Abstract
Neonatal, fetal, and very old animals are particularly sensitive to chemical carcinogenesis. Reasons for this increased sensitivity could be due to increased susceptibility of “target” organs or cells, peculiar hormonal levels at these age groups, relatively deficient immune functions, or combinations of these and/or other factors. During the late fetal and first three weeks of neonatal life, the immune system is rapidly maturing, is relatively incompetent, and its diverse components are developing at different rates. For example, thymus-dependent (T) alloreactive cells capable of proliferating in mixed lymphocyte reactions (T helper cells) develop by 7 days of age, but precursors of T killer cells are not competent until approximately 14 days of age. Bursa equivalent-dependent (B) cells capable of generating antibody responses are present in fetal liver but are extremely sensitive to tolerance induction until 10-14 days of age when IgD cell surface receptors are detectable. Marrow-dependent (M) cells responsible for regulation of suppressor cells and for natural cytotoxicity to transformed tumor cells do not mature until 3 weeks of age. In very old animals, the thymus is atrophic and cell-mediated immunity is moderately suppressed. Natural cytotoxicity against tumor cells is less than normal but antibody formation (B cell function) is adequate.
Gonadotrophic hormones of the pituitary or placenta are high during pregnancy, the early neonatal period, after the menopause, and in a large fraction of men over 60 years of age. These and other hormones are immunosuppressive and could theoretically facilitate carcinogenesis. The particular immune cell type, if any, responsible for resistance to chemically induced tumors has not been determined. One can only state that susceptibility to chemical carcinogenesis is associated with a relative dysfunction of the immune system and that age is an important factor.
Full text
PDF





Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adcock E. W., 3rd, Teasdale T., August C. S., Cox S., Meschia G., Ballaglia T. C., Naughton M. A. Human chorionic gonadotropin: its possible role in maternal lymphocyte suppression. Science. 1973 Aug 31;181(4102):845–847. doi: 10.1126/science.181.4102.845. [DOI] [PubMed] [Google Scholar]
- Albright J. F., Makinodan T., Deitchman J. W. Presence of life-shortening factors in spleens of aged mice of long lifespan and extension of life expectancy by splenectomy. Exp Gerontol. 1969 Dec;4(4):267–276. doi: 10.1016/0531-5565(69)90015-1. [DOI] [PubMed] [Google Scholar]
- Armuth V., Berenblum I. Systemic promoting action of phorbol in liver and lung carcinogenesis in AKR mice. Cancer Res. 1972 Oct;32(10):2259–2262. [PubMed] [Google Scholar]
- Bach F. H., Widmer M. B., Bach M. L., Klein J. Serologically defined and lymphocyte-defined components of the major histocompatibility complex in the mouse. J Exp Med. 1972 Dec 1;136(6):1430–1444. doi: 10.1084/jem.136.6.1430. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bennett M., Baker E. E. Marrow-dependent cell function in early stages of infection with Listeria monocytogenes. Cell Immunol. 1977 Sep;33(1):203–210. doi: 10.1016/0008-8749(77)90147-2. [DOI] [PubMed] [Google Scholar]
- Bennett M. Graft-versus-host reactions in mice. I. Kinetic and immunogenetic studies of alloantigen-sensitive units of lymphoid tissue. Transplantation. 1971 Feb;11(2):158–169. [PubMed] [Google Scholar]
- Blaese R. M. Macrophage function in the development of immunocompetence and in immunodeficiency. J Reticuloendothel Soc. 1976 Jul;20(1):67–70. [PubMed] [Google Scholar]
- Calkins C. E., Stutman O. Changes in suppressor mechanisms during postnatal development in mice. J Exp Med. 1978 Jan 1;147(1):87–97. doi: 10.1084/jem.147.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cheers C., Waller R. Activated macrophages in congenitally athymic "nude mice" and in lethally irradiate mice. J Immunol. 1975 Sep;115(3):844–847. [PubMed] [Google Scholar]
- Chiscon M. Q., Golub E. S. Functional development of the interacting cells in the immune response. I. Development of T cell and B cell function. J Immunol. 1972 May;108(5):1379–1386. [PubMed] [Google Scholar]
