Download PDF
Horm Metab Res 2003; 35(11/12): 656-663
DOI: 10.1055/s-2004-814161
Original
© Georg Thieme Verlag Stuttgart · New York

The Thymic Insulin-like Growth Factor Axis: Involvement in Physiology and Disease

V.  Geenen1
  • 1 University of Liege Center of Immunology (CIL), Institute of Pathology, Liege-Sart Tilman, Belgium
Further Information

Publication History

Received 28 August 2003

Accepted after Revision 25 September 2003

Publication Date:
07 January 2004 (online)

Also available at
    Permissions and Reprints

Abstract

A repertoire of neuroendocrine-related genes is transcribed in the non-lymphoid compartment of the thymus, transposing the dual physiological role of this organ at the molecular level in T-cell development towards the establishment of central T-cell self-tolerance. The ”neuroendocrine self” has been defined as a series of antigen sequences processed from precursors predominantly expressed in the thymus and first encountered by differentiating T-lymphocytes in their early life. All the members of the insulin gene family are expressed in the thymus according to a precise hierarchy and cellular topography, whereby IGF-II (epithelium of the subcapsular cortex and medulla) exceeds IGF-I (macrophages), which in turn far exceeds INS (rare subsets of medullary epithelial cells). This hierarchy in the degree of their respective thymic expression explains why IGF-II is more tolerated than IGF-I, and much more so than insulin. Evidence has been found for significant regulatory/tolerogenic properties in the IGF-II B:11 - 25 sequence after analysis of the cytokine secretion profile in peripheral blood mononuclear cells isolated from ten DQ8+ type 1 diabetic adolescents. In the thymus, IGF ligands and receptors also intervene in the control of T-cell proliferation and differentiation. Here, we also discuss how a disturbance in the intrathymic IGF-mediated signaling could contribute to the pathogenesis of T-cell leukemia.

Key words

Thymus epithelium - Self-tolerance - Autoimmunity - Type 1 diabetes - T-cell leukemia - Tolerogenic vaccine

References

  • 1 Benoist C, Mathis D. T-lymphocyte Differentiation and Biology. In: Paul WE (ed) Fundamental Immunology 4th Edition. Philadelphia; Lippincott-Raven 1999: 367-409
    Search in Google Scholar
  • 2 Mason D, Powrie F. Control of immune pathology by regulatory T-cells.  Curr Opin Immunol. 1998;  10 649-655
    CrossrefPubMedSearch in Google Scholar
  • 3 Sakagushi S. Policing the regulators.  Nat Immunol. 2001;  2 283-284
    CrossrefPubMedSearch in Google Scholar
  • 4 Kamradt T, Mitchison N A. Tolerance and autoimmunity.  N Engl J Med. 2001;  344 655-664
    PubMedSearch in Google Scholar
  • 5 Bennett A R, Farley A, Blair N F, Gordon J, Sharp L, Blackburn C C. Identification and characterization of thymic epithelial progenitor cells.  Immunity. 2002;  16 803-814
    CrossrefPubMedSearch in Google Scholar
  • 6 Girr J, Malin M, Holländer G A, Boyd R. Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells.  Nat Immunol. 2002;  3 635-642
    CrossrefPubMedSearch in Google Scholar
  • 7 Penninger J, Rieker T, Romani N, Klima J, Salvenmoser W, Dietrich H, Stössel H, Wick G. Ultrastructural analysis of thymic nurse cell epithelium.  Eur J Immunol. 1993;  24 222-229
    PubMedSearch in Google Scholar
  • 8 Lorenz R G, Allen P M. Thymic cortical epithelial cells can present self-antigens in vivo. .  Nature. 1989;  337 560-562
    CrossrefPubMedSearch in Google Scholar
  • 9 Ashton-Rickardt P G, Tonegawa S. A differential-affinity model for T-cell selection.  Immunol Today. 1994;  15 362-366
    CrossrefPubMedSearch in Google Scholar
  • 10 Geenen V, Robert F, Martens H, De Groote D, Franchimont P. The thymic education of developing T-cells in self neuroendocrine principles.  J Endocr Invest. 1992;  15 621-629
    PubMedSearch in Google Scholar
  • 11 Robert F, Martens H, Cormann N, Benhida A, Schoenen J, Geenen V. The recognition of hypothalamo-neurohypophysial functions by developing T-cells.  Dev Immunol. 1992;  2 131-140
    PubMedSearch in Google Scholar
  • 12 Jolicoeur C, Hanahan D, Smith K M. T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous genes in the thymus.  Proc Natl Acad Sci USA. 1994;  91 6707-6711
    PubMedSearch in Google Scholar
  • 13 Hanahan D. Peripheral-antigen-expressing cells in thymus medulla: factors in self-tolerance and autoimmunity.  Curr Opin Immunol. 1998;  10 656-662
    CrossrefPubMedSearch in Google Scholar
  • 14 Savino W, Dardenne M. Neuroendocrine control of thymus physiology.  Endocr Rev. 2000;  21 412-443
    CrossrefPubMedSearch in Google Scholar
  • 15 Kyewski B, Derbinski J, Gotter J, Klein L. Promiscuous gene expression and central T-cell tolerance: more than meets the eye.  Trends Immunol. 2002;  23 364-371
    CrossrefPubMedSearch in Google Scholar
  • 16 Geenen V, Legros J J, Franchimont P, Baudrihaye M, Defresne M P, Boniver J. The thymus as a neuroendocrine organ: coexistence of oxytocin and neurophysin in the human thymus.  Science. 1986;  232 508-511
    PubMedSearch in Google Scholar
  • 17 Ericsson A, Geenen V, Robert F, Legros J J, Vrindts-Gevaert Y, Franchimont P, Brene S, Persson H. Expression of preprotachykinin-A and neuropeptide-Y messenger RNA in the thymus.  Mol Endocr. 1990;  4 1211-1218
    PubMedSearch in Google Scholar
  • 18 Funder J W. Paracrine, cryptocrine, acrocrine.  Mol Cell Endocrinol. 1990;  70 C21-C24
    CrossrefPubMedSearch in Google Scholar
  • 19 Geenen V, Goxe B, Martens H, Vandersmissen E, Vanneste Y, Achour I, Kecha O, Lefebvre P J. Cryptocrine signaling in the thymus network and T-cell education to neuroendocrine self-antigens.  J Mol Med. 1995;  73 449-455
    PubMedSearch in Google Scholar
  • 20 Geenen V, Vandersmissen E, Martens H, Cormann-Goffin N, Degiovanni G, Legros J J, Benhida A, Martial J, Franchimont P. Membrane translocation and association with MHC class I of a human thymic neurophysin-like protein.  Thymus. 1993;  22 55-66
    PubMedSearch in Google Scholar
  • 21 Vanneste Y, Ntodou-Thome A, Vandersmissen E, Charlet C, Franchimont D, Martens H, Schimpff R M, Rostene W, Geenen V. Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules.  J Neuroimmunol. 1997;  76 161-166
    CrossrefPubMedSearch in Google Scholar
  • 22 Geenen V, Brilot F, Hansenne I, Charlet C, