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Involution of the Mammalian Thymus and Its Role in the Overall Aging Process

  • Chapter
Immunological Aspects of Neoplasia — The Role of the Thymus

Part of the book series: Cancer Growth and Progression ((CAGP,volume 17))

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Abstract

During the last century of research concerning the thymus, the fact that every mammalian thymus undergoes marked morphological changes during the complex process of aging has been defined as a basic histogenetical rule. In characterizing the physiological (i.e. chronic) involution of the mammalian thymus, the term “Altersinvolution” referring to age-related involution is used. All other types of thymic involution are associated with an initial trigger and a relatively “acute” mechanism. In all of these factor-dependent cases of thymic involution, we use the term “akzidentelle involution” (i.e. acute accidental thymic involution). Temporary thymic involution occurs during pregnancy, with a full restoration of the cellular microenvironment at the end of lactation. It is now clear that pregnancy alters the well-established adaptational homeostasis between the neuroendocrine and immune axes. Such non-progressive involution has also been observed during various seasons in various animals (i.e. seasonal involution). Changes characteristic of thymic involution begin during or soon after the first year after birth, and continue progressively throughout the entire life span. The 3% to 5% annual reduction rate of the cells of the human thymic microenvironment continues until middle age, when it slows down to less than 1% per year. According to the extrapolation of these results total loss of thymic reticulo-epithelial tissue and the associated thymocytes should occur only at age of 120 years in humans. This serious reduction of the thymic cellular microenvironment is a well controlled physiological process and is presumably under both local and global regulation by the cells of the RE meshwork and by the neuroendocrine, respectively. In humans, the age related decline in serum facteur thymique serique (FTS) levels begins after 20 years of age and FTS completely disappears from the blood between the 5th and 6th decade of life. In contrast, the serum levels of thymosin-α1 and thymopoietin seem to decline earlier, starting as early as 10 years of age. The influences of a variety of other hormones on the involution of the thymus have also been characterized: testosterone, estrogen and hydrocortisone treatment results in marked involution, cortisone and progesterone administration causes slight to moderate, while use of desoxycorticosterone has no effect. The experimental administration of thyroxine yielded dose dependent results: low doses resulted in thymic hypertrophy, higher doses produced a slight hypertrophy and the highest employed doses caused thymic atrophy. The atrophy was of apicnotic type, very different from that detected after treatment with corticoid hormones. Thymus transplantation experiments indicate that age-related, physiological thymic involution has been genetically preprogrammed. Grafting of the thymus from one week old C3H leukemic strain mice into 6 month old hosts resulted in changes in thymic weight and an involution pattern that were synchronous in all recipients, in direct correlation with the glands in the donor, but not in the host. These data strongly suggest that the stimulus for thymus cell proliferation and differentiation is genetically determined within the organ implant. Since the thymus is the primary T-lymphopoietic organ during ontogenesis in the mammalian organism, its age-related involution with the already mentioned morphological alterations can be held responsible only for a decline in antigen-specific T lymphocyte immune functions. Thymic involution and diminished T lymphocyte proliferation can be partially restored by thymic tissue transplantation or use of thymic hormones. The leading physiological role of the thymic cellular microenvironment as a “clock” of the mammalian aging process is also discussed.

“If present cells have come from pre-existing cells, then all cells can trace their ancestry back to the first formed cell in an unbroken line of descent.” — Rudolf Virchow, 1858 (1)

“I have never noticed the absence of the thymus gland except in cases of true acephalism.” Simon, 1845 (2)

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References

  1. Virchow R: Cellular pathology, Churchill, London, pp1–511. 1858.

    Google Scholar 

  2. Simon J: A Physiological Essay on the Thymus Gland. Henry Renshaw Publ, London, 1845.

    Google Scholar 

  3. Miller JFAP: Immunological function of the thymus. Lancet 2: 748–749, 1961.

    Article  PubMed  CAS  Google Scholar 

  4. Miller JFAP: Effect of thymectomy in adult mice on immunological responsiveness. Nature 208: 1337–1338, 1965.

    Article  PubMed  CAS  Google Scholar 

  5. Verheyen P: De Thymo. Louvain, 1706.

    Google Scholar 

  6. Bidloo GB: Exercitatio Anatomica de Thymo. London, 1706.

    Google Scholar 

  7. Morand S: Recherches Anatomiques sur la Structure et ľusage de Thymus. Paris, 1759.

    Google Scholar 

  8. von Haller A: Elementa Physiologiae Corporus Humani. vol 3, Bousquet et Sociorum M-M, Lucerne, 1766.

    Google Scholar 

  9. Hewson W: Experimental Inquiries: Part the Second: A Description of the Lymphatic System in the Human Subject and in Other Animals. Johnson J, London, 1774.

    Google Scholar 

  10. Lucae SC: Anatomische Untersuchungen der Thymus in Menschen und Tieren. vol 2, Nurnberg, 1811.

    Google Scholar 

  11. Cooper A: Anatomy of the Thymus Gland. Lea & Blanchard, Philadelphia, 1845.

    Google Scholar 

  12. Stannius H: Handbuch der Anatomie der Wirbelthiere. von Veit, Berlin, 1854.

    Google Scholar 

  13. Prenant A: Contribution a ľétude du développement organique et histologique du thymus, de la glande thyroide et de la glande carotidienne. La Cellule 10: 85–184, 1894.

    Google Scholar 

  14. Bell ET: The development of the thymus. Am J Anat 5: 29–62, 1905.

    Article  Google Scholar 

  15. Hammar JA: Über Gewicht, Involution und Persistenz des Thymus im Postfötalleben des Menschen. Arch Anat Physiol Anat Abt [Suppl] 91–182, 1906.

    Google Scholar 

  16. Hammar JA: Die Menschenthymus in Gesundheit und Krankheit: Ergebnisse der numerischen Analyse von mehr als tausend menschlichen Thymusdrüsen. Teil I. Das normale Organ — zugleich eine kritische Beleuchtung der Lehre des “Status thymicus”. Z Mikr Anat Forsch (Leipzig) 6: 1–570, 1926.

    Google Scholar 

  17. Hammar JA: Die normal-morphologische Thymusforschung im letzten Vierteljahrhundert. Analyse und Synthese. Leipzig, Barth, pp 1–453, 1936.

    Google Scholar 

  18. Maximow AA: Untersuchungen über Blut und Bindegewebe. II. Über die Histogenese der Thymus bei Säugetieren. Arch mikr Anat 74: 525–621, 1909.

    Google Scholar 

  19. Tamemori Y: Untersuchungen über die Thymusdrüse im Stadium der Altersinvolution. Virchows Arch pathol Anat 242: 255–266, 1914.

    Google Scholar 

  20. Fenger F: On the size and composition of the thymus gland. J Biol Chem 20: 115–118, 1915.

    CAS  Google Scholar 

  21. von Haberer H: Zur klinischen Bedeutung der Thymusdrüse. Arch klin Chir 109: 193–248, 1917.

    Google Scholar 

  22. Gedda E: Zur Altersanatomie der Kaninchenthymus. Upsala Lakaref Forh 26: 1–27, 1921.

    Google Scholar 

  23. De Sanctis S: Les enfants dysthymiques. Encephale 18: 1, 88, 156, 1923.

    Google Scholar 

  24. Bratton AB: The normal weight of the human thymus. J Pathol Bacteriol 28: 609–620, 1925.

    Article  Google Scholar 

  25. Scammon RE: The prenatal growth of the human thymus. Proc Soc Exp Biol Med 24: 906–909, 1927.

    Google Scholar 

  26. Young M, Turnbull HM: An analysis of the data collected by the status lymphaticus investigation committee. J Pathol Bacteriol 34: 213–258, 1931.

    Article  Google Scholar 

  27. Boyd E: The weight of the thymus gland in health and in disease. Am J Dis Child 43: 1162–1214, 1932.

    Google Scholar 

  28. Carr JL: Status thymicolymphaticus. J Pediatr 27: 1–43, 1945.

    Article  Google Scholar 

  29. Manning MJ: A comparative view of the thymus in vertebrates. In: The Thymus Gland (Kendall MD, ed). New York, Academic Press, pp 7–20, 1981.

    Google Scholar 

  30. Simpson JG, Gray ES, Beck JS: Age involution in the normal adult thymus. Clin Exp Immunol 19: 261–265, 1975.

    PubMed  CAS  Google Scholar 

  31. Bodey B: Histomorphology and histochemistry of the human thymus during its prenatal ontogenesis. Dissertation, Inst Morphol, Bulg Acad Sci, Sofia, Bulgaria, 1977, pp 1–360.

    Google Scholar 

  32. von Gaudecker B: Ultrastructure of the age-involuted adult human thymus. Cell Tissue Res 186: 507–525, 1978.

