Advertisement

A biodynamical model of human T-cell development and pathology: design, testing and validation

  • Michael E. Brandt
  • Gerhard R. F. Krueger
  • Guanyu Wang
Part of the Cancer Growth and Progression book series (CAGP, volume 11)

Abstract

We describe a coupled ordinary differential equation model of human T-cell proliferative disorders based upon documented changes in various pools such as the bone marrow, thymic compartments and peripheral blood. The conceptual design of the model is based upon previously collected experimental data, its testing and validation by comparing with normal human cell pool data at various ages as well as their changes in response to HTLV-1, HHV-6 and HIV-1 viral infections. These viruses were chosen because they all target the same CD4 lymphocyte, yet produce different response patterns such as hyperplasia, aplasia and neoplasia. They were also selected because respective cell pool data were available for comparison with detailed human studies. The ultimate task of this modeling effort is to simulate the development of T-cell lymphomas and other immunoproliferative or aproliferative (i.e. aplastic) abnormalities reported in the literature.

Keywords

Immune system T-lymphocytes Proliferative diseases Biocomputational modeling 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Allison JP (1987) Structure, function and serology of the T-cell antigen complex. Annu Rev Immunol 5:503–540.PubMedCrossRefGoogle Scholar
  2. Appasamy PM (1999) Biological and clinical implications of interleukin-7 and lymphopoiesis. Cytokines Cell Mol Ther 5:25–39.PubMedGoogle Scholar
  3. Appay V, Nixon DF, Donahoe SM, Gillespie GM, Dong T, King A, Ogg GS, Spiegel HM, Conlon C, Spina CA, Havlir DV, Richman DD, Waters A, Easterbrook P, McMichael AJ, Rowland-Jones SL (2000) HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192:63–75.PubMedCrossRefGoogle Scholar
  4. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signalling: cell fate control and signal integration in development. Science 284:770–776.PubMedCrossRefGoogle Scholar
  5. Arzt E, Kovalovsky D, Igaz LM, Costas M, Plazas P, Refogo D, Paez-Pareda M, Reul JM, Stalla G, Holsboer F (2000) Functional cross-talk among cytokines, T-cell receptor, and glucocorticoid receptor transcriptional activity and action. Ann NY Acad Sci 917:672–677.PubMedGoogle Scholar
  6. Atkins B, Mueller C, Okada CY, Reinert RA, Weissman IL, Spangrude GJ (1987) Early events in T-cell maturation. Annu Rev Immunol 5:325–365.CrossRefGoogle Scholar
  7. Azuara V, Grigoriadu K, Lembezat MP, Nagler-Anderson C, Perreira P (2001) Strain-specific TCR repertoire selection of IL-4-producing Thy-1 dull gamma delta thymocytes. Eur J Immunol 31:205–214.PubMedCrossRefGoogle Scholar
  8. Bar-Or RL, Segel LA (1998) On the role of a possible dialogue between cytokine and TCR presentation mechanisms in the regulation of autoimmune disease. J Theor Biol 190:161–178.PubMedCrossRefGoogle Scholar
  9. Bodey B, Bodey Jr., B, Siegel SE, Kaiser HE (1999) Molecular biological ontogenesis of the thymic reticulo-epithelial cell network during the organization of the cellular microenvironment. In Vivo 13:267–294.PubMedGoogle Scholar
  10. Bodey B, Bodey Jr., B, Siegel SE, Kaiser HE (2000) The role of the reticulo-epithelial (RE) cell network in the immuno-neuroendocrine regulation on intrathymic lymphopoiesis. Anticancer Res 20:1871–1888.PubMedGoogle Scholar
