Impact of the somatotrope Growth Hormone (GH)/Insulin-like Growth Factor 1 (IGF-1) axis upon thymus function: Pharmacological implications in regeneration of immune functions
[en] The thymus is the central lymphoid structure where T-cell differentiation takes place, and a crucial organ for the maintenance of homeostasis in the immune system. Thymopoiesis includes intrathymic proliferation of T-cell precursors, selection and output of both self-tolerant and competent effector T cells, as well as of natural regulatory T cells (nTreg). In the crosstalk between the neuroendocrine and immune systems, peptide hormones have been more and more implicated in immunomodulation for the last thirty years. The somatotrope growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in particular has been repeatedly shown to play a major regulatory role upon thymus function and T-cell development. This review will focus on the important thymotropic properties of the somatotrope GH/IGF-1 axis, and will try to discriminate these properties in function of the endocrine or paracrine/autocrine pathways involved in their mediation. Most importantly, in light of an increasing number of recent studies, GH and IGF-1 now appear as a novel therapeutic agents that could be used for enhancing thymopoiesis in different cases of immune deficiencies, including aging-related immune dysfunction.
Geenen, Vincent ; Université de Liège - ULiège > Centre d'immunologie
Martens, Henri ; Université de Liège - ULiège > Centre d'immunologie
Language :
English
Title :
Impact of the somatotrope Growth Hormone (GH)/Insulin-like Growth Factor 1 (IGF-1) axis upon thymus function: Pharmacological implications in regeneration of immune functions
Publication date :
2011
Journal title :
Immunology, Endocrine and Metabolic Agents - Medicinal Chemistry
ISSN :
1871-5222
Publisher :
Bentham Science Publishers
Volume :
11
Pages :
10-20
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Pfizer [US-NY] [US-NY] FRIA - Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture [BE] DGTRE - Région wallonne. Direction générale des Technologies, de la Recherche et de l'Énergie [BE]
Besedovsky, H.O.; del Rey, A. Immune-neuro-endocrine interactions:facts and hypotheses. Endocr. Rev., 1996, 17(1), 64-102.
Arpin, C.; Pihlgren, M.; Fraichard, A.; Aubert, D.; Samarut, J.; Chassande, O.; Marvel, J. Effects of T3R alpha 1 and T3R alpha 2gene deletion on T and B lymphocyte development. J. Immunol., 2000, 164(1), 152-160.
Smith, P. The effect of hypophysectomy upon the involution of thethymus in the rat. Anat. Rec., 1930, 47, 119-143.
Morrhaye, G.; Kermani, H.; Legros, J.J.; Baron, F.; Beguin, Y.; Moutschen, M.; Cheynier, R.; Martens, H.J.; Geenen, V. Impact ofgrowth hormone (GH) deficiency and GH replacement upon thymusfunction in adult patients. PLoS One, 2009, 4(5), e5668.
Miller, J.F., The discovery of thymus function and of thymusderivedlymphocytes. Immunol. Rev., 2002, 185, 7-14.
Haynes, B.F.; Heinly, C.S. Early human T cell development: analysisof the human thymus at the time of initial entry of hematopoieticstem cells into the fetal thymic microenvironment. J. Exp. Med., 1995, 181(4), 1445-1458.
Larsen, W.J. Development of the Head and Neck. In: Human Embryology 1st ed.; Larsen, W.J. Ed.; Churchill Livingstone; NewYork, 1993, pp. 311-340.
Blackburn, C.C.; Manley, N.R. Developing a new paradigm forthymus organogenesis. Nat. Rev. Immunol., 2004, 4(4), 278-289.
Gordon, J.; Wilson, V.A.; Blair, N.F.; Sheridan, J.; Farley, A.; Wilson, L.; Manley, N.R.; Blackburn, C.C. Functional evidence fora single endodermal origin for the thymic epithelium. Nat. Immunol., 2004, 5(5), 546-553.
Jotereau, F.; Heuze, F.; Salomon-Vie, V.; Gascan, H. Cell kineticsin the fetal mouse thymus: precursor cell input, proliferation, andemigration. J. Immunol., 1987, 138(4), 1026-1030.
Rossi, S.W.; Jenkinson, W.E.; Anderson, G.; Jenkinson, E.J. Clonalanalysis reveals a common progenitor for thymic cortical and medullaryepithelium. Nature, 2006, 441(7096), 988-991.