    Article  Google Scholar 

  33. Kendall MD, Johnson HR, Singh J: The weight of the human thymus gland at necropsy. J Anat 131: 483–488, 1981.

    Google Scholar 

  34. Oosterom R, Kater L: The thymus in the aging individual. I. Mitogen responsiveness of human thymocytes. Clin Immunol Immunopathol 18: 187–194, 1981.

    Article  PubMed  CAS  Google Scholar 

  35. Oosterom R, Kater L: The thymus in the aging individual. II. Thymic epithelial function in vitro in aging and in thymus pathology. Clin Immunol Immunopathol 18: 195–202, 1981.

    Article  PubMed  CAS  Google Scholar 

  36. Steinmann GG, Klaus B, Müller-Hermelink H-K: The involution of the ageing human thymic epithelium is independent of puberty. Scand J Immunol 22: 563–575, 1985.

    Article  PubMed  CAS  Google Scholar 

  37. Simmons VP: Thymic “atrophy” at puberty is a myth. Med Hypotheses 22: 299–301, 1987.

    Article  PubMed  CAS  Google Scholar 

  38. George AJT, Ritter MA: Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today 17: 267–272, 1996.

    Article  PubMed  CAS  Google Scholar 

  39. Strandberg A: Zur Frage des intrathymischen Bindegewebes. Anat Hefte 55: 169–186, 1917—18.

    Article  Google Scholar 

  40. Täkhä H: The weight of the thymus in children of 0–2 years of age. Acta Paediatr Scand 40: 469–485, 1951.

    Article  Google Scholar 

  41. Blau JN: Histological changes and macrophage activity in the adult guinea-pig thymus. Br J Exp Pathol 52: 142–146, 1971.

    PubMed  CAS  Google Scholar 

  42. von Gaudecker B: Die fortschreitende Erweiterung mesodermaler perivaskulärer Räume im Thymus des Menschen. Verh Anat Ges 71: 783–787, 1977.

    Google Scholar 

  43. Kendall MD: The morphology of perivascular space in the thymus. Thymus 13: 157–164, 1989.

    PubMed  CAS  Google Scholar 

  44. Herrmann T: Das Auftreten des Fettgewebes im menschlichen Thymus. Anat Anz 46: 357–359, 1914.

    Google Scholar 

  45. Marine D, Manley OT, Baumann EJ: The influence of thyroidectomy, gonadectomy, suprarenalectomy, and splenectomy on the thymus glands of rabbits. J Exp Med 40: 429–443, 1924.

    Article  PubMed  CAS  Google Scholar 

  46. Metalnikof AE: Rôle du systéme nerveux et des facteurs biologiques et psychiques dans ľimmunité. Masson, Paris, 1934.

    Google Scholar 

  47. Evans HM, Simpson ME: Reduction of the thymus by gonadotropic hormone. Anat Rec 60: 423–435, 1934.

    Article  CAS  Google Scholar 

  48. Dougherty TF: Effect of hormones on lymphatic tissue. Physiol Rev 32: 379–401, 1952.

    PubMed  CAS  Google Scholar 

  49. Pierpaoli W, Sorkin E: Relationship between thymus and hypophysis. Nature 215: 834–837, 1967.

    Article  Google Scholar 

  50. Trainin N: Thymic hormones and the immune response. Physiol Rev 54: 272–315, 1974.

    PubMed  CAS  Google Scholar 

  51. Trainin N, Kook AI, Umel T, Albala M: The nature and mechanism of stimulation of immune responsiveness by thymus extracts. Ann NY Acad Sci 249: 349–361, 1975.

    Article  PubMed  CAS  Google Scholar 

  52. Bach J-F, Carnaud C: Thymic factors. Prog Allergy 21: 342–408, 1976.

    PubMed  CAS  Google Scholar 

  53. Bach J-F, Dardenne M, Pleau J-M: Biochemical characterization of a serum thymic factor. Nature 266: 55–56, 1977.

    Article  PubMed  CAS  Google Scholar 

  54. Grossman CJ: Regulation of the immune system by sex steroid. Endocrine Rev 5: 435–454, 1984.

    CAS  Google Scholar 

  55. Berczi I: Immunoregulation by pituitary hormones. In: Pituitary Function and Immunity (Berczi I, ed) Boca Raton, CRC Press, pp 227–240, 1986.

    Google Scholar 

  56. Hiestand PC, Mekler P, Nordmann R, Grieder A, Permmongkol C: Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosporin. Proc Natl Acad Sci USA 83: 2599–2603, 1986.

    Article  PubMed  CAS  Google Scholar 

  57. Jankovic BD: Neuroimmunomodulation: facts and dilemmas. Immunol Lett 21: 101–118, 1989.

    Article  PubMed  CAS  Google Scholar 

  58. Dardenne M, Kelly PA, Bach JF, Savino W: Identification and functional activity of prolactin receptors in thymic epithelial cells. Proc Natl Acad Sci USA 88: 9700–9704, 1991.

    Article  PubMed  CAS  Google Scholar 

  59. Greenstein BD, de Bridges EF, Fitzpatrick FT: Aromatase inhibitors regenerate the thymus in aging male rats. Int J Immunopharmacol 14: 541–553, 1992.

    Article  PubMed  CAS  Google Scholar 

  60. Besedovsky HO, del Rey A: Immune-neuroendocrine circuits: integrative role of cytokines. Front Neuroendocrinol 13: 61–94, 1992.

    PubMed  CAS  Google Scholar 

  61. Clarke AG, Kendall MD: The thymus in pregnancy: the interplay of neural, endocrine and immune influences. Immunol Today 15: 545–551, 1994.

    Article  PubMed  CAS  Google Scholar 

  62. Hartwig M, Steinmann G: On a causal mechanism of chronic thymic involution in man. Mech Ageing Develop 75: 151–156, 1994.

    Article  CAS  Google Scholar 

  63. Deschaux P, Khan NA: Immunophysiology: The immune system as a multifunctional physiological unit. Cell Mol Biol Res 41: 1–10, 1995.

    PubMed  CAS  Google Scholar 

  64. Eidinger D, Garrett TJ: Studies of the regulatory effects of the sex hormones on antibody formation and stem cell differentiation. J Exp Med 136: 1098–1116, 1972.

    Article  PubMed  CAS  Google Scholar 

  65. Pearce PT, Khalid BA, Funder JW: Progesterone receptors in rat thymus. Endocrinology 113: 1287–1291, 1983.

    PubMed  CAS  Google Scholar 

  66. Barr IG, Pyke KW, Pearce P, Toh B-H, Funder JW: Thymic sensitivity to sex hormones develops post-natally; an in vivo and in vitro study. J Immunol 132: 1095–1099, 1984.

    PubMed  CAS  Google Scholar 

  67. Luster MI, Hayes HT, Korach K, Tucker AN, Dean JH, Greenlee WF, Boorman GA: Estrogen immunosuppression is regulated through estrogenic responses in the thymus. J Immunol 133: 110–116, 1984.

    PubMed  CAS  Google Scholar 

  68. Carr DJJ: Neuroendocrine peptide receptors on cells of the immune system. In: Neuroimmunoendocrinology (Blalock JE, ed) Basel, Karger, pp 84–99, 1992.

    Google Scholar 

  69. Halnan ET, Marshall FHA: On the relation between the thymus and the generative organs and the influence of these organs upon growth. Proc Roy Soc s B 88: 68–89, 1914.

    Google Scholar 

  70. Pappenheimer AM: The thymus gland and its possible relation to the female genital tract. Surg Gynec Obstr 25: 276–283, 1917.

    CAS  Google Scholar 

  71. Paton DN: The relationship of the thymus and testes to growth. Edinborough Med J 33: 351–356, 1926.

    Google Scholar 

  72. Plagge JC: The thymus gland in relation to sex hormones and reproductive processes in albino rat. J Morphol 68: 519–545, 1941.

    Article  Google Scholar 

  73. Ross MA, Korenchevsky V: The thymus of rat and sex hormones. J Pathol Bacteriol 52: 349–360, 1941.

    Article  CAS  Google Scholar 

  74. Grégoire C: Hormones sexuelles, thymus et tissu lymphoïde. Compt Rend Soc Biol 138: 131–132, 1944.

    Google Scholar 

  75. Grégoire C: Sur le mécanisme de ľhypertrophie thymique déclenchée par la castration. Arch Internat Pharmacodyn Thérap 71: 147–163, 1945.

    Google Scholar 

  76. Grégoire C: Failure of lactogenic hormone to maintain pregnancy involution of thymus. J Endocrinol 5: 115–120, 1947.

    PubMed  Google Scholar 

  77. Smith EM: Hormonal activities of lymphokines, monokines and other cytokines. Prog Allergy 43: 121–139, 1988.

    PubMed  CAS  Google Scholar 

  78. Smith EM: Hormonal activities of cytokines. In: Neuroimmunoendocrinology (Blalock JE, ed) Basel, Karger, pp 154–169, 1992.