  11. Bondurant MC, Koury MJ (1999). Origin and development of blood cells. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Rodger G (ed) Wintrob’s clinical hematology 10th edn. Williams & Wilkins, Baltimore, pp 145–168.Google Scholar
  12. Brandt ME, Chen G (2001) Feedback control of a biodynamical model of HIV-1. IEEE T Bio-Med Eng 48:754–759.CrossRefGoogle Scholar
  13. Brandt ME, Wang G, Krueger GRF, Buja LM (2002) A biodynamical regulatory model of the T-cell system. Proceedings of the Second Joint IEEE EMBS/BMES Conference.Google Scholar
  14. Carrol AM, DeSousa M (1983) Thymus cell differentiation and in vivo T-cell migration: Migration of lectin-selected thymocytes. Cell Immunol 23:356–375.Google Scholar
  15. Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M, Forster R, Rowland-Jones S, Sekaly RP, McMichael AJ, Pantaleo G (2001) Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410:106–111.PubMedCrossRefGoogle Scholar
  16. Chen CH, Six A, Kubota T, Tsuji S, Kong FK, Gobel TW, Cooper MD (1996) T cell receptors and T cell development. Curr Top Microbiol Immunol 212:37–53.PubMedGoogle Scholar
  17. Clark EA, Brugge JS (1995) Integrins and signal transduction pathways: the road taken. Science 268:233–239.PubMedCrossRefGoogle Scholar
  18. Correla-Neves M, Mathis D, Benoist C (2001) A molecular chart of thymocyte positive selection. Eur J Immunol 31:2583–2592.CrossRefGoogle Scholar
  19. Crouse DA, Jordan RK, Sharp JG (1980). T-cell differentiation. In: Battisto and Knight (ed) Immunoglobulin genes and cell differentiation. Elsevier, North Holland/Amsterdam, The Netherlands, pp 65–78.Google Scholar
  20. Crouse DA, Turpen JB, Sharp JG (1985) Thymic non-lymphoid cells. Surv Immunol Res 4:120–134.PubMedGoogle Scholar
  21. Cyster JG (1999) Chemokines and cell migration in secondary lymphoid organs. Science 286:2098–2102.PubMedCrossRefGoogle Scholar
  22. Daefler S, Krueger GRF (1989a) Expression of proliferation and differentiation antigens in response to modulation of membrane lipid fluidity in chronic lymphatic leukemia lymphocytes. Anticancer Res 9:501–506.PubMedGoogle Scholar
  23. Daefler S, Krueger GRF (1989b) Lack of dynamic lipid changes after binding of interleukin-2 in chronic lymphocytis leukemia lymphocytes indicates defective transmembrane signaling. Anticancer Res 9:743–748.PubMedGoogle Scholar
  24. Dappen GE, Crouse DA, Anderson RW, Jordan RK, Robinson JH, Sharp JG (1982) Morphological assessment of immunologically relevant cells in the thymus. Adv Exp Biol Med 149:389–399.Google Scholar
  25. Dardenne M, Pleau JM, Man NK, Bach JF (1977) Structure of circulating thymic factor: a peptide isolated from pig serum. I. Isolation and purification. J Biol Chem 252:8040–8044.PubMedGoogle Scholar
  26. Davis MH, Chien YH (1999). T-cell antigen receptors. In: Paul WE (ed) Fundamental immunology, 4th edn. Lippincott-Raven, Philadelphia, pp 341–366.Google Scholar
  27. de la Hera A, Marston W, Aranda C, Toribio ML, Martinez C (1989) Thymic stroma is required for the development of human T cell lineages in vitro. Int Immunol 1:471–478.PubMedCrossRefGoogle Scholar
  28. Dieu-Nosjean MC, Massacrier C, Vanbervliet B, Fridman WH, Caux C (2001) Il-10 induces CCR6 expression during Langerhans cell development while IL-4 and IFN-gamma suppress it. J Immunol 167:5594–5602.PubMedGoogle Scholar
  29. Dunon D, Courtois D, Vainio O, Six A, Chen CH, Cooper MD, Dangy JP, Imhof BA (1997) Ontogeny of the immune system: gamma/delta and alpha/beta T cells migrate from thymus to the periphery in alternating waves. J Exp Med 186:977–988.PubMedCrossRefGoogle Scholar
  30. Ehrlich GD, Poiesz BJ (1988) Clinical and molecular parameters of HTLV-1 infection. Clin Lab Med 8:65–84.PubMedGoogle Scholar
  31. Eren R, Zharhary D, Abel L, Globerson A (1987) Ontogeny of T cells: development of pre-T cells from fetal liver and yolk sac in the thymus microenvironment. Cell Immunol 108:76–84.PubMedCrossRefGoogle Scholar
  32. Feaux de Lacroix W, Deying T, Krueger GRF (1981). Cell proliferation in the T lymphocyte lineage during the latent period of Moloney virus induced lymphomagenesis. Eleventh European Study Group for Cytokinetics in Pathology Meeting, Aarhus, Denmark (book of abstracts).Google Scholar
  33. Fiorini E, Marchisio PC, Scupoli MT, Poffe O, Tagliabue E, Brentegnani M, Colombatti M, Santini F, Tridente G, Ramarli D (2000) Adhesion of immature and mature T cells induces in human thymic epithelial cells (TEC) activation of IL-6 gene transcription factors (NF-kappab and NF-IL6) and IL-6 gene expression: role of alpha3beta1 and alpha6beta4 integrins. Dev Immunol 7:195–208.PubMedCrossRefGoogle Scholar
  34. Forrest S, Hofmeyr SA (2000). Immunology as information processing. In: Segel LA, Cohen IR (ed) Design principles for immune system and other distributed autonomous systems. Oxford University Press, New York, pp 361–387.Google Scholar
  35. Gessain A, Vernant JC, Maurs L (1985) Antibodies to human T-lymphotropic virus type 1 in patients with tropical spastic paraparesis. Lancet II 407–409.CrossRefGoogle Scholar
  36. Goldstein G (1977) Molecular control of proliferation and differentiation. Ann NY Acad Sci 249:177–185.CrossRefGoogle Scholar
  37. Greenberger JS (1991) The hematopoietic microenvironment. Crit Rev Oncol Hematol 11:65–84.PubMedCrossRefGoogle Scholar
  38. Guerin S, Mari B, Fernandez E, Belhacene N, Toribio ML, Auberger P (1997) CD10 is expressed on human thymic epithelial cell lines and modulates thymopentin-induced cell proliferation. FASEB J 11:1003–1011.PubMedGoogle Scholar
  39. Haas W, Deying T, Krueger GRF, Feaux de Lacroix W (1982) Autoradiographic and immunocytologic identification of atypical cell proliferation during Moloneyvirus induced lymphoma development. In: Yoh DS, Blakeslee JR (eds) Advances in comparative leukemia research. Elsevier Biomedical, Amsterdam, The Netherlands, pp 241–243.Google Scholar
  40. Harris CA, Andryuk PJ, Cline S, Chan HK, Natarajan A, Siekierka JJ, Goldstein G (1994) Three distinct human thymopoietins are derived from alternatively spliced mrnas. Proc Natl Acad Sci USA 91:6283–6287.PubMedCrossRefGoogle Scholar
  41. Heine UI, Krueger GRF, Karpinski A, Munoz E, Krueger MB (1983a) Quantitative light and electron microscopic changes in thymic reticular epithelial cells during Moloneyvirus induced lymphoma development. J Cancer Res Clin Oncol 106:102–111.PubMedCrossRefGoogle Scholar
  42. Heine UI, Krueger GRF, Munoz E, Karpinski A (1983b) Altered thymic epithelial cells may be decisive for Moloneyvirus induced lymphoma development. In: Bailey GW (ed) Proceedings of the 41st Annual Meeting of the Electron Microscopic Society of America, pp 784–785.Google Scholar
  43. Hochberg EP, Chillemi AC, Wu CJ, Neuberg D, Canning C, Hartman K, Alyea EP, Soiffer RJ, Kalams SA, Ritz J (2001) Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults. Blood 98:1116–1121.PubMedCrossRefGoogle Scholar
  44. Inghirami G, Knowles DM (1992) The immune system, structure and function. In: Knowles DM (ed) Neoplastic hematopathology Williams & Wilkins, Baltimore, pp 27–72.Google Scholar