Anderson, G.; Pongracz, J.; Parnell, S.; Jenkinson, E.J. Notchligand-bearing thymic epithelial cells initiate and sustain Notchsignaling in thymocytes independently of T cell receptor signaling. Eur. J. Immunol., 2001, 31(11), 3349-3354.
van Ewijk, W.; Shores, E.W.; Singer, A. Crosstalk in the mousethymus. Immunol. Today, 1994, 15(5), 214-217.
Ciofani, M.; Zuniga-Pflucker, J.C. The thymus as an inductive sitefor T lymphopoiesis. Annu. Rev. Cell. Dev. Biol., 2007, 23, 463-493.
Muller, S.M.; Terszowski, G.; Blum, C.; Haller, C.; Anquez, V.; Kuschert, S.; Carmeliet, P.; Augustin, H.G.; Rodewald, H.R. Genetargeting of VEGF-A in thymus epithelium disrupts thymus bloodvessel architecture. Proc. Natl. Acad. Sci. USA, 2005, 102(30), 10587-10592.
Gray, D.H.; Tull, D.; Ueno, T.; Seach, N.; Classon, B.J.; Chidgey, A.; McConville, M.J.; Boyd, R.L. A unique thymic fibroblast populationrevealed by the monoclonal antibody MTS-15. J. Immunol., 2007, 178(8), 4956-4965.
Raviola, E.; Karnovsky, M.J. Evidence for a blood-thymus barrierusing electron-opaque tracers. J. Exp. Med., 1972, 136(3), 466-498.
Anderson, M.; Anderson, S.K.; Farr, A.G. Thymic vasculature:organizer of the medullary epithelial compartment? Int. Immunol., 2000, 12(7), 1105-1110.
Scollay, R.; Smith, J.; Stauffer, V. Dynamics of early T cells:prothymocyte migration and proliferation in the adult mouse thymus. Immunol. Rev., 1986, 91, 129-157.
Savino, W.; Mendes-da-Cruz, D.A.; Silva, J.S.; Dardenne, M.; Cotta-de-Almeida, V. Intrathymic T-cell migration: a combinatorialinterplay of extracellular matrix and chemokines? Trends Immunol., 2002, 23(6), 305-313.
Park, J.H.; Adoro, S.; Guinter, T.; Erman, B.; Alag, A.S.; Catalfamo, M.; Kimura, M.Y.; Cui, Y.; Lucas, P.J.; Gress, R.E.; Kubo, M.; Hennighausen, L.; Feigenbaum, L.; Singer, A. Signaling by intrathymiccytokines, not T cell antigen receptors, specifies CD8lineage choice and promotes the differentiation of cytotoxic-lineageT cells. Nat. Immunol., 2010, 11(3), 257-264.
Douek, D.C.; McFarland, R.D.; Keiser, P.H.; Gage, E.A.; Massey, J.M.; Haynes, B.F.; Polis, M.A.; Haase, A.T.; Feinberg, M.B.; Sullivan, J.L.; Jamieson, B.D.; Zack, J.A.; Picker, L.J.; Koup, R.A. Changes in thymic function with age and during the treatment ofHIV infection. Nature, 1998, 396(6712), 690-695.
Poulin, J.F.; Viswanathan, M.N.; Harris, J.M.; Komanduri, K.V.; Wieder, E.; Ringuette, N.; Jenkins, M.; McCune, J.M.; Sekaly, R.P. Direct evidence for thymic function in adult humans. J. Exp. Med., 1999, 190(4), 479-486.
Castermans, E.; Baron, F.; Willems, E.; Schaaf-Lafontaine, N.; Meuris, N.; Gothot, A.; Vanbellighen, J.F.; Herens, C.; Seidel, L.; Geenen, V.; Cheynier, R.; Beguin, Y. Evidence for neo-generationof T cells by the thymus after non-myeloablative conditioning. Haematologica, 2008, 93(2), 240-247.
Geenen, V.; Poulin, J.F.; Dion, M.L.; Martens, H.; Castermans, E.; Hansenne, I.; Moutschen, M.; Sekaly, R.P.; Cheynier, R. Quantificationof T cell receptor rearrangement excision circles to estimatethymic function: an important new tool for endocrine-immunephysiology. J. Endocrinol., 2003, 176(3), 305-311.