    Google Scholar 

  79. Kavelaars A, Ballieux RE, Heijnen CJ: The role of interleukin in the CRF and AVP induced secretion of β endorphin by human peripheral blood mononuclear cells. J Immunol 142: 2338–2342, 1989.

    PubMed  CAS  Google Scholar 

  80. Besedovsky HO, del Rey A: Immune-Neuro-Endocrine Interactions: Facts and Hypotheses. Endocrine Rev 17: 64–102, 1996.

    Article  CAS  Google Scholar 

  81. Besedovsky HO, Sorkin E: Involvement of the thymus in female sexual maturation. Nature 249: 356–358, 1974.

    Article  PubMed  CAS  Google Scholar 

  82. Gottschall PE, Katsuura G, Arimura A: Interleukin-1β is more potent than interleukin-1α in suppressing folliclestimulating hormone-induced differentiation of ovarian granulosa cells. Biochem Biophys Res Commun 163: 764–770, 1989.

    Article  PubMed  CAS  Google Scholar 

  83. Rivier C, Vale W: Cytokines act within the brain to inhibit luteinizing hormone secretion and ovulation in the rat. Endocrinology 127: 849–856, 1990.

    PubMed  CAS  Google Scholar 

  84. Kalra PS, Sahu A, Kalra SP: Interleukin-1 inhibits the ovarian steroid induced luteinizing hormone surge and release of hypothalamic luteinizing hormone-releasing hormone in rats. Endocrinology 126: 2145–2152, 1990.

    PubMed  CAS  Google Scholar 

  85. DiGeorge AM: Congenital absence of the thymus and its immunological consequences: Concurrence with congenital hypothyroidism. Birth Defects Orig Artic Ser 4: 116, 1968.

    Google Scholar 

  86. Cardier AC, Haumont SM: Development of thymus, parathyroids, and ultimobranchial-bodies NMRI and nude mice. Am J Anat 157: 227–263, 1980.

    Article  Google Scholar 

  87. Lindeberg W: Ueber den Einfluss der Thymektomie auf den Gesamtorganismus und auf die Drusen mit innerer Sekretion, insbesondere die Epiphyse und Hypophyse. Folia neuropathol eston 2: 42–108, 1924.

    Google Scholar 

  88. Greenstein BD, Fitzpatrick FTA, Adcock IM, Kendall MD, Wheeler MJ: Reappearance of the thymus in old rats after orchidectomy: inhibition of regeneration by testosterone. J Endocrinol 110: 417–422, 1986.

    PubMed  CAS  Google Scholar 

  89. Kelley KW, Davila DR, Brief S, Simon J, Arkins S: A Pituitary-Thymus Connection during Aging. Ann NY Acad Sci 521: 88–98, 1988.

    Article  PubMed  CAS  Google Scholar 

  90. Charleton W: Exercitat. phys. anat. de oeconomia minimalum. Amstelod, 1659.

    Google Scholar 

  91. Comsa J: Hormonal interactions of the thymus. In: Thymic Hormones (Luckey TD, ed) Baltimore, University Park Press, 1973.

    Google Scholar 

  92. Smith KA, Crabtree GR, Kennedy SJ, Munck AU: Glucocorticoid receptors and glucocorticoid sensitivity of mitogen stimulated and unstimulated human lymphocytes. Nature 267: 523–525, 1977.

    Article  PubMed  CAS  Google Scholar 

  93. Comsa J, Leonhardt H, Wekerle H: Hormonal Coordination of the Immune Response. Rev Physiol Biochem Pharmacol 92: 115–191, 1982.

    Article  PubMed  CAS  Google Scholar 

  94. Smith LR, Brown SL, Blalock JE: Interleukin-2 induction of ACTH secretion: presence of an interleukin-2 receptor α-chain-like molecule on pituitary cells. J Neuroimmunology 21: 249–254, 1989.

    Article  CAS  Google Scholar 

  95. Cardarelli NF (ed): The Thymus in Health and Senescence, Volume 2: Aging and Endocrinology. Boca Raton, CRC Press, pp 43–78, 1989.

    Google Scholar 

  96. Basch K: Die Beziehung der Thymus zur Schilddruse. Ztschr exp Pathol Ther 12: 180–206, 1912/13.

    Article  Google Scholar 

  97. Fabris N, Muzzioli M, Mocchegiani E: Recovery of agedependent immunological deterioration in Balb/C mice by short-term treatment with L-thyroxine. Mech Aging Dev 18: 327–338, 1982.

    Article  PubMed  CAS  Google Scholar 

  98. Fulci F: Die Restitutionsfahigkeit des Thymus der Saugetiere nach der Schwangerschaft: vorlaufige Mitteilung. Zentralbl allgem Pathol pathol Anat 24: 968–974, 1913.

    Google Scholar 

  99. Grinevich IuA, Kokhanevich EV, Iugrinova LG, Labunets IF, Patskan II, Tsip NI: Changes in the neuroendocrine and immune state of adaptational homeostasis in normal pregnancy. Fiziolog Zhurnal 39: 61–67, 1993.

    Google Scholar 

  100. Pepper FJ: The effect of age, pregnancy and lactation on the thymus gland and lymph nodes of the mouse. J Endocrinol 22: 335–348, 1961.

    PubMed  CAS  Google Scholar 

  101. Soffer LJ, Gabrilove JL, Wolf BS: Effect of ACTH on thymic masses. J Clin Endocrinol 12: 690–696, 1952.

    Article  CAS  Google Scholar 

  102. Arrenbrecht S: Specific binding of growth hormone to thymocytes. Nature 252: 255–257, 1974.

    Article  PubMed  CAS  Google Scholar 

  103. Salas MA, Evans SW, Levell MJ, Whicher JT: Interleukin-6 and ACTH act synergistically to stimulate the release of corticosterone from adrenal gland cells. Clin Exp Immunol 79: 470–473, 1990.

    PubMed  CAS  Google Scholar 

  104. Hussein MF, Badir N, el-Ridi R, Akef M: Differential effect on seasonal variation on lymphoid tissue of the lizard, Chalcides ocellatus. Dev Comp Immunol 2: 297–309, 1978.

    Article  PubMed  CAS  Google Scholar 

  105. Hussein MF, Badir N, el-Ridi R, Akef M: Effect of seasonal variation on lymphoid tissues of the lizards, Mabuya quinquetaeniata Licht. and Uromastyx aegyptia Forsk. Dev Comp Immunol 2: 469–478, 1978.

    Article  PubMed  CAS  Google Scholar 

  106. Zapata AG, Varas A, Torroba M: Seasonal variations in the immune system of lower vertebrates. Immunol Today, 142: 142–147, 1992.

    Article  Google Scholar 

  107. Browman LG, Sears HS: Cyclic variation in the mule deer thymus. Proc Soc Exp Biol Med 93: 161–162, 1956.

    PubMed  CAS  Google Scholar 

  108. Bargmann W: Der Thymus. In: Handbuch der mikroskopischen Anatomie des Menschen, Blutgefäss-und Lymphgefässapparat Innersekretorische Drüsen. Ergänzung zu Band VI/1 (von Möllendorf W, herausgeben). Berlin, Springer Verlag, pp 1–172, 1943.

    Google Scholar 

  109. Henry L: “Accidental” involution of the human thymus. J Pathol Bacteriol 96: 337–343, 1968.

    Article  PubMed  CAS  Google Scholar 

  110. Kendall MD, Johnson HR, Singh J: The weight of the human thymus gland at necropsy. J Anat 131: 483–497, 1980.

    PubMed  CAS  Google Scholar 

  111. Kendall MD: Age and seasonal changes in the thymus. In: The thymus gland (Kendall MD, ed). London, Academic Press, pp 21–35, 1981.

    Google Scholar 

  112. Calvo W, Fliedner TM, Herbst EW, Hugl E, Bodey B: Degenerative changes and recovery of the thymus of lethally irradiated dogs, rescued by transfusion of cryopreserved autologous blood leukocytes. Exp Hematol 15: 1171–1178, 1987.

    PubMed  CAS  Google Scholar 

  113. Titova LD, Yarilin AA, Sharova NI, Oradovskaya IV: The quantitatives of T-cell subpopulation and level of α1-thymosin and autoantibodies reacting with thymic epithelium in serum of persons, who worked in 30-km zone of Chernobyl atomic electronic station. Radiatzion Biol Radioekol 36: 601–609, 1996.

    CAS  Google Scholar 

  114. Metcalf D, Sparrow N, Nakamura K, Ishidate M: The behaviour of thymus grafts in high and low leukaemia strains of mice. Australian J Exp Biol Med Sci 39: 441–453, 1961.