  45. Jaleco AC, Neves H, Hooijberg E, Gameiro P, Clode N, Haury M, Henrique D, Parreira L (2001) Differential effects of notch ligands delta-1 and jagged-1 in human lymphoid differentiation. J Exp Med 194:991–1002.PubMedCrossRefGoogle Scholar
  46. Janossy G, Campana D, Akbar A (1989) Kinetics of T cell development. Curr T Pathol 79:59–99.Google Scholar
  47. Kam N, Cohen IR, Harel D (2001) The immune system as a reactive system: modeling T cell activation with statecharts. Proceedings of Symposia Human-Centric Computing Languages and Environments. IEEE Computer Society Press, Stresa, Italy, pp 15–22.Google Scholar
  48. Kerre TCC, DeSmet G, DeSmedt M, Offner F, DeBosscher J, Plum J, Vanderkerckhove B (2001) Both CD34+38+ and CD34+38− cells home specifically to the bone marrow of NOD/ltsz scid/scid mice but sahow different kinetics in expansion. J Immunol 167:3692–3698.PubMedGoogle Scholar
  49. Kim JK, Takahashi I, Kai Y, Kiyono H (2001) Influence of enterotoxin in mucosal intranet: selective inhibition of extrathymic T cell development in intestinal intraepithelial lymphocytes by oral exposure to heat-labile toxin. Eur J Immunol 31:2960–2969.PubMedCrossRefGoogle Scholar
  50. Kondo M, Scherer DC, Miyamoto T, King AG, Akashi K, Sugamura K, Weissman IL (2000) Cell fate conversion of lymphoid committed progenitors by instructive action of cytokines. Nature 407:383–386.PubMedCrossRefGoogle Scholar
  51. Kong F, Chen CH, Cooper MD (1998) Thymic function can be accurately monitored by the level of recent T cell emigrants in the circulation. Immunity 8:97–104.PubMedCrossRefGoogle Scholar
  52. Kong FK, Chen CL, Six A, Hockett RD, Cooper MD (1999) T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc Natl Acad Sci USA 96:1536–1540.PubMedCrossRefGoogle Scholar
  53. Korsmeyer J (1987) Immunoglobulin and T-cell receptor genes reveal the clonality, lineage and translocations of lymphoid neoplasms. In: DeVita VT, Hellman S, Rosenberg (ed) Important advances in oncology. Lippincott, Philadelphia, pp 3–25.Google Scholar
  54. Koury MJ, Bondurant MC (1993) Prevention of programmed death in hematopoietic progenitor cells by hematopoietic growth factors. News Physiol Sci (NIPS) 8:170–174.Google Scholar
  55. Kraus M, Krueger GRF (1981) T- and B-cell determination in various lymphoid tissues of mice during N-nitrosobutylurea (NBU) leukemogenesis. J Cancer Res Clin Oncol 100:149–165.PubMedCrossRefGoogle Scholar
  56. Kronenberg M, Siu G, Hood LE, Shastri N (1986) The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. Annu Rev Immunol 4:529–591.PubMedCrossRefGoogle Scholar
  57. Krueger GRF (1972) Chronic immunosuppression and lymphomagenesis in man and mice. Natl Cancer I Monogr 35:183–190.Google Scholar
  58. Krueger GRF (1985) Klinische immunpathologie. W. Kohlhammer, Stuttgart, Germany.Google Scholar
  59. Krueger GRF (1989a) The pathology of diphenylhydantoin-induced lymphoproliferative reactions in animals. In: Kammueller ME, Blocksma N, Deinen W (ed) Autoimmunity and toxicology Elsevier, Amsterdam, The Netherlands, pp 391–413.Google Scholar
  60. Krueger GRF (1989b) Abnormal variation of the immune system as related to cancer. In: Kaiser HE (ed) Cancer growth and progression Kluwer, Dordrecht, The Netherlands, pp 139–161.Google Scholar
  61. Krueger GRF (1993) Pathology of lymphoproliferative disorders in HIV infection. In: Schrappe M, Mauff G (ed) AIDS-SIDA, a comparison between Europe and Africa. Ed Roche, Basel pp 239–253.Google Scholar