Dion, M.L.; Poulin, J.F.; Bordi, R.; Sylvestre, M.; Corsini, R.; Kettaf, N.; Dalloul, A.; Boulassel, M.R.; Debre, P.; Routy, J.P.; Grossman, Z.; Sekaly, R.P.; Cheynier, R. HIV infection rapidly inducesand maintains a substantial suppression of thymocyte proliferation. Immunity, 2004, 21(6), 757-768.
van den Dool, C.; de Boer, R.J. The effects of age, thymectomy, and HIV Infection on alpha and beta TCR excision circles in naiveT cells. J. Immunol., 2006, 177(7), 4391-4401.
Dulude, G.; Cheynier, R.; Gauchat, D.; Abdallah, A.; Kettaf, N.; Sekaly, R.P.; Gratton, S. The magnitude of thymic output is geneticallydetermined through controlled intrathymic precursor T cellproliferation. J. Immunol., 2008, 181(11), 7818-7824.
Dion, M.L.; Sekaly, R.P.; Cheynier, R. Estimating thymic functionthrough quantification of T-cell receptor excision circles. MethodsMol. Biol., 2007, 380, 197-213.
Leonard, W.J. Type 1 Cytokines and Interferons and Their Receptor. In: Fundamental Immunology 5th ed.; Paul, W.E. Ed.; LippincottWilliams & Wilkins; Philadelphia, 2003, pp. 701-747.
Cosman, D.; Lyman, S.D.; Idzerda, R.L.; Beckmann, M.P.; Park, L.S.; Goodwin, R.G.; March, C.J. A new cytokine receptor superfamily. Trends Biochem. Sci., 1990, 15(7), 265-270.
Heim, M.H. The Jak-STAT pathway: cytokine signalling from thereceptor to the nucleus. J. Recept. Signal Transduct. Res., 1999, 19(1-4), 75-120.
Tripathi, A.; Sodhi, A. Growth hormone-induced production ofcytokines in murine peritoneal macrophages in vitro: role ofJAK/STAT, PI3K, PKC and MAP kinases. Immunobiology, 2009, 214(6), 430-440.
Wang, X.; Yang, N.; Deng, L.; Li, X.; Jiang, J.; Gan, Y.; Frank, S.J. Interruption of growth hormone signaling via SHC and ERK in3T3-F442A preadipocytes upon knockdown of insulin receptorsubstrate-1. Mol. Endocrinol., 2009, 23(4), 486-496.
Flores-Morales, A.; Greenhalgh, C.J.; Norstedt, G.; Rico-Bautista, E. Negative regulation of growth hormone receptor signaling. Mol. Endocrinol., 2006, 20(2), 241-253.
Mayo, K.E.; Miller, T.L.; DeAlmeida, V.; Zheng, J.; Godfrey, P.A. The growth-hormone-releasing hormone receptor: signal transduction, gene expression, and physiological function in growth regulation. Ann. NY Acad. Sci., 1996, 805, 184-203.
Tentler, J.J.; Hadcock, J.R.; Gutierrez-Hartmann, A. Somatostatinacts by inhibiting the cyclic 3', 5'-adenosine monophosphate(cAMP)/protein kinase A pathway, cAMP response elementbindingprotein (CREB) phosphorylation, and CREB transcriptionpotency. Mol. Endocrinol., 1997, 11(7), 859-866.
van der Lely, A.J.; Tschop, M.; Heiman, M.L.; Ghigo, E. Biological, physiological, pathophysiological, and pharmacological aspectsof ghrelin. Endocr. Rev., 2004, 25(3), 426-457.
Kojima, M.; Kangawa, K. Ghrelin: structure and function. Physiol. Rev., 2005, 85(2), 495-522.
Chawla, R.K.; Parks, J.S.; Rudman, D. Structural variants of humangrowth hormone: biochemical, genetic, and clinical aspects. Annu. Rev. Med., 1983, 34, 519-547.
Maggiano, N.; Piantelli, M.; Ricci, R.; Larocca, L.M.; Capelli, A.; Ranelletti, F.O. Detection of growth hormone-producing cells inhuman thymus by immunohistochemistry and non-radioactive insitu hybridization. J. Histochem. Cytochem., 1994, 42(10), 1349-1354.