    Article  CAS  Google Scholar 

  115. Metcalf D: The autonomous behaviour of normal thymus grafts. Australian J Exp Biol Med Sci 41: 437–447, 1963.

    Article  Google Scholar 

  116. Davies AJS, Leuchars E, Wallis V, Koller PC: The mitotic response of thymus-derived cells to antigenic stimulus. Transplantation 4: 438–451, 1966.

    PubMed  CAS  Google Scholar 

  117. Metcalf D, Moulds R, Pike B: Influence of the spleen and thymus on immune responses in ageing mice. Clin Exp Immunol 2: 109–120, 1967.

    PubMed  CAS  Google Scholar 

  118. Price GB, Makinodan T: Immunologic deficiencies in senescence. II. Characterization of extrinsic deficiencies. J Immunol 108: 413–417, 1972.

    PubMed  CAS  Google Scholar 

  119. Kelley KW, Brief S, Westly HJ, Novakofski J, Bechtel PJ, Simon J, Walker EB: GH3 pituitary adenoma cells can reverse thymic aging in rats. Proc Natl Acad Sci USA 83: 5663–5667, 1986.

    Article  PubMed  CAS  Google Scholar 

  120. Gottlieb M, Strober S, Kaplan HS: Allogeneic marrow transplantation after total lymphoid irradiation (TLI): effect of dose/fraction, thymic irradiation, delayed marrow infusion, and presensitization. J Immunol 123: 379–383, 1979.

    PubMed  CAS  Google Scholar 

  121. Blomgren H, Andersson B: Reappearance and relative importance of immunocompetent cells in the thymus, spleen and lymph nodes following lethal x-irradiation and bone marrow reconstitution in mice. J Immunol 106: 831–834, 1971.

    PubMed  CAS  Google Scholar 

  122. Grégoire C: Action des rayons X sur le thymus au cours de ľhistogénèse. C R Assoc Anat (Paris) 27: 328–335, 1932.

    Google Scholar 

  123. Tyan ML: Impaired thymic regeneration in lethally irradiated mice given bone marrow from aged donors. Proc Soc Exp Biol Med 152: 33–35, 1976.

    PubMed  CAS  Google Scholar 

  124. Tyan ML: Age-related decrease in mouse T cell progenitors. J Immunol 118: 846–851, 1977.

    PubMed  CAS  Google Scholar 

  125. Hinsull SM, Bellamy D, Franklin A: A quantitative histological assessment of cellular death, in relation to mitosis, in rat thymus during growth and age involution. Age Ageing 6: 77–84, 1977.

    Article  PubMed  CAS  Google Scholar 

  126. Evans RL, Wall DW, Platsoucas CD, Siegal FP, Fikrig SM, Testa CM, Good RA: Thymus-dependent membrane antigens in man: inhibition of cell-mediated lympholysis by monoclonal antibodies to the TH2 antigen. Proc Natl Acad Sci USA 78: 544–548, 1981.

    Article  PubMed  CAS  Google Scholar 

  127. Steinmann GG: Changes in the human thymus during aging. In: The Human Thymus. Current Topics in Pathology, Volume 75 (Müller-Hermelink HK, ed) Berlin, Springer Verlag, pp 43–88, 1986.

    Google Scholar 

  128. Bodey B: Development of lymphopoiesis as a function of the thymic microenvironment. Use of CD8+ cytotoxic T lymphocytes for cellular immunotherapy of human cancer. IN VIVO 8: 915–943, 1994.

    PubMed  CAS  Google Scholar 

  129. Tosi P, Kraft R, Luzi P, Cintorino M, Fankhauser G, Hess MW, Cottier H: Involution patterns of the human thymus. I. Size of the cortical area as a function of age. Clin Exp Immunol 47: 497–504, 1982.

    PubMed  CAS  Google Scholar 

  130. Dunn RJ, Luedecker CJ, Haugen HS, Clegg CH, Farr AG: Thymic overexpression of CD40 ligand disrupts normal thymic epithelial organization. J Histochem Cytochem 45: 129–141, 1997.

    PubMed  CAS  Google Scholar 

  131. Kaye J, Ellenberger DL: Differentiation of an immature T cell line: a model of thymic positive selection. Cell 71: 423–435, 1992.

    Article  PubMed  CAS  Google Scholar 

  132. Hollander GA, Wang B, Nichogiannopoulou A, Platenburg PP, van Ewijk W, Burakoff SJ, Gutierrez-Ramos J-C, Terhorst C: Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373: 350–353, 1995.

    Article  PubMed  CAS  Google Scholar 

  133. Collins C, Norris S, McEntee G, Traynor O, Bruno L, von Boehmer H, Hegarty J, O’Farrelly C: RAG1, RAG2 and pre-T cell receptor a chain expression by adult human hepatic T cells: evidence for extrathymic T cell maturation. Eur J Immunol 26: 3114–3118, 1996.

    Article  PubMed  CAS  Google Scholar 

  134. Groves T, Parsons M, Miyamoto NG, Guidos CJ: TCR engagement of CD4+ CD8+thymocytes in vitro induces early aspects of positive selection, but not apoptosis. J Immunol 158: 65–75, 1997.

    PubMed  CAS  Google Scholar 

  135. Kruisbeek AM, Astaldi GCB: Distinct effects of thymic epithelial culture supernatants on T cell properties of mouse thymocytes separated by the use of peanut agglutinin. J Immunol 123: 984–991, 1979.

    PubMed  CAS  Google Scholar 

  136. van Ewijk W, Rouse RV, Weisman IL: Distribution of H-2 microenvironments in the mouse thymus. Immunoelectron microscopic identification of I-A and H-2K bearing cells. J Histochem Cytochem 28: 1089–1099, 1980.

    PubMed  Google Scholar 

  137. van Vliet E, Melis M, Ewijk W: Monoclonal antibodies to stromal cell types of the mouse thymus. Eur J Immunol 14: 524–529, 1984.

    Article  PubMed  Google Scholar 

  138. Kendall MD, van de Wijngaert FP, Schuurman HJ, Rademakers LH, Kater L: Heterogeneity of the human thymus epithelial microenvironment at the ultrastructural level. Adv Exp Med Biol 186: 289–297, 1985.

    PubMed  CAS  Google Scholar 

  139. de Maagd RA, MacKenzie WA, Schuurman HJ, Ritter MA, Price KM, Broekhuizen R, Kater L: The human thymus microenvironment: heterogeneity detected by monoclonal anti-epithelial cell antibodies. Immunology 54: 745–754, 1985.

    PubMed  Google Scholar 

  140. Ritter MA, Schuurman HJ, MacKenzie WA, de Maagd RA, Price KM, Broekhuizen R, Kater L: Heterogeneity of human thymus epithelial cells revealed by monoclonal antiepithelial cell antibodies. Adv Exp Med Biol 186: 283–288, 1985.

    PubMed  CAS  Google Scholar 

  141. von Gaudecker B, Steinmann GG, Hansmann ML, Harpprecht J, Milicevic NM, Müller-Hermelink HK: Immunocytochemical characterization of the thymic microenvironment. A light-microscopic and ultrastructural immunocytochemical study. Cell Tissue Res 244: 403–412, 1986.

    Article  Google Scholar 

  142. van Ewijk W: T-cell differentiation is influenced by thymic microenvironments. Annu Rev Immunol 9: 591–615, 1991.

    Article  PubMed  Google Scholar 

  143. Anderson G, Jenkinson EJ, Moore NC, Owen JJ: MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362: 70–73, 1993.

    Article  PubMed  CAS  Google Scholar 

  144. Muller KP, Kyewski BA: T cell receptor targeting to thymic cortical epithelial cells in vivo induces survival, activation and differentiation of immature thymocytes. Eur J Immunol 23: 1661–1670, 1993.

    Article  PubMed  CAS  Google Scholar 

  145. Bodey B, Kaiser HE: Development of Hassall’s bodies of the thymus in humans and other vertebrates (especially mammals) under physiological and pathological conditions: Immunocytochemical, electronmicroscopic and in vitro observations. In Vivo 11: 61–86, 1997.

    PubMed  CAS  Google Scholar 

  146. Bhan AK, Reinherz EL, Poppema S, McCluskey RT, Schlossman SF: Location of T cell and major histocompatibility complex antigens in the human thymus. J Exp Med 152: 771–782, 1980.

    Article  PubMed  CAS  Google Scholar 

  147. Janossy G, Thomas JA, Bollum FJ, Granger S, Pizzolo G, Bradstock KF, Wong L, McMichael A, Ganeshaguru K, Hoffbrand AV: The human thymic microenvironment: an immunohistologic study. J Immunol 125: 202–212, 1980.