  62. Krueger GRF, Ferrer Argote V (1994) A unifying concept of viral immunopathogeneis of proliferative and aproliferative diseases (working hypothesis). In Vivo 8:493–500.PubMedGoogle Scholar
  63. Krueger GRF, Malmgren RA, Berard CW (1971) Malignant lymphomas and plasmacytosis in mice under chronic immunosuppression and persistent antigenic stimulation. Transplantation 11:128–144.CrossRefGoogle Scholar
  64. Krueger G, Fischer RM, Flesch HG (1979) Sequential changes in T- and B-cells, virus antigen expression and primary histologic diagnosis in virus-induced lymphomagenesis in mice. Zeitschrift fuer Krebsforschung 92:41–54.Google Scholar
  65. Krueger GRF, Karpinski A, Heine UI, Koch B (1983) Differentiation block of prethymic lymphocytes during Moloneyvirus induced lymphoma development associated with a thymic epitheliel defect. J Cancer Res Clin Oncol 106:153–157.PubMedCrossRefGoogle Scholar
  66. Krueger GRF, Stolzenburg T, Muller C (1987a) Cell membrane lipid fluidity and receptor expression in Moloney- and Friendvirus transformed cells. In Vivo 1:343–246.PubMedGoogle Scholar
  67. Krueger GRF, Papadakis T, Schaefer HJ (1987b) Persistent active Epstein-Barr virus infection and atypical lymphoproliferation. Am J Surg Pathol 11:972–981.PubMedCrossRefGoogle Scholar
  68. Krueger GRF, Ablashi DV, Salahuddin SZ, Josephs SF (1988) Diagnosis and differential diagnosis of progressive lymphoproliferation and malignant lymphoma in persistent active herpesvirus infection. J Virol Methods 21:255–264.PubMedCrossRefGoogle Scholar
  69. Krueger GRF, Bertram G, Ramon A, Koch B, Ablashi DV, Brandt ME, Wang G, Buja LM (2001a) Dynamics of infection with human herpesvirus-6 in EBV-negative infectious mononucleosis: data acquisition for computer modeling. In Vivo 15:373–380.PubMedGoogle Scholar
  70. Krueger GRF, Koch B, Hoffmann A, Rojo J, Brandt ME, Wang G, Buja LM (2001b) Dynamics of chronic active herpesvirus-6 infection in patients with chronic fatigue syndrome: data acquisition for computer modeling. In Vivo 15:461–466.PubMedGoogle Scholar
  71. Krueger GRF, Nguyen A, Uthman M, Brandt ME, Buja LM (2001c) Dysregulative lymphoma theory revisited: what can we learn from cytokines, CD classes and genes? Anticancer Res 21:3653–3662.PubMedGoogle Scholar
  72. Krueger GRF, Koch B, Deninger Weldner J, Tymister G, Ramon A, Brandt ME, Wang G, Buja LM (2002a) Dynamics of active progressive infection with HIV1: data acquisition for computer modeling. In Vivo 15:513–518.Google Scholar
  73. Krueger GRF, Brandt ME, Wang G, Buja LM (2002b) Dynamics of HTLV-1 leukemogenesis: data acquisition for computer modeling. In Vivo 16:87–92.PubMedGoogle Scholar
  74. Krueger GRF, Marshall GR, Junker U, Schroeder H, Buja LM, Brandt ME, Wang G (2002c) Growth Factors, Cytokines, Chemokines and Neuropeptides in the Modeling of T-Cells, In Vivo 16:365–386.PubMedGoogle Scholar
  75. Krueger GRF, Brandt ME, Wang G, Berthold F, Buja LM (2002d) A computational analysis of Canale-Smith syndrome: chronic lymphadenopathy simulating malignant lymphoma. Anticancer Res 22:2365–2372.PubMedGoogle Scholar
  76. Krueger GRF, Brandt ME, Wang G, Buja LM (2003) TCM-1: A nonlinear dynamical computational model to simulate cellular changes in the T cell system; Conceptional design and validation, Anticancer Res 23:123–136.PubMedGoogle Scholar
  77. Le PT, Adams KL, Zaya N, Mathews HL, Storkus WJ, Ellis TM (2001) Human thymic epithelial cells inhibit IL-15 and IL-2 driven differentiation of NK cells from the early human thymic progenitors. J Immunol 166:2194–2201.PubMedGoogle Scholar