- Denckla W. D. Interactions between age and the neuroendocrine and immune systems. Fed Proc. 1978 Apr;37(5):1263–1267. [PubMed] [Google Scholar]
- Dilman V. M. Age-associated elevation of hypothalamic, threshold to feedback control, and its role in development, ageine, and disease. Lancet. 1971 Jun 12;1(7711):1211–1219. doi: 10.1016/s0140-6736(71)91721-1. [DOI] [PubMed] [Google Scholar]
- FISCUS W. G., MORRIS B. T., Jr, SESSION J., TRENTIN J. J. Specificity, host-age effect, and pathology of homologous disease induced in unirradiated F1 hybrid mice by transplantation of parental lymphoid tissue. Ann N Y Acad Sci. 1962 Oct 24;99:355–373. doi: 10.1111/j.1749-6632.1962.tb45320.x. [DOI] [PubMed] [Google Scholar]
- Fernandes G., Yunis E. J., Good R. A. Age and genetic influence on immunity in NZB and autoimmune-resistant mice. Clin Immunol Immunopathol. 1976 Nov;6(3):318–333. doi: 10.1016/0090-1229(76)90085-4. [DOI] [PubMed] [Google Scholar]
- Gerbase-DeLima M., Meredith P., Walford R. L. Age-related changes, including synergy and suppression, in the mixed lymphocyte reaction in long-lived mice. Fed Proc. 1975 Feb;34(2):159–161. [PubMed] [Google Scholar]
- Goldstein A. L., Asanuma Y., White A. The thymus as an endocrine gland: properties of thymosin, a new thymus hormone. Recent Prog Horm Res. 1970;26:505–538. doi: 10.1016/b978-0-12-571126-5.50016-9. [DOI] [PubMed] [Google Scholar]
- Gruber D. F., Zucali J. R., Wleklinski J., LaRussa V., Mirand E. A. Temporal transition in the site of rat erythropoietin production. Exp Hematol. 1977 Sep;5(5):399–407. [PubMed] [Google Scholar]
- Haller O., Wigzell H. Suppression of natural killer cell activity with radioactive strontium: effector cells are marrow dependent. J Immunol. 1977 Apr;118(4):1503–1506. [PubMed] [Google Scholar]
- Han T. Human chorionic gonadotropin. Its inhibitory effect on cell-mediated immunity in vivo and in vitro. Immunology. 1975 Sep;29(3):509–515. [PMC free article] [PubMed] [Google Scholar]
- Han T. Inhibitory effect of human chorionic gonadotrophin on lymphocyte blastogenic response to mitogen, antigen and allogeneic cells. Clin Exp Immunol. 1974 Dec;18(4):529–535. [PMC free article] [PubMed] [Google Scholar]
- Hanna M. G., Jr, Nettesheim P., Snodgrass M. J. Decreasing immune competence and development of reticulum cell sarcomas in lymphatic tissue of aged mice. J Natl Cancer Inst. 1971 Apr;46(4):809–824. [PubMed] [Google Scholar]
- Heilman D. H., Gambrill M. R., Leichner J. P. The effect of hydrocortisone on the incorporation of tritiated thymidine by human blood lymphocytes cultured with phytohaemagglutinin and pokeweed mitogen. Clin Exp Immunol. 1973 Oct;15(2):203–212. [PMC free article] [PubMed] [Google Scholar]
- Iványi P., Hámpl R., Stárka L., Micková M. Genetic association between H-2 gene and testosterone metabolism in mice. Nat New Biol. 1972 Aug 30;238(87):280–281. doi: 10.1038/newbio238280a0. [DOI] [PubMed] [Google Scholar]
- Kay M. M., Makinodan T. Immunobiology of aging: evaluation of current status. Clin Immunol Immunopathol. 1976 Nov;6(3):394–413. doi: 10.1016/0090-1229(76)90093-3. [DOI] [PubMed] [Google Scholar]
- Kiessling R., Klein E., Wigzell H. "Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol. 1975 Feb;5(2):112–117. doi: 10.1002/eji.1830050208. [DOI] [PubMed] [Google Scholar]
- Kumar V., Eckner R. J., Bennett M. Mechanism of genetic resistance to immune suppression by Friend leukemia virus: the role of marrow-dependent cells. Ann N Y Acad Sci. 1976;276:217–228. doi: 10.1111/j.1749-6632.1976.tb41648.x. [DOI] [PubMed] [Google Scholar]
- Kurland J. I., Bockman R. S., Broxmeyer H. E., Moore M. A. Limitation of excessive myelopoiesis by the intrinsic modulation of macrophage-derived prostaglandin E. Science. 1978 Feb 3;199(4328):552–555. doi: 10.1126/science.304600. [DOI] [PubMed] [Google Scholar]
- Lafferty K. J., Jones M. A. Reactions of the graft versus host (GVH) type. Aust J Exp Biol Med Sci. 1969 Feb;47(1):17–54. doi: 10.1038/icb.1969.3. [DOI] [PubMed] [Google Scholar]
- Lassila O., Eskola J., Toivanen P., Martin C., Dieterlen-Lievre F. The origin of lymphoid stem cells studied in chick yold sac-embryo chimaeras. Nature. 1978 Mar 23;272(5651):353–354. doi: 10.1038/272353a0. [DOI] [PubMed] [Google Scholar]