    PubMed  CAS  Google Scholar 

  148. Wolf SS, Cohen A: Expression of cytokines and their receptors by human thymocytes and thymic stromal cells. Immunology 77: 362–368, 1992.

    PubMed  CAS  Google Scholar 

  149. Wekerle H, Ketelsen U-P, Ernst M: Thymic nurse cells. Lymphoepithelial complexes in murine thymuses: morphological and serological characterization. J Exp Med 151: 925–944, 1980.

    Article  PubMed  CAS  Google Scholar 

  150. Vakharia DD: Demonstration of keratin filaments in thymic nurse cells (TNC) and alloreactivity of TNC-T cell population. Thymus 5: 43–52, 1983.

    PubMed  CAS  Google Scholar 

  151. Vakharia DD, Mitchison NA: Helper T cell activity demonstrated by thymic nurse cells (TNC-T). Immunol 51: 269–273, 1984.

    CAS  Google Scholar 

  152. van Vliet E, Melis M, van Ewijk W: Immunohistology of thymic nurse cells. Cell Immunol 87: 101–109, 1984.

    Article  PubMed  Google Scholar 

  153. Geenen V, Defresne MP, Robert F, Legros JJ, Franchimont P, Boniver J: The neurohormonal thymic microenvironment: immunocytochemical evidence that thymic nurse cells are neuroendocrine cells. Neuroendocrinology 47: 365–368, 1988.

    Article  PubMed  CAS  Google Scholar 

  154. Penninger J: Phenotypic and functional analysis of thymic nurse cell (TNC)-lymphocytes. Wien Klin Wochenschr 103: 45–50, 1991.

    PubMed  CAS  Google Scholar 

  155. Carr K, Lowry T, Li LL, Tsai C, Stoolman L, Fox DA: Expression of CD60 on multiple cell lineages in inflammatory synovitis. Lab Invest 73: 332–338, 1995.

    PubMed  CAS  Google Scholar 

  156. Bodey B, Bodey B Jr, Kemshead JT, Siegel SE, Kaiser HE: Identification of neural crest derived cells within the cellular microenvironment of the human thymus employing a library of monoclonal antibodies raised against neuronal tissues. In Vivo 10: 39–47, 1996.

    PubMed  CAS  Google Scholar 

  157. Miller HC, Vito C: Action of a thymic cytokine TsIF™ in reversing the autoimmune disease state of the MRL/1pr mouse. Mol Biother 1: 213–217, 1989.

    PubMed  CAS  Google Scholar 

  158. Grégoire C: Recherches sur le symbiose lymphoepitheliale au niveau du thymus de mammifere. Arch Biol 46: 717–820, 1935.

    Google Scholar 

  159. Grégoire C, Duchateau G: A study on lympho-epithelial symbiosis in thymus. Reactions of the lymphatic tissue to extracts and to implants of epithelial components of thymus. Arch Biol 68: 269–296, 1956.

    Google Scholar 

  160. Kendall MD, van de Wijngaert FP, Schuurman H-J, Rademakers LHPM, Kater L: Heterogeneity of the human thymus epithelial microenvironment at the ultrastructural level. In: Microenvironment in the lymphoid system. Adv Exp Med Biol 186: 289–297, 1985.

    PubMed  CAS  Google Scholar 

  161. Hirokawa K, Saitoh K: Abstract # 3-3-14, 4th International Congress of Immunology, Paris, 1980.

    Google Scholar 

  162. Monier JC, Dardenne M, Pléau JM, Schmitt D, Deschaux P, Bach JF: Characterization of facteur thymique sérique (FTS) in the thymus. I. Fixation of anti-FTS antibodies on thymic reticuloepithelial cells. Clin Exp Immunol 42: 470–476, 1980.

    PubMed  CAS  Google Scholar 

  163. Schmitt D, Monier JC, Dardenne M, Pléau JM, Deschaux P, Bach JF: Cytoplasmic localization of FTS (facteur thymique sérique) in thymic epithelial cells. An immunoelectronmicroscopical study. Thymus 2: 177–186, 1980.

    PubMed  CAS  Google Scholar 

  164. Schmitt D, Monier JC, Dardenne M, Pléau JM, Bach JF: Location of FTS (facteur thymique sérique) in the thymus of normal and auto-immune mice. Thymus 4: 221–231, 1982.

    PubMed  CAS  Google Scholar 

  165. Jambon B, Montagne P, Bene MC, Brayer MP, Faure G, Duheille J: Immunohistologic localization of “facteur thymique sérique” (FTS) in human thymic epithelium. J Immunol 127: 2055–2059, 1981.

    PubMed  CAS  Google Scholar 

  166. Savino W, Dardenne M: Thymic hormone containing cells. VI. Immunohistologic evidence for the simultaneous presence of thymulin, thymopoietin and thymosin α1 in normal and pathological human thymuses. Eur J Immunol 14: 987–992, 1984.

    Article  PubMed  CAS  Google Scholar 

  167. Bach JF, Dardenne M, Papiernik M, Barois A, Levasseur P, LeBrigand H: Evidence of a serum factor produced by the human thymus. Lancet 2: 1056–1058, 1972.

    Article  PubMed  CAS  Google Scholar 

  168. Goldstein AL, Guha A, Zatz MM, Hardy MA, White A: Purification and biological activity of thymosin, a hormone of the thymus gland. Proc Natl Acad Sci USA 69: 1800–1803, 1972.

    Article  PubMed  CAS  Google Scholar 

  169. Goldstein G: Isolation of bovine thymIn: A polypeptide hormone of the thymus. Nature 247: 11–14, 1974.

    Article  PubMed  CAS  Google Scholar 

  170. Hirokawa K, McClure JE, Goldstein AL: Age-related changes in localization of thymosin in the human thymus. Thymus 4: 19–29, 1982.

    PubMed  CAS  Google Scholar 

  171. Goldstein AL (ed): Thymic Hormones and Lymphokines. New York, Plenum Press, pp 1–600, 1984.

    Google Scholar 

  172. Fabris N, Mocchegiani E, Amadio L, Zannotti M, Licastro F, Franceschi C: Thymic hormone deficiency in normal aging and Down’s syndrome: Is there a primary failure of the thymus? Lancet 1: 983–986, 1984.

    Article  PubMed  CAS  Google Scholar 

  173. Okimoto T, Kinoshita Y, Hato F, Toyokawa T, Kimura S, Kinoshita H: Effects of thymosin on soybean lectin responsiveness of thymic small lymphocyte subsets from streptozotocin-induced diabetic rats. Cell Mol Biol 34: 465–472, 1988.

    PubMed  CAS  Google Scholar 

  174. Kawashima I, Sakabe K, Seiki K, Fujii-Hanamoto H, Akatsuka A, Tsukamoto H: Localization of sex steroid receptor cells, with special reference to thymulin (FTS)-producing cells in female rat thymus. Thymus 18: 79–93, 1991.

    PubMed  CAS  Google Scholar 

  175. Goldstein AL, Hooper JA, Schulof RS, Cohen GH, Thurman GB, McDaniel MC, White A, Dardenne M: Thymosin and the immunopathology of aging. Fed Proc 33: 2053–2056, 1974.

    PubMed  CAS  Google Scholar 

  176. Lewis VM, Twomey JJ, Bealmear P, Goldstein G, Good RA: Age, thymic involution and circulating thymic hormone activity. J Clin Endocrinol Metab 47: 145–150, 1978.

    Article  PubMed  CAS  Google Scholar 

  177. Waring AJ: The thymus gland in infancy and childhood. J Med Assoc Georgia Atlanta 13: 295–297, 1924.

    Google Scholar 

  178. Andrew W: The Anatomy of Aging in Man and Animals. Grune & Stratton, New York, 1971.

    Google Scholar 

  179. Newberne PM: Dietary fat, immunological response, and cancer in rats. Cancer Res 41: 3783–3785, 1981.

    PubMed  CAS  Google Scholar 

  180. Ritter MA, Lampert IA: The thymus. In: Oxford Textbook of Pathology. Volume 26: Pathology of Systems (McGee JO’D, Isaacson PG, Wright NA, eds). Oxford University Press, pp 1807–1821, 1992.

    Google Scholar 

  181. Hirokawa K, Utsuyama M, Kasai M, Kurashima C, Ishijima S, Zeng YX: Understanding the mechanism of the age-change of thymic function to promote T cell differentiation. Immunol Lett 40: 269–277, 1994.

    Article  PubMed  CAS  Google Scholar 

  182. Cristofalo VJ, Gerhard GS, Pignolo RJ: Molecular biology of aging. Surg Clinics North America 74: 1–21, 1994.

    CAS  Google Scholar 

  183. Toussaint O, Remacle J: Revue critique des theories du vieillissement cellulaire. Du concept de base de Hayflick au concept de seuil critique ďaccumulation ďerreurs. Pathologie Biologie 42: 313–321, 1994.