Weigent, D.A.; Blalock, J.E. The production of growth hormone bysubpopulations of rat mononuclear leukocytes. Cell. Immunol., 1991, 135(1), 55-65.
Guarcello, V.; Weigent, D.A.; Blalock, J.E. Growth hormone releasinghormone receptors on thymocytes and splenocytes fromrats. Cell. Immunol., 1991, 136(2), 291-302.
Weigent, D.A.; Blalock, J.E. Effect of the administration ofgrowth-hormone-producing lymphocytes on weight gain and immunefunction in dwarf mice. Neuroimmunomodulation, 1994, 1(1), 50-58.
Kooijman, R.; Malur, A.; Van Buul-Offers, S.C.; Hooghe-Peters, E.L. Growth hormone expression in murine bone marrow cells isindependent of the pituitary transcription factor Pit-1. Endocrinology, 1997, 138(9), 3949-3955.
Arrenbrecht, S. Specific binding of growth hormone to thymocytes. Nature, 1974, 252(5480), 255-257.
Mertani, H.C.; Morel, G. In situ gene expression of growth hormone(GH) receptor and GH binding protein in adult male rat tissues. Mol. Cell. Endocrinol., 1995, 109(1), 47-61.
Adams, T.E.; Epa, V.C.; Garrett, T.P.; Ward, C.W. Structure andfunction of the type 1 insulin-like growth factor receptor. Cell. Mol. Life Sci., 2000, 57(7), 1050-1093.
Bu, Y.H.; He, Y.L.; Zhou, H.D.; Peng, D.; Liu, W.; Tang, A.G.; Tang, L.L.; Xie, H.; Huang, Q.X.; Luo, X.H.; Liao, E.Y. Insulin receptorsubstrate 1 regulates the cellular differentiation and the matrixmetalloproteinase expression of preosteoblastic cells. J. Endocrinol., 2010, 206(3), 271-277.
Stewart, C.E.; Rotwein, P. Growth, differentiation, and survival:multiple physiological functions for insulin-like growth factors. Physiol. Rev., 1996, 76(4), 1005-1026.
Daughaday, W.H.; Rotwein, P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr. Rev., 1989, 10(1), 68-91.
Lupu, F.; Terwilliger, J.D.; Lee, K.; Segre, G.V.; Efstratiadis, A. Roles of growth hormone and insulin-like growth factor 1 in mousepostnatal growth. Dev. Biol., 2001, 229(1), 141-162.
Yakar, S.; Liu, J.L.; Stannard, B.; Butler, A.; Accili, D.; Sauer, B.; LeRoith, D., Normal growth and development in the absence ofhepatic insulin-like growth factor I. Proc. Natl. Acad. Sci. USA, 1999, 96(13), 7324-7329.
Kecha, O.; Brilot, F.; Martens, H.; Franchimont, N.; Renard, C.; Greimers, R.; Defresne, M.P.; Winkler, R.; Geenen, V. Involvementof insulin-like growth factors in early T cell development: astudy using fetal thymic organ cultures. Endocrinology, 2000, 141(3), 1209-1217.
Verland, S.; Gammeltoft, S. Functional receptors for insulin-likegrowth factors I and II in rat thymocytes and mouse thymoma cells. Mol. Cell. Endocrinol., 1989, 67(2-3), 207-216.
Kelley, K.W.; Meier, W.A.; Minshall, C.; Schacher, D.H.; Liu, Q.; VanHoy, R.; Burgess, W.; Dantzer, R. Insulin growth factor-I inhibits apoptosis in hematopoietic progenitor cells. Implications inthymic aging. Ann. NY Acad. Sci., 1998, 840, 518-524.
Beschorner, W.E.; Divic, J.; Pulido, H.; Yao, X.; Kenworthy, P.; Bruce, G. Enhancement of thymic recovery after cyclosporine byrecombinant human growth hormone and insulin-like growth factorI. Transplantation, 1991, 52(5), 879-884.
Hinton, P.S.; Peterson, C.A.; Dahly, E.M.; Ney, D.M. IGF-I alterslymphocyte survival and regeneration in thymus and spleen afterdexamethasone treatment. Am. J. Physiol., 1998, 274(4 Pt 2), R912-920.