  78. Leclercq G, Plum J (1996) Thymic and extrathymic T cell development. Leukemia 10:1853–1859.PubMedGoogle Scholar
  79. Liu CP, Auerbach R (1991) Ontogeny of murine T cells: thymus-regultade development of T cell receptor-bearing cells derived from embryonal yolk sac. Eur J Immunol 21:1849–1855.PubMedCrossRefGoogle Scholar
  80. Lobach DF, Haynes BF (1987) Ontogeny of the human thymus during fetal development. J Clin Immunol 7:81–97.PubMedCrossRefGoogle Scholar
  81. MacDonald WA, Radtke F (2001) Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymuc. J Exp Med 194:1003–1012.PubMedCrossRefGoogle Scholar
  82. Marrack P, Lo D, Brinster R, Palmiter R, Burkly L, Flavell RH, Kappler J (1988) The effect of thymus environment on T cell development and tolerance. Cell 53:627–634.PubMedCrossRefGoogle Scholar
  83. Metcalf D (1971) The nature of leukemia: neoplasm or disorder of haematopoietic regulation? Med J Australia 2:739–746.PubMedGoogle Scholar
  84. Miescher C, Howe RC, Budd RC, MacDonald HR (1988) Expression of T-cell receptors by functionally distinct subsets of immature adult thymocytes. Ann NY Acad Sci 532:8–17.PubMedCrossRefGoogle Scholar
  85. Miyai I, Saida T, Fujita M, Kitahara Y, Hirono N (1987) Familial cases of HTLV-1 associated myelopathy. Ann Neurol 22:601–605.PubMedCrossRefGoogle Scholar
  86. Mollet L, Tai-Sheng L, Samri A, Tournai C, Tubiana R, Calvez V, Debre P, Katlama C, Autran B (2000) Dynamics of HIV-specific CD8+ T lymphocytes with changes in viral load. J Immunol 165:1692–1704.PubMedGoogle Scholar
  87. Montecino-Rogriguez E, Truong LT, Henderson AJ (2001) Long-term bone marrow cultures provide access to early lymphoid progenitors. J Hematother Stem Cell Res 10:107–114.CrossRefGoogle Scholar
  88. Nakauchi H, Sudo K, Ema H (2001) Quantitative assessment of the stem cell self-renewal capacity. Ann NY Acad Sci 938:18–24.PubMedCrossRefGoogle Scholar
  89. Ogawa T, Kitagawa M, Hirokawa K (2000) Age-related changes of human bone marrow: a histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages. Mech Aging Dev 117:57–68.PubMedCrossRefGoogle Scholar
  90. O’Sullivan NL, Skaandera CA, Montgomry PC (2001) Development of T cell lineages in rat lacrimal glands. J Curr Eye Res 22:375–383.CrossRefGoogle Scholar
  91. Paul W (1999) Fundamental immunology. Lippincott-Raven, Philadelphia.Google Scholar
  92. Paraskevas F, Foerster J (1999) The lymphatic system (Chapter 18). In: Lee GR, Foerster J, Lukens J, Paraskevas F, Rodger G (ed) Wintrob’s clinical hematology, 10th edn. Williams & Wilkins, Baltimore pp 430–463.Google Scholar
  93. Pawelec G, Muller R, Rehbein A, Hahnel K, Ziegler BL (1998) Extrathymic T cell differentiation in vitro from human CD34 + stem cells. J Leukoc Biol 64:733–739.PubMedGoogle Scholar
  94. Pawelec G, Muller R, Rehbein A, Hahnel K, Ziegler BL (1999) Finite life spans of t cell clones derived from CD34+ human haematopoietic stem cells in vitro. Exp Gerontol 34:69–77.PubMedCrossRefGoogle Scholar
  95. Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T, Nagler A, Ben-Hur H, Many A, Shultz L, Lider O, Alon R, Zipori D, Lapidot T (1999) Dependence of human stem cell engraftment and repopulation mice on CXCR4. Science 283:845–848.PubMedCrossRefGoogle Scholar
  96. Pestano GA, Zhou Y, Trimble LA, Daley J, Weber GF, Cantor H (1999) Inactivation of misselected CD8 T cells by CD8 gene methylation and cell death. Science 284: 1187–1191.PubMedCrossRefGoogle Scholar
  97. Petri HT, Livak F, Burtrum D, Mazel ST (1995) T cell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production. J Exp Med 182:121–127.CrossRefGoogle Scholar