    PubMed  CAS  Google Scholar 

  184. Weissman A: Essays on Heredity. Clarendon Press, Oxford, England, 1889.

    Google Scholar 

  185. Weissman A: The duration of life. In: Weissman on Heredity. Edition 2 (Poulton EB, Schonland S, Shipley AE, eds) London, Oxford University Press, 1891.

    Google Scholar 

  186. Carrel A: On the permanent life of tissues outside of the organism. J Exp Med 15: 516–528, 1912.

    Article  PubMed  CAS  Google Scholar 

  187. Hayflick L: The establishment of a line (WISH) of human amnion cells in continuous cultivation. Exp Cell Res 23: 14–20, 1961.

    Article  PubMed  CAS  Google Scholar 

  188. Hayflick L, Moorhead PS: The serial cultivation of human diploid cell strains. Exp Cell Res 25: 585–621, 1961.

    Article  Google Scholar 

  189. Hayflick L: The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37: 614–636, 1965.

    Article  PubMed  CAS  Google Scholar 

  190. Hayflick L: The cell biology of human aging. N Engl J Med 295: 1302–1308, 1976.

    Article  PubMed  CAS  Google Scholar 

  191. Kohn RR: Aging and cell division. Science 188: 203–204, 1975.

    Article  PubMed  CAS  Google Scholar 

  192. Bell E, Marek LF, Levinstone DS, Merrill C, Sher S, Young IT, Eden M: Loss of division potential in vitro: Aging or differentiation? Science 202: 1158–1163, 1978.

    Article  PubMed  CAS  Google Scholar 

  193. Williams GC: Pleiotropy, natural selection and the evolution of senescence. Evolution 11: 398–411, 1957.

    Article  Google Scholar 

  194. Szilard L: On the nature of the aging process. Proc Natl Acad Sci USA 45: 30–45, 1959.

    Article  PubMed  CAS  Google Scholar 

  195. Strehler BL: Time, Cells, and Aging. 2nd ed. New York, Academic Press, 1977.

    Google Scholar 

  196. Kohn RR: Aging of animals: Possible mechanism. In: Principles of Mammalian Aging. 2nd Edition. Englewood Cliffs, Prentice-Hall, 1978.

    Google Scholar 

  197. Medawar PB: An unsolved problem of biology. In: The Uniqueness of the Individual. Dover, New York, 1981.

    Google Scholar 

  198. Masoro EJ: Metabolism. In: Handbook of the Biology of Aging. 2nd Edition (Finch CE, Schneider EL, eds) New York, Van Nostrand Reinhold, p 540, 1985.

    Google Scholar 

  199. Rose MR: Evolutionary Biology of Aging. New York, Oxford University Press, 1991.

    Google Scholar 

  200. Moodie RL: General considerations of the evidence of pathological conditions found among fossil animals. In: Diseases in Antiquity (Brothwell D, Sandison AT, eds) Springfield, Charles C. Thomas, p 31, 1967.

    Google Scholar 

  201. Walford RL: Auto-immunity and aging. J Gerontol 17: 281–285, 1962.

    PubMed  CAS  Google Scholar 

  202. Walford RL: Further consideration towards an immunologic theory of aging. Exp Gerontol 1: 67–76, 1964.

    Article  Google Scholar 

  203. Walford RL: Immunology and aging. Philip Levine Award. Am J Clin Pathol 74: 247–253, 1980.

    PubMed  CAS  Google Scholar 

  204. Warner HR, Price AR: Involvement of DNA repair in cancer and aging. J Gerontol 44: 45–54, 1989.

    PubMed  CAS  Google Scholar 

  205. Ram JS: Aging and immunological phenomena: a review. J Gerontol 22: 92–107, 1967.

    PubMed  CAS  Google Scholar 

  206. Burnet FM: An immunological approach to aging. Lancet 2: 358–360, 1970.

    Article  PubMed  CAS  Google Scholar 

  207. Burnet FM: Immunology, Aging and Cancer: Medical Aspects of Mutation and Selection. WH. Freeman & Co, San Francisco, CA, 1976.

    Google Scholar 

  208. Kay MMB: The thymus: Clock for immunologic aging? J Invest Dermatol 73: 29–38, 1979.

    Article  Google Scholar 

  209. Rabin BS: The effect of diet on immune responsiveness and aging. Med Hypoth 8: 495–503, 1982.

    Article  CAS  Google Scholar 

  210. Chandra RK: Trace elements and immune response. Immunol Today, 4: 322–325, 1983.

    Article  CAS  Google Scholar 

  211. Christinck ER, Luscher MA, Barber BH, Williams DB: Peptide binding to class I MHC on living cells and quantitation of complexes required for CTL lysis. Nature 352: 67–70, 1991.

    Article  PubMed  CAS  Google Scholar 

  212. McMichael A: Cytotoxic T lymphocytes and immune surveillance. Cancer Surv 13: 5–21, 1992.

    PubMed  CAS  Google Scholar 

  213. Segre D, Miller RA, Abraham GN, Weigle WO, Warner HR: Aging and the immune system. J Gerontol 44: B164–B168, 1989.

    PubMed  CAS  Google Scholar 

  214. Hu Y, Dietrich H, Herold M, Heinrich PC, Wick G: Disturbed immune-endocrine communication via the hypothalamus-pituitary-adrenal axis in autoimmune disease. Int Arch Allergy Immunol 102: 232–241, 1993.

    Article  PubMed  CAS  Google Scholar 

  215. Everitt AV: The neuroendocrine system and aging. Gerontology 26: 108–119, 1980.

    Article  PubMed  CAS  Google Scholar 

  216. Cotzias GC, Miller ST, Nicholson AR Jr, Maston WH, Tang LC: Prolongation of the life-span in mice adapted to large amounts of L-dopa. Proc Natl Acad Sci USA 71: 2466–2469, 1974.

    Article  PubMed  CAS  Google Scholar 

  217. Levin P, Janda JK, Joseph JA, Ingram DK, Roth GS: Dietary restriction retards the age-associated loss of rat striated dopaminergic receptors. Science 214: 561–562, 1981.

    Article  PubMed  CAS  Google Scholar 

  218. Goya RG, Castro MG, Saphier PW, Sosa YE, Lowry PJ: Thymus-pituitary interactions during ageing. Age Ageing 22: S19–S25, 1993.

    PubMed  CAS  Google Scholar 

  219. Spangelo BL: The thymic-endocrine connection. J Endocrinol 147: 5–10, 1995.

    PubMed  CAS  Google Scholar 

  220. Cutler RG: Evolutionary Biology of Senescence. In: The Biology of Aging (Behnke JA, Finch CE, Moment GB, eds). New York, Plenum Press, pp 311–360, 1978.

    Google Scholar 

  221. Cutler RG: Longevity is determined by specific genes; testing the hypothesis. In: Testing the Theories of Aging (Adelman RC, Roth GS, eds) Boca Raton, CRC Press, p 25, 1982.

    Google Scholar 

  222. Sacher GA: Evolution of longevity and survival characteristics in mammals. In: The Genetics of Aging (Schneider EA, ed) New York, Plenum Press, pp 151–167, 1978.

    Google Scholar 

  223. Sacher GA: 1976 Robert W. Kleemeier Award Lecture: Longevity, aging, and death: an evolutionary perspective. Gerontologist 18: 112–119, 1978.

    PubMed  CAS  Google Scholar 

  224. Selye H: Thymus and adrenals in the response of the organism to injuries and intoxications. Br J Exp Pathol 17: 234–248, 1936.

    CAS  Google Scholar 

  225. Grégoire C: Factors involved in maintaining involution of thymus suckling. J Endocrinol 5: 68–87, 1947.

    PubMed  Google Scholar 

  226. Goodall A: The postnatal changes in the thymus of guineapigs and the effect of castration on thymus structure. J Physiol 32: 191–198, 1905.

    PubMed  CAS  Google Scholar 

  227. Fitzpatrick FTA, Kendall MD, Wheeler MJ, Adcock TM, Greenstein BD: Reappearance of thymus of ageing rats after orchidectomy. J Endocrinol 106: R17–R19, 1985.

    PubMed  CAS  Google Scholar 

  228. Kirkwood TB: Evolution of ageing. Nature 270: 301–304, 1977.

    Article  PubMed  CAS  Google Scholar 

  229. Denckla WD: Systems analysis of possible mechanisms of mammalian aging. Mech Ageing Dev 6: 143–152, 1977.

    Article  PubMed  CAS  Google Scholar 

  230. Holliday R, Huschtscha LI, Tarrant GM, Kirkwood TBL: Testing the commitment theory of cellular aging. Science 198: 366–372, 1977.