Kelley, K.W.; Brief, S.; Westly, H.J.; Novakofski, J.; Bechtel, P.J.; Simon, J.; Walker, E.B. GH3 pituitary adenoma cells can reversethymic aging in rats. Proc. Natl. Acad. Sci. USA, 1986, 83(15), 5663-5667.
Clark, R.; Strasser, J.; McCabe, S.; Robbins, K.; Jardieu, P. Insulinlikegrowth factor-1 stimulation of lymphopoiesis. J. Clin. Invest., 1993, 92(2), 540-548.
van Buul-Offers, S.C.; Kooijman, R. The role of growth hormoneand insulin-like growth factors in the immune system. Cell. Mol. Life Sci., 1998, 54(10), 1083-1094.
Zhou, R.; Flaswinkel, H.; Schneider, M.R.; Lahm, H.; Hoeflich, A.; Wanke, R.; Wolf, E. Insulin-like growth factor-binding protein-4inhibits growth of the thymus in transgenic mice. J. Mol. Endocrinol., 2004, 32(2), 349-364.
Sabharwal, P.; Varma, S. Growth hormone synthesized and secretedby human thymocytes acts via insulin-like growth factor I asan autocrine and paracrine growth factor. J. Clin. Endocrinol. Metab., 1996, 81(7), 2663-2669.
Yamada, M.; Hato, F.; Kinoshita, Y.; Tominaga, K.; Tsuji, Y. Theindirect participation of growth hormone in the thymocyte proliferationsystem. Cell Mol. Biol. (Noisy-le-grand), 1994, 40(2), 111-121.
Timsit, J.; Savino, W.; Safieh, B.; Chanson, P.; Gagnerault, M.C.; Bach, J.F.; Dardenne, M. Growth hormone and insulin-like growthfactor-I stimulate hormonal function and proliferation of thymicepithelial cells. J. Clin. Endocrinol. Metab., 1992, 75(1), 183-188.
Tsuji, Y.; Kinoshita, Y.; Hato, F.; Tominaga, K.; Yoshida, K. The in vitro proliferation of thymus epithelial cells stimulated withgrowth hormone and insulin-like growth factor-I. Cell Mol. Biol. (Noisy-le-grand), 1994, 40(8), 1135-1142.
Aiuti, A.; Tavian, M.; Cipponi, A.; Ficara, F.; Zappone, E.; Hoxie, J.; Peault, B.; Bordignon, C. Expression of CXCR4, the receptorfor stromal cell-derived factor-1 on fetal and adult human lymphohematopoieticprogenitors. Eur. J. Immunol., 1999, 29(6), 1823-1831.
Smaniotto, S.; de Mello-Coelho, V.; Villa-Verde, D.M.; Pleau, J.M.; Postel-Vinay, M. C.; Dardenne, M.; Savino, W. Growth hormonemodulates thymocyte development in vivo through a combinedaction of laminin and CXC chemokine ligand 12. Endocrinology, 2005, 146(7), 3005-3017.
Golde, D.W.; Bersch, N.; Li, C.H. Growth hormone: speciesspecificstimulation of erythropoiesis in vitro. Science, 1977, 196(4294), 1112-1113.
Duquesnoy, R.J.; Pedersen, G. Immunologic and hematologicdeficiencies of the hypopituitary dwarf mouse. In: ImmunologicDefects in Laboratory Animals; Gershwin, M.E., Merchant, B. Eds.; Plenum; New York, 1981, Vol. 1, pp 309-324.
Merchav, S.; Tatarsky, I.; Hochberg, Z. Enhancement of humangranulopoiesis in vitro by biosynthetic insulin-like growth factorI/somatomedin C and human growth hormone. J. Clin. Invest., 1988, 81(3), 791-797.
Murphy, W.J.; Tsarfaty, G.; Longo, D.L. Growth hormone exertshematopoietic growth-promoting effects in vivo and partially counteractsthe myelosuppressive effects of azidothymidine. Blood, 1992, 80(6), 1443-1447.
Murphy, W.J.; Durum, S. K.; Longo, D.L. Differential effects ofgrowth hormone and prolactin on murine T cell development andfunction. J. Exp. Med., 1993, 178(1), 231-236.
Dorshkind, K.; Horseman, N.D., Anterior pituitary hormones, stress, and immune system homeostasis. Bioessays, 2001, 23(3), 288-294.
Taub, D.D.; Tsarfaty, G.; Lloyd, A.R.; Durum, S.K.; Longo, D.L.; Murphy, W.J. Growth hormone promotes human T cell adhesionand migration to both human and murine matrix proteins in vitroand directly promotes xenogeneic engraftment. J. Clin. Invest., 1994, 94(1), 293-300.
Savino, W.; de Mello-Coelho, V.; Dardenne, M. Control of thethymic microenvironment by growth hormone/insulin-like growthfactor-I-mediated circuits. Neuroimmunomodulation, 1995, 2(6), 313-318.
de Mello-Coelho, V.; Villa-Verde, D.M.; Dardenne, M.; Savino, W. Pituitary hormones modulate cell-cell interactions betweenthymocytes and thymic epithelial cells. J. Neuroimmunol., 1997, 76(1-2), 39-49.
Montecino-Rodriguez, E.; Clark, R.; Dorshkind, K. Effects ofinsulin-like growth factor administration and bone marrow transplantationon thymopoiesis in aged mice. Endocrinology, 1998, 139(10), 4120-4126.
Tseng, Y.H.; Kessler, M.A.; Schuler, L.A. Regulation of interleukin(IL)-1alpha, IL-1beta, and IL-6 expression by growth hormoneand prolactin in bovine thymic stromal cells. Mol. Cell. Endocrinol., 1997, 128(1-2), 117-127.
Goya, R.G.; Gagnerault, M.C.; De Moraes, M.C.; Savino, W.; Dardenne, M. In vivo effects of growth hormone on thymus functionin aging mice. Brain Behav. Immun., 1992, 6(4), 341-354.
Dorshkind, K.; Horseman, N.D. The roles of prolactin, growthhormone, insulin-like growth factor-I, and thyroid hormones inlymphocyte development and function: insights from genetic modelsof hormone and hormone receptor deficiency. Endocr. Rev., 2000, 21(3), 292-312.
Auernhammer, C.J.; Strasburger, C.J. Effects of growth hormoneand insulin-like growth factor I on the immune system. Eur. J. Endocrinol., 1995, 133(6), 635-645.
de Mello-Coelho, V.; Gagnerault, M.C.; Souberbielle, J.C.; Strasburger, C.J.; Savino, W.; Dardenne, M.; Postel-Vinay, M.C. Growth hormone and its receptor are expressed in human thymiccells. Endocrinology, 1998, 139(9), 3837-3842.
Kooijman, R.; Scholtens, L.E.; Rijkers, G.T.; Zegers, B.J. Type Iinsulin-like growth factor receptor expression in different developmentalstages of human thymocytes. J. Endocrinol., 1995, 147(2), 203-209.
Baxter, J.B.; Blalock, J.E.; Weigent, D.A. Expression of immunoreactivegrowth hormone in leukocytes in vivo. J. Neuroimmunol., 1991, 33(1), 43-54.
Han, Y.; Leaman, D.W.; Watling, D.; Rogers, N.C.; Groner, B.; Kerr, I.M.; Wood, W.I.; Stark, G.R. Participation of JAK andSTAT proteins in growth hormone-induced signaling. J. Biol. Chem., 1996, 271(10), 5947-5952.
Savino, W.; Postel-Vinay, M.C.; Smaniotto, S.; Dardenne, M. Thethymus gland: a target organ for growth hormone. Scand. J. Immunol., 2002, 55(5), 442-452.
Froesch, E.R.; Hussain, M. Recombinant human insulin-likegrowth factor-I: a therapeutic challenge for diabetes mellitus. Diabetologia, 1994, 37(Suppl. 2), S179-185.
Kecha, O.; Martens, H.; Franchimont, N.; Achour, I.; Hazee-Hagelstein, M.T.; Charlet-Renard, C.; Geenen, V.; Winkler, R. Characterization of the insulin-like growth factor axis in the humanthymus. J. Neuroendocrinol., 1999, 11(6), 435-440.
Rosenfeld, R.G.; Rosenbloom, A.L.; Guevara-Aguirre, J. Growthhormone (GH) insensitivity due to primary GH receptor deficiency. Endocr. Rev., 1994, 15(3), 369-390.
Benini, S.; Manara, M.C.; Cerisano, V.; Perdichizzi, S.; Strammiello, R.; Serra, M.; Picci, P.; Scotlandi, K. Contribution ofMEK/MAPK and PI3-K signaling pathway to the malignant behaviorof Ewing's sarcoma cells: therapeutic prospects. Int. J. Cancer, 2004, 108(3), 358-366.
de Mello Coelho, V.; Villa-Verde, D.M.; Farias-de-Oliveira, D.A.; de Brito, J.M.; Dardenne, M.; Savino, W. Functional insulin-likegrowth factor-1/insulin-like growth factor-1 receptor-mediated circuitin human and murine thymic epithelial cells. Neuroendocrinology, 2002, 75(2), 139-150.
Sivan, B.; Lilos, P.; Laron, Z. Effects of insulin-like growth factor-Ideficiency and replacement therapy on the hematopoietic system inpatients with Laron syndrome (primary growth hormone insensitivity). J. Pediatr. Endocrinol. Metab., 2003, 16(4), 509-520.
Christ, E.R.; Cummings, M.H.; Westwood, N.B.; Sawyer, B.M.; Pearson, T.C.; Sonksen, P.H.; Russell-Jones, D.L. The importanceof growth hormone in the regulation of erythropoiesis, red cellmass, and plasma volume in adults with growth hormone deficiency. J. Clin. Endocrinol. Metab., 1997, 82(9), 2985-2990.
Huang, J.; Durum, S.K.; Muegge, K. Cutting edge: histone acetylationand recombination at the TCR gamma locus follows IL-7 induction. J. Immunol., 2001, 167(11), 6073-6077.
Aspinall, R. T cell development, ageing and Interleukin-7. Mech. Ageing Dev., 2006, 127(6), 572-578.
Bazzoni, N.; Ambrosi, B.; Arosio, M.; Barbareschi, M.; Losa, M.; Faglia, G. Acromegaly and thymic hyperplasia: a case report. J. Endocrinol. Invest., 1990, 13(11), 931-935.
Taub, D.D.; Longo, D.L. Insights into thymic aging and regeneration. Immunol. Rev., 2005, 205, 72-93.
Pfister, G.; Savino, W. Can the immune system still be efficient inthe elderly? An immunological and immunoendocrine therapeuticperspective. Neuroimmunomodulation, 2008, 15(4-6), 351-364.
Koo, G.C.; Huang, C.; Camacho, R.; Trainor, C.; Blake, J. T.; Sirotina-Meisher, A.; Schleim, K.D.; Wu, T.J.; Cheng, K.; Nargund, R.; McKissick, G. Immune enhancing effect of a growthhormone secretagogue. J. Immunol., 2001, 166(6), 4195-4201.
Spadoni, G.L.; Rossi, P.; Ragno, W.; Galli, E.; Cianfarani, S.; Galasso, C.; Boscherini, B. Immune function in growth hormonedeficientchildren treated with biosynthetic growth hormone. ActaPaediatr. Scand., 1991, 80(1), 75-79.
Dixit, V.D.; Schaffer, E.M.; Pyle, R.S.; Collins, G.D.; Sakthivel, S.K.; Palaniappan, R.; Lillard, J.W. Jr.; Taub, D.D. Ghrelin inhibitsleptin- and activation-induced proinflammatory cytokine expressionby human monocytes and T cells. J. Clin. Invest., 2004, 114(1), 57-66.
Haynes, B.F.; Hale, L.P.; Weinhold, K.J., Patel, D.D.; Liao, H.X.; Bressler, P.B.; Jones, D.M.; Demarest, J.F.; Gebhard-Mitchell, K. Haase, A.T.; Bartlett, J.A. Analysis of the adult thymus in reconstitutionof T lymphocytes in HIV-1 infection. J. Clin. Invest., 1999 103(4), 453-460.
Bandera, A.; Ferrario, G.; Saresella, M.; Marventano, I.; Soria, A.; Zanini, F.; Sabbatini, F.; Airoldi, M.; Marchetti, G.; Franzetti, F.; Trabattoni, D.; Clerici, M.; Gori, A. CD4+ T cell depletion, immuneactivation and increased production of regulatory T cells inthe thymus of hiv-infected individuals. PLoS One, 2010, 5, e10788.