  98. Plum J (1999) Can T cell immunity in an adult be regenerated? Verhandlingen af Koninglike Akademie for Geneeskunde Belgie 61:457–464.Google Scholar
  99. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC (1980) Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T cell lymphoma. Proc Natl Acad Sci USA 77:7415–7419.PubMedCrossRefGoogle Scholar
  100. Purtilo DT, Tatsumi E, Manolov G, Manolova Y, Harada S, Lipscomb H, Krueger GRF (1985) Epstein-Barr virus as an etiological agent in the pathogenesis of lymphoproliferative and aproliferative diseases in immune deficient patients. Int Rev Exp Pathol 27:113–183.PubMedGoogle Scholar
  101. Robetamanith T, Schroder B, Bug G, Muller P, Klenner T, Knaus R, Hoelzer D, Ottmann OG (2001) Interleukin 3 improves the ex vivo expansion of primitive human cord blood progenitor cells and maintains the engraftment potential of scid repopulating cells. Stem Cells 19:313–320.CrossRefGoogle Scholar
  102. Robey E (1999) T cell fate by notch. Annu Rev Immunol 17:283–295.PubMedCrossRefGoogle Scholar
  103. Romagnani P, Annunziato F, Piccini MP, Maggi E, Romagnani S (2000) Cytokines and chemokines in T lymphopoiesis and T cell effector function. Trends Immunol Today 21:416–418.CrossRefGoogle Scholar
  104. Rothenberg E, Lugo JP (1985) Differentiation and cell division in the mammalian thymus. Dev Biol 112:1–17.PubMedCrossRefGoogle Scholar
  105. Sanchez M, Alfani E, Visconti G, Passarelli AM, Migliaccio AR, Migliaccio G (1998) Thymus-independent T-cell differentiation in vitro. Brit J Haematol 103:1198–1205.CrossRefGoogle Scholar
  106. Sarun S, Dalloul AH, Laurent C, Blanc C, Schmitt C (1998) Human CD34+ thymocyte maturation: pre-T and NK cell differentiation on neonatal thymic stromal cell culture. Cell Immunol 190:23–32.PubMedCrossRefGoogle Scholar
  107. Sasada T, Reinherz EL (2001) A critical role for CD2 in both thymic selection events and mature T cell function. J Immunol 166:2394–2403.PubMedGoogle Scholar
  108. Schonnebeck M, Krueger GRF, Braun M, Fischer M, Koch B, Ablashi DV, Balachandran N (1991) Human herpesvirus-6 infection may predispose cells for superinfection by other viruses. In Vivo 5:255–264.PubMedGoogle Scholar
  109. Segel LA, Bar-Or RL (1999) On the role of feedback in promoting conflicting goals of the adaptive immune system. J Immunol 163:1342–1349.PubMedGoogle Scholar
  110. Sen J (2001) Signal transduction in thymus development. Cell Mol Biol 47:197–215.PubMedGoogle Scholar
  111. Sing GK, Keller JR, Ellingsworth LR, Ruscetti FW (1988) Transforming growth factor-a selectively inhibits normal and leukemic human bone marrow cell growth in vitro. Blood 72:1504–1511.PubMedGoogle Scholar
  112. Singh VK, Biswas S, Mathur KB, Haq W, Garg SK, Agarwal SS (1998) Thymopentin and splenopentin as immunomodulators; Current status. Immunol Res 17:345–368.PubMedCrossRefGoogle Scholar
  113. Smith DJ, Forrest S, Ackley DH, Perelson AS Smith (1998) Using lazy evaluation to simulate realistic-size repertoires in models of the immune system. Bull Math Biol 60:647–658.PubMedCrossRefGoogle Scholar
  114. Spiegel HM, Ogg GS, DeFalcon E, Sheehy ME, Monard S, Haslett PA, Gillespie G, Donahoe SM, Pollack H, Borkowsky W, McMichael AJ, Nixon DF (2000) Human immunodeficiency virus type 1- and cytomegalovirus-specific cytotoxic T lymphocytes can persist at high frequency for prolonged periods in the absence of circulating peripheral CD4(+) T cells. J Virol 74:1018–1022.PubMedCrossRefGoogle Scholar