    Article  PubMed  CAS  Google Scholar 

  231. Kirkwood TB, Holliday R: The evolution of ageing and longevity. Proc Royal Soc London Ser B Bio Sci 205: 531–546, 1979.

    CAS  Google Scholar 

  232. Holliday R, Huschtscha LI, Kirkwood TBL: Cellular aging: Further evidence for the commitment theory. Science 213: 1505–1508, 1981.

    Article  PubMed  CAS  Google Scholar 

  233. Kirkwood TB, Franceschi C: Is aging as complex as it would appear? New perspectives in aging research. Ann NY Acad Sci 663: 412–417, 1992.

    Article  PubMed  CAS  Google Scholar 

  234. Brunelli R, Frasca D, Spano M, Zichella L, Doria G: Gonadectomy in old mice induces thymus regeneration but does not recover mitotic responsiveness. Ann NY Acad Sci 673: 252–255, 1992.

    Article  PubMed  CAS  Google Scholar 

  235. von Boehmer H, Teh HS, Kisielow P: The thymus selects the useful, neglects the useless and destroys the harmful. Immunol Today 10: 57–61, 1989.

    Article  Google Scholar 

  236. Shortman K, Egerton M, Spangrude GJ, Scollay R: The generation and fate of thymocytes. Sem Immunol 2: 3–12, 1990.

    CAS  Google Scholar 

  237. Aronson M: Hypothesis: Involution of the thymus with aging—programmed and beneficial. Thymus 18: 7–13, 1991.

    PubMed  CAS  Google Scholar 

  238. Aronson M: Involution of the thymus revisited: Immunological trade-offs as an adaptation to aging. Mech Ageing Dev 72: 49–55, 1993.

    Article  PubMed  CAS  Google Scholar 

  239. Hartwig M: Immune control of mammalian aging: A T-cell model. Mech Ageing Dev 63: 207–213, 1992.

    Article  PubMed  CAS  Google Scholar 

  240. Wick G, Hu Y, Schwarz S, Kroemer G: Immunoendocrine communication via the hypothalamus-pituitary-adrenal axis in autoimmune diseases. Endocrine Rev 14: 539–563, 1993.

    Article  CAS  Google Scholar 

  241. Hirokawa K, Utsuyama M, Kasai M, Konno A, Kurashima C, Moriizumi E: Age-related hyperplasia of the thymus and T-cell system in the Buffalo rat. Virchows Arch B Cell Pathol 59: 38–47, 1990.

    Article  CAS  Google Scholar 

  242. Jetten AM, Jetten MER: Possible role of retinoic acid binding protein in retinoid stimulation of embryonal carcinoma cell differentiation. Nature 278: 180–182, 1979.

    Article  PubMed  CAS  Google Scholar 

  243. Trown PW, Palleroni AV, Bohoslawec O, Richelo BN, Halpern JM, Gizzi N, Geiger R, Lewinski C, Machlin LJ, Jetten AM, Jetten MER: Relationship between binding affinities to cellular retionic acid-binding protein and in vivo and in vitro properties for 18 retinoids. Cancer Res 40: 212–220, 1980.

    PubMed  CAS  Google Scholar 

  244. Jetten AM, Deluca LM: Induction of differentiation of embryonal carcinoma cells by retinol: Possible mechanisms. Biochem Biophys Res Commun 114: 593–599, 1983.

    Article  PubMed  CAS  Google Scholar 

  245. Eglitis MA, Sherman MI: Murine embryonal carcinoma cells differentiate in vitro in response to retinol. Exp Cell Res 146: 289–296, 1983.

    Article  PubMed  CAS  Google Scholar 

  246. Strickland S, Breitman TR, Frickel F, Nurrenbach A, Hadicke E, Sporn MB: Structure-activity relationships of a new series of retinoidal benzoic acid derivatives as measured by induction of differentiation of murine F9 teratocarcinoma cells and human HL-60 promyelocytic leukemia cells. Cancer Res 43: 5268–5272, 1983.

    PubMed  CAS  Google Scholar 

  247. Jetten AM: Induction of differentiation of embryonal carcinoma cells by retinoids. In: Retinoids and Cell Differentiation (Sherman MI, ed). Boca Raton, CRC Press, p 105, 1986.

    Google Scholar 

  248. Jetten AM, Anderson K, Deas MA, Kagechika H, Lotan R, Rearick JI, Shudo K: New benzoic acid derivatives with retinoid activity: Lack of direct correlation between biological activity and binding to cellular retinoic acid binding protein. Cancer Res 47: 3523–3527, 1987.

    PubMed  CAS  Google Scholar 

  249. Giguere V, Ong ES, Segui P, Evans RM: Identification of a receptor for the morphogen retinoic acid. Nature 330: 624–629, 1987.

    Article  PubMed  CAS  Google Scholar 

  250. Pierce GB: Teratocarcinoma: Model for a developmental concept of cancer. Curr Top Dev Biol 2: 223–246, 1967.

    Article  PubMed  CAS  Google Scholar 

  251. Sherman MI, Solter D (eds): Teratomas and Differentiation. New York, Academic Press, 1975.

    Google Scholar 

  252. Martin GR: Teratocarcinomas and mammalian embryogenesis. Science 209: 768–776, 1980.

    Article  PubMed  CAS  Google Scholar 

  253. Bolande RP: Models and concepts derived from human teratogenesis and oncogenesis in early life. J Histochem Cytochem 32: 878–884, 1984.

    PubMed  CAS  Google Scholar 

  254. Astigiano S, Sherman MI, Abarzua P: Regulation and patterns of endogenous and exogenous gene expression during differentiation of embryonal carcinoma cells. Envir Health Persp 80: 25–38, 1989.

    Article  CAS  Google Scholar 

  255. Strickland S, Mahdavi V: The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell 15: 393–403, 1978.

    Article  PubMed  CAS  Google Scholar 

  256. Strickland S, Smith KK, Marotti KR: Hormonal induction of differentiation in teratocarcinoma stem cells: Generation of parietal endoderm by retinoic acid and dibutyryl cAMP. Cell 21: 347–355, 1980.

    Article  PubMed  CAS  Google Scholar 

  257. Grover A, Oshima RG, Adamson ED: Epithelial layer formation in differentiating aggregates of F9 embryonal carcinoma cells. J Cell Biol 96: 1690–1696, 1983.

    Article  PubMed  CAS  Google Scholar 

  258. Grover A, Adamson ED: Evidence for the existence of an early common biochemical pathway in the differentiation of F9 cells into visceral or parietal endoderm: Modulation by cyclic AMP. Dev Biol 114: 492–503, 1986.

    Article  PubMed  CAS  Google Scholar 

  259. Good RA, Fernandez G, West A: Nutrition, immunity, and cancer — A review. Part 1: Influence of protein or protein-calorie malnutrition and zinc deficiency on immunity. Clin Bull 9: 3–12, 1979.

    PubMed  CAS  Google Scholar 

  260. Iwata T, Incefy GS, Tanaka T, Fernandes G, Menendez-Botet CI, Pih K, Good RA: Circulating thymic hormone levels in zinc deficiency. Cell Immunol 47: 100–105, 1979.

    Article  PubMed  CAS  Google Scholar 

  261. Prasad AS: Clinical, endocrinological and biochemical effect of zinc-deficiency. Clin Endocrinol Metab 14: 567–589, 1985.

    Article  PubMed  CAS  Google Scholar 

  262. Chandra RK: Nutritional regulation of immunity and risk of infection in old age. Immunology 67: 141–147, 1989.

    PubMed  CAS  Google Scholar 

  263. Sugarman B, Munro HN: Altered (Zn65) chloride accumulation by aged rats adipocytes in vitro. J Nutr 110: 2317–2321, 1985.

    Google Scholar 

  264. Turnlund JR, Durvin N, Costa F, Margen S: Stable isotope studies of zinc absorption and retention in young and elderly men. J Nutr 116: 1239–1247, 1986.

    PubMed  CAS  Google Scholar 

  265. Dardenne M, Boukaiba M-C, Gagnerault F, Homo-Delarche F, Chappnis FP, Lemmonier D, Savino W: Restoration of the thymus in aging mice by in vivo zinc supplementation. Clin Immunol Immunopathol 66: 127–135, 1993.

    Article  PubMed  CAS  Google Scholar 

  266. Fabris N, Mocchegiani E, Muzzioli M, Provinciali M: Zinc, immunity and aging. In: Biochemical Advances in Aging (Goldstein AL, ed) New York, Plenum Press, pp 271–281, 1990.

    Google Scholar 

  267. Fabris N: Neuroendocrine-immune aging: An integrative view on the role of zinc. Ann N Y Acad Sci 719: 353–368, 1994.

    Article  PubMed  CAS  Google Scholar 

  268. Mocchegiani E, Santarelli L, Muzzioli M, Fabris N: Reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice. Int J Immunopharmacol 17: 703–718, 1995.

