specific (as is M H C ) but may be represented by a determ i n a n t shared, for instance, within the species (as are tissue-specific antigens or differentiation markers of lymphoid cells). T h u s the restriction of reactivity o f T cells may not be only M H C related. This could account for the unusual reactivity of T cells in allogeneic mixed lymphocyte culturess. Furthermore the essence of the autologous mixed lymphocyte reaction could lie in the expression of a 'forbidden' combination of self determinants on cultured syngeneic lymphocytes.
References
Lymph nodes, accessory cells and the staging of AIDS
antigen presentation and regulatory functions ~. This could partly account for the occurrence of both opportunistic infections and unusual malignant tumors in AIDS. Histopathologic studies, the determination of T4/T8 ratios, the demonstration of proliferation antigens as well as the analysis of accessory cells such as macrophages, FD cells and natural killer cells in lymph nodes of patients with LAS or AIDS, should eventually facilitate a morphologic and functional classification of the disease process. This in turn could serve as a basis for an exact immunologic staging of LAS and AIDS. Such a staging would, in analogy to, for instance, Hodgkin's lymphoma, not only be valuable with regard to prognosis but would also guide the development of stagespecific controlled therapeutic protocols. With respect to therapeutic trials involving substances with considerable side-effects such as suramine, interleukin 2 or interferons a reliable classification and staging could allow predictions of the affected individuals' response to therapy. In addition, appropriate studies of lymphatic tissue utilizing ultrastructural and immunohistochemical techniques should further our understanding of the disease process and of the role of the different cell types involved. We therefore advocate despite their invasive nature - lymph node biopsies in patients with LAS and AIDS and their careful evaluation by a pathologist experienced with the special problems related to this complex disease. []
SIR,
Describing ultrastmctural evidence for retrovirus infection of follicular dendritic (FD) cells in lymph nodes from AIDS patients, J. A. Armstrong and coworkers (Immunol. Today, 1985, 6, 122-122) emphasize the possible role of accessory cells in the pathogenesis of AIDS. We recently studied lymph nodes from four patients with the lymphadenopathy syndrome (LAS) and four others with AIDS, all of whom were serologically positive for H T L V III virus. T4+, T8 ÷ and B lymphocytes, macrophages and FD cells were identified; sections were also stained for H L A - D R , proliferation antigens and interleukin-2 receptors (our unpublished results). All LAS patients exhibited a marked increase in the n u m b e r of FD cells and B lymphocytes, whereas in AIDS patients, all cell types were depleted. In comparison with LAS patients T4/T8 ratios in lymph nodes of AIDS patients were further reduced but in both groups lymph nodes stained strongly positive for H L A - D R , reflecting a high degree of activation. These results support the conclusion of Armstrong a n d co-workers that FD cells are probably involved in the pathogenesis of AIDS, since the numerical increase in FD cells parallels that of B lymphocytes and the development of generalized persistent lymphadenopathy in LAS. Conversely, in full blown AIDS the n u m b e r of FD cells is reduced, and the lymph nodes appear lymphocyte-depleted although some activated T4 lymphocytes are still present. Apart from their possible role in the transmission of H T L V III to lymphocytes, FD cells damaged by direct cytopathic effects of the virus could be responsible for a disturbance of
1 K6hler, H. (1984) In: Idiotypy in Biology and Medicine H. Kohler, J. Urbain and P. A. Gazenave, eds. AcademicPress, New York, pp. 3-14 2 Bukovsk~, A., Presl, J. and Holub, M. (1984) Cell Tissue Res. 236, 717-724 3 Russo, C., Flomberg, N., Dupont, B. etal. (1984) CellularImmunol. 88, 228-232 4 Bukovsk~, A., Presl, J. and Zidovsk~, J. (1984) Immunology 52, 631-640 5 Kearns, M. and Lala, P. K. (1982).]'. Exp. Med. 155, 1537-1554 6 Zinkernagel, R. M. and Doherty, P. C. (1974) Nature(London) 248, 701-703 7 Abruzzo, L. V. and Rowley, D. A. (1984) Science 222, 581-585 8 Bukovsk~, A. and Presl, J. (1985) Med. Hypotheses 16, 241-252 ANTON~N BUKOVSK~r and JI~[ PRESL Institute for the Care ofMother and Child, Prague, CS147, 10 Czechoslovakia
References
1 Klaus, G. G. B., Humphrey, J. H., KunkI, A. and Dongworth, D. W. (1980) Immunol. Rev. 53, 3-28 H. MULLER S. FALK H.J. STUTTE Department of Pathology, University of Frankfurt, D-6OO Frankfurt, FR G