  115. Stutman O (1978) Intrathymic and extrathymic T-cell maturation. Immunol Rev 42:138–184.PubMedCrossRefGoogle Scholar
  116. Surh CD, Sprent J (1999). The thymus and T-cell development (Chapter 9) In: Gallin JI et al. (ed) Inflammation: basic principles and clinical correlates Lippincott Williams & Wilkins, Philadelphia pp 137–149.Google Scholar
  117. Suzuki K, Oida T, Hamada H, Hitotsumatsu O, Watanaba M, Hibi T, Yamamoto H, Kubota E, Kaminogawa S, Ishikawa H (2000) Gut cryptopatches: direct evidence of extrathymic anatomical sites for intestinal T lymphopoiesis. Immunity 13:691–702.PubMedCrossRefGoogle Scholar
  118. Szewczuk Z, Wieczorek Z, Stefanowicz P, Wilczynski A, Siemion IZ (1997) Further investigations on thymopentin-like fragments of HLA-DQ and their analogs. Arch Immunol Exp Ther (Warsaw) 45:335–341.Google Scholar
  119. Tedder TF, Steeber DA, Chen A, Engel P (1995) The selectins: vascular adhesion molecules. FASEB J 9:866–873.PubMedGoogle Scholar
  120. Theodor L, Shoham J, Berger R, Gokkel E, Trachtenbrot L, Simon AJ, Brok-Simon F, Nir U, Ilan E, Zevin-Sonkin D, Friedman E, Rechavi G (1997) Ubiquitous expression of a cloned murine thymopoietin cdna. Acta Haematol 97:153–163.PubMedCrossRefGoogle Scholar
  121. Thiele J, Wickenhauser C, Baldus SE, Kuemmel T, Zirbes TK, Drebber U, Wirtz R, Thiel A, Hansmann ML, Fischer R (1995) Characterization of CD34+ human hematopoietic progenitor cells from the peripheral blood: enzyme-, carbohydrate- and immunocytochemistry, morphometry, and ultrastructure. Leukemia Lymphoma 16:483–491.PubMedCrossRefGoogle Scholar
  122. Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H (1977) Adult T cell leukemia: clinical and hematological features of 16 cases. Blood 50:481–492.PubMedGoogle Scholar
  123. Varas A, Vicente A, Sacedon R, Zapata AG (1998) Interleukin-7 influences the development of thymic dendritic cells. Blood 92:93–100.PubMedGoogle Scholar
  124. Warrender C, Forrest S and Segel L (2001) Effective feedback in the immune system. In: Genetic and Evolutionary Computation Conference Workshop Program. Morgan & Kaufmann, pp 329–332.Google Scholar
  125. Weber PJ, Eckhard CP, Gonser S, Otto H, Folkers G, Beck-Sickinger AG (1999) On the role of thymopoietins in cell proliferation. Immunochemical evidence for new members of the human thymopoietin family. Biol Chem380:653–660.PubMedCrossRefGoogle Scholar
  126. Wognum AW, DeJong MO, Wagemaker G (1996) Differential expression of receptors for hematopoietic growth factors on subsets of CD34+ hemopoietic cells. Leukemia Lymphoma 24:11–25.PubMedCrossRefGoogle Scholar
  127. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188:2205–2213.PubMedCrossRefGoogle Scholar
  128. Zajac AJ, Vance RE, Held W, Sourdive DJ, Altman JD, Raulet DH, Ahmed R (1999) Impaired anti-viral T cell responses due to expression of the Ly49A inhibitory receptor. J Immunol (Baltimore, MD.; 1950) 163:5526–5534.PubMedGoogle Scholar
  129. Zevin-Sonkin D, Ilan E, Guthmann D, Riss J, Theodor L, Shoham J (1992) Molecular cloning of bovine thymopoietin gene and its expression in different calf issues: evidence for a predominant expression in thymocytes. Immunol Lett 31:301–309.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V 2008

Authors and Affiliations

  • Michael E. Brandt
    • 1
    • 2
  • Gerhard R. F. Krueger
    • 1
  • Guanyu Wang
    • 1
  1. 1.University of Texas-Houston Health Science Center – Medical SchoolUSA
  2. 2.School of Health Information SciencesUSA

Personalised recommendations