    Article  PubMed  CAS  Google Scholar 

  269. Mocchegiani E, Fabris N: Age-related thymus involution: zinc reverses in vitro the thymulin secretion defect. Int J Immunopharmacol 17: 745–749, 1995.

    Article  PubMed  CAS  Google Scholar 

  270. Saha AR, Hadden EM, Hadden JW: Zinc induces thymulin secretion from human thymic epithelial cells in vitro and augments splenocyte and thymocyte responses in vivo. Int J Immunopharmacol 17: 729–733, 1995.

    Article  PubMed  CAS  Google Scholar 

  271. Boukaiba N, Flament C, Acher S, Chappuis P, Piau A, Fusselier M, Dardenne M, Lemonnier D: A physiological amount of zinc supplementation: Effects on nutritional, lipid, and thymic status in an elderly population. Am J Clin Nutr 57: 566–572, 1993.

    PubMed  CAS  Google Scholar 

  272. Weksler ME, Innes JB, Goldstein G: Immunologic studies of aging. IV. The contribution of thymic involution to the immune deficiencies of aging mice and reversal with thymopoietin. J Exp Med 148: 996–1006, 1978.

    Article  PubMed  CAS  Google Scholar 

  273. Weksler ME: The immune system and the aging process in man. Proc Soc Exp Biol Med 165: 200–205, 1980.

    PubMed  CAS  Google Scholar 

  274. van der Griend RJ, Carzeno M, van Doorn R, Lempers CJM, van den Ende A, Wijermans P, Oosterhuis HJGH, Astaldi A: Changes in human T lymphocytes after thymectomy and during senescence. J Clin Immunol 2: 289–295, 1982.

    Article  PubMed  Google Scholar 

  275. Good RA, Dalmasso AP, Martinez C, Archer OK, Pierce JC, Papermaster BW: The role of the thymus in development of immunologic capacity in rabbits and mice. J Exp Med 116: 773–796, 1962.

    Article  PubMed  CAS  Google Scholar 

  276. Gross L: Immunologic defect in aged population and its relation to cancer. Cancer 18: 201–204, 1965.

    Article  PubMed  CAS  Google Scholar 

  277. Bach MA: Lymphocyte-mediated cytotoxicity: Effects of ageing, adult thymectomy and thymic factor. J Immunol 119: 641–647, 1977.

    PubMed  CAS  Google Scholar 

  278. Czlonkowska A, Korlak J: The immune response during aging. J Gerontol 34: 9–14, 1979.

    PubMed  CAS  Google Scholar 

  279. Apostoloff E, Friedel E, Apostoloff G, Jakobza D: Zelluläre Immunreaktionen in vivo und in vitro bei Menschen in höheren Lebensalter. ZFA 35: 211–213, 1980.

    PubMed  CAS  Google Scholar 

  280. Abe T, Morimoto C, Toguchi T, Kiyotaki M, Homma M: Evidence of aberration of T-cell subsets in aged individuals. Scand J Immunol 13: 151–157, 1981.

    Article  PubMed  CAS  Google Scholar 

  281. Alder SJ, Morley AA, Seshadri RS: Reduced lymphocyte colony formation with age. Clin Exp Immunol 49: 129–134, 1982.

    PubMed  CAS  Google Scholar 

  282. Moore AV, Korobkin M, Olanow W, Heaston DK, Ram PC, Dunnick NR, Silverman PM: Age related changes in the thymus gland. CT-pathologic correlation. AJR 141: 291, 1983.

    Google Scholar 

  283. Staiano-Coico L, Darzynkiewicz Z, Hefton JM, Dutkowski R, Darlington GJ, Weksler ME: Increased sensitivity of lymphocytes from people over 65 to cell cycle arrest and chromosomal damage. Science 219: 1335–1337, 1983.

    Article  PubMed  CAS  Google Scholar 

  284. Steinmann GG: Altersveränderungen des menschlichen Thymus. Habilitationsschrift, Medizinische Fakultät, Universität Kiel, 1984.

    Google Scholar 

  285. Bjorkholm M, Holm G, Johansson B, Hakan M: T-lymphocyte deficiency following adult thymectomy in man. Scand J Haematol 14: 210–215, 1975.

    PubMed  CAS  Google Scholar 

  286. Walford RL: The Immunologic Theory of Aging. Munksgaard, Copenhagen, pp 1–248, 1969.

    Google Scholar 

  287. Makinodan T, Kay MMB: Age influence on the immune system. Adv Immunol 29: 287–330, 1980.

    Article  PubMed  CAS  Google Scholar 

  288. Benner R, Rijnbeek AM, Bernabe RR, Martinez-Alonso C, Coutinho A: Frequencies of background immunoglobulin-secreting cells in mice as a function of organ, age, and immune status. Immunobiology 158: 225–238, 1981.

    PubMed  CAS  Google Scholar 

  289. Zatz MM, Goldstein AL: Thymosins, lymphokines, and the immunology of aging. Gerontology 31: 263–277, 1985.

    Article  PubMed  CAS  Google Scholar 

  290. Saltzman RL, Peterson PK: Immunodeficiency of the elderly. Rev Infect Dis 9: 1127–1139, 1987.

    PubMed  CAS  Google Scholar 

  291. Ales-Martinez JE, Alvarez-Mon M, Merino F, Bonilla F, Martinez C, Durantez A, De la Hera A: Decreased TcR-CD3+ T cell numbers in healthy aged humans. Evidence that T cell defects are masked by a reciprocal increase of TcR-CD3− CD2+ natural killer cells. Eur J Immunol 18: 1827–1830, 1988.

    Article  PubMed  CAS  Google Scholar 

  292. Brodsky FM, Lem L, Bresnahan PA: Antigen processing and presentation. Tissue Antigens 47: 464–471, 1996.

    Article  PubMed  CAS  Google Scholar 

  293. Kay MMB, Makinodan T: Immunobiology of aging: evaluation of current status. Clin Immunol Immunopathol 6: 394–414, 1976.

    Article  PubMed  CAS  Google Scholar 

  294. Kay MMB, Makinodan T: Relationship between aging and the immune system. Prog Allergy 29: 134–181, 1981.

    PubMed  CAS  Google Scholar 

  295. Bodey B, Calvo W, Prummer O, Fliedner TM, Borysenko M: Development and histogenesis of the thymus in dog. A light and electronmicroscopical study. Dev Comp Immunol 11: 227–238, 1987.

    Article  PubMed  CAS  Google Scholar 

  296. Kincade PW, Lee G, Pietrangeli CE, Hayashi SI, Gimble JM: Cells and molecules that regulate B lymphopoiesis in bone marrow. Ann Rev Immunol 7: 111–143, 1989.

    Article  CAS  Google Scholar 

  297. Sharp A, Zipori D, Toledo J, Tal S, Resnitzky P, Globerson A: Age related changes in hemopoietic capacity of bone marrow cells. Mech Ageing Dev 48: 91–99, 1989.

    Article  PubMed  CAS  Google Scholar 

  298. Dworzak MN, Fritsch G, Buchinger P, Fleischer C, Printz D, Zellner A, Schollhammer A, Steiner G, Ambros PF, Gadner H: Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood. Blood 83: 415–425, 1994.

    PubMed  CAS  Google Scholar 

  299. Olweus J, Lund-Johansen F, Terstappen LW: CD64/Fc γ RI is a granulo-monocytic lineage marker on CD34+ hematopoietic progenitor cells. Blood 85: 2402–2413, 1995.

    PubMed  CAS  Google Scholar 

  300. Tjonnfjord GE, Steen R, Veiby OP, Egeland T: Thymic stromal cells support differentiation of natural killer cells from CD34+ bone marrow cells in vitro. Eur J Haematol 54: 46–50, 1995.

    PubMed  CAS  Google Scholar 

  301. de Bruijn MF, Ploemacher RE, Mayen AE, Voerman JS, Slieker WA, van Ewijk W, Leenen PJ: High-level expression of the ER-MP58 antigen on mouse bone marrow hematopoietic progenitor cells marks commitment to the myeloid lineage. Eur J Immunol 26: 2850–2858, 1996.

    Article  PubMed  Google Scholar 

  302. Dobber R, van den Bergh P, Tielemans M, Schuitemaker J, Nagelkerken L: The sensitivity of IL-4 production for cAMP inducers is lost in CD4+ T cells from aged mice. Int Immunol 5: 1167–1176, 1993.

    Article  PubMed  CAS  Google Scholar 

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(2004). Involution of the Mammalian Thymus and Its Role in the Overall Aging Process. In: Immunological Aspects of Neoplasia — The Role of the Thymus. Cancer Growth and Progression, vol 17. Springer, Dordrecht. https://doi.org/10.1007/1-4020-2185-2_8

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