- Lawton A. R., Kincade P. W., Cooper M. D. Sequential expression of germ line genes in development of immunoglobulin class diversity. Fed Proc. 1975 Jan;34(1):33–39. [PubMed] [Google Scholar]
- Makinodan T., Adler W. H. Effects of aging on the differentiation and proliferation potentials of cells of the immune system. Fed Proc. 1975 Feb;34(2):153–158. [PubMed] [Google Scholar]
- McConnachie P. R., Rachelefsky G., Stiehm E. R., Terasaki P. I. Antibody-dependent lymphocyte killer function and age. Pediatrics. 1973 Dec;52(6):795–800. [PubMed] [Google Scholar]
- Meltzer M. S. Tumoricidal responses in vitro of peritoneal macrophages from conventionally housed and germ-free nude mice. Cell Immunol. 1976 Mar 1;22(1):176–181. doi: 10.1016/0008-8749(76)90018-6. [DOI] [PubMed] [Google Scholar]
- Moore M. A., Metcalf D. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br J Haematol. 1970 Mar;18(3):279–296. doi: 10.1111/j.1365-2141.1970.tb01443.x. [DOI] [PubMed] [Google Scholar]
- Moore M. A., Owen J. J. Chromosome marker studies in the irradiated chick embryo. Nature. 1967 Sep 2;215(5105):1081–1082. doi: 10.1038/2151081a0. [DOI] [PubMed] [Google Scholar]
- Morton J. I., Siegel B. V. Transplantation of autoimmune potential. I. Development of antinuclear antibodies in H-2 histocompatible recipients of bone marrow from New Zealand Black mice. Proc Natl Acad Sci U S A. 1974 Jun;71(6):2162–2165. doi: 10.1073/pnas.71.6.2162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mosier D. E., Mathieson B. J., Campbell P. S. Ly phenotype and mechanism of action of mouse neonatal suppressor T cells. J Exp Med. 1977 Jul 1;146(1):59–73. doi: 10.1084/jem.146.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Olding L. B., Oldstone M. B. Lymphocytes from human newborns abrogate mitosis of their mother's lymphocytes. Nature. 1974 May 10;249(453):161–162. doi: 10.1038/249161a0. [DOI] [PubMed] [Google Scholar]
- Pazmiño N. H., Yuhas J. M. Senescent loss of resistance to murine sarcoma virus (Moloney) in the mouse. Cancer Res. 1973 Nov;33(11):2668–2672. [PubMed] [Google Scholar]
- Pierpaoli W., Haran-Ghera N., Kopp H. G. Role of host endocrine status in murine leukaemogenesis. Br J Cancer. 1977 May;35(5):621–629. doi: 10.1038/bjc.1977.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rao G. R., Rawls W. E., Perey D. Y., Tompkins W. A. Macrophage activation in congenitally athymic mice raised under conventional or germ-free conditions. J Reticuloendothel Soc. 1977 Jan;21(1):13–20. [PubMed] [Google Scholar]
- Rice J. M. Perinatal period and pregnancy: intervals of high risk for chemical carcinogens. Environ Health Perspect. 1979 Apr;29:23–27. doi: 10.1289/ehp.792923. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shearer G. M., Cudkowicz G., Connell M. S., Priore R. L. Cellular differentiation of the immune system of mice. I. Separate splenic antigen-sensitive units for different types of anti-sheep antibody-forming cells. J Exp Med. 1968 Sep 1;128(3):437–457. doi: 10.1084/jem.128.3.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Singhal S. K., Roder J. C., Duwe A. K. Suppressor cells in immunosenescence. Fed Proc. 1978 Apr;37(5):1245–1252. [PubMed] [Google Scholar]
- Stutman O. Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science. 1974 Feb 8;183(4124):534–536. doi: 10.1126/science.183.4124.534. [DOI] [PubMed] [Google Scholar]
- Vandeputte M., Eyssen H., Sobis H., de Somer P. Induction of polyoma tumors in athymic nude mice. Int J Cancer. 1974 Oct 15;14(4):445–450. doi: 10.1002/ijc.2910140404. [DOI] [PubMed] [Google Scholar]
- Wigzell H., Stjernswärd J. Age-dependent rise and fall of immunological reactivity in the CBA mouse. J Natl Cancer Inst. 1966 Oct;37(4):513–517. [PubMed] [Google Scholar]
- Wolf N. S., Trentin J. J. Hemopoietic colony studies. V. Effect of hemopoietic organ stroma on differentiation of pluripotent stem cells. J Exp Med. 1968 Jan 1;127(1):205–214. doi: 10.1084/jem.127.1.205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M., Callahan G. N., Althage A., Cooper S., Streilein J. W., Klein J. The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help. J Exp Med. 1978 Mar 1;147(3):897–911. doi: 10.1084/jem.147.3.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