Mallewa, J.E.; Wilkins, E.; Vilar, J.; Mallewa, M.; Doran, D.; Back, D.; Pirmohamed, M. HIV-associated lipodystrophy: A reviewof underlying mechanisms and therapeutic options. J. Antimicrob. Chemother., 2008, 62(4), 648-660.
Zirilli, L.; Orlando, G.; Diazzi, C.; Squillace, N.; Carani, C.; Guaraldi, G.; Rochira, V. Hypopituitarism and hiv-infection: A newcomorbidity in the HAART era? J. Endocrinol. Invest., 2008, 31(9s), 33-38.
Nguyen, B.Y.; Clerici, M.; Venzon, D.J.; Bauza, S.; Murphy, W.J.; Longo, D.L.; Baseler, M.; Gesundheit, N.; Broder, S.; Shearer, G.; Yarchoan, R. Pilot study of the immunologic effects of recombinanthuman growth hormone and recombinant insulin-like growthfactor in HIV-infected patients. AIDS, 1998, 12(8), 895-904.
Vigano, A.; Saresella, M.; Trabattoni, D.; Giacomet, V.; di Natale, B.; Merlo, M.; Venuto, A.; Villa, M.L.; Vanzulli, S.; Ferrante, P. Clerici, M. Growth hormone in T-lymphocyte thymic and postthymicdevelopment: A study in HIV-infected children. J. Pediatr., 2004, 145(4), 542-548.
Redelman, D.; Welniak, L.A.; Taub, D.; Murphy, W.J. Neuroendocrinehormones such as growth hormone and prolactin are integralmembers of the immunological cytokine network. Cell. Immunol., 2008, 252(1-2), 111-121.
Verinaud, L.; Da Cruz-Hofling, M.A. Sakurada, J.K.; Rangel, H.A.; Vassallo, J.; Wakelin, D.; Sewell, H.F.; Camargo, I.J. Immunodepressioninduced by trypanosoma cruzi and mouse hepatitis virustype 3 is associated with thymus apoptosis. Clin. Diagn. Lab. Immunol., 1998, 5(2), 186-191.
Savino, W. The thymus is a common organ target for infectiousdiseases. PLoS Pathog., 2006, 2, e62.
Correa-de-Santana, E.; Paez-Pereda, M.; Theodoropoulou, M.; Kenji Nihei, O.; Gruebler, Y.; Bozza, M.; Arzt. E.; Villa-Verde, D.M.; Renner, U.; Stalla, J.; Stalla, G.K.; Savino, W. Hypothalamus-pituitary-adrenal axis during trypanosoma cruzi acute infectionin mice. J. Neuroimmunol., 2006, 173(1-2), 12-22.
Correa-de-Santana, E.; Paez-Pereda, M.; Theodoropoulou, M.; Renner, U.; Stalla, J.; Stalla, G.K.; Savino, W. Modulation ofgrowth hormone and prolactin secretion in T. cruzi-infected mammosomatotrophiccells. Neuroimmunomodulation, 2009, 16(3), 208-212.
Lemos, E.M.; Reis, D.; Adad, S.J.; Silva, G.C.; Crema, E.; Correa-Oliveira, R. Decreased CD4+ circulating T lymphocytes in patientswith gastrointestinal chagas disease. Clin. Immunol. Immunopathol., 1998, 88(2), 150-155.
Mendes-da-Cruz, D.A.; Silva, J.S.; Cotta-de-Almeida, V.; Savino, W. Altered thymocyte migration during experimental acute trypanosomacruzi infection: Combined role of fibronectin and thechemokines CXCL12 and CCL4. Eur. J. Immunol., 2006, 36, 1486-1493.
Mendes-da-Cruz, D.A.; de Meis, J.; Cotta-de-Almeida, V.; Savino, W. Experimental trypanosoma cruzi infection alters the shaping ofthe central and peripheral t-cell repertoire. Microbes Infect., 2003, 5, 825-832.
Fernandez-Mestre, M.T.; Jaraquemada, D.; Bruno, R.E.; Caro, J.; Layrisse, Z. Analysis of the t-cell receptor beta-chain variableregion(Vbeta) repertoire in chronic human chagas' disease. TissueAntigens, 2002, 60, 10-15.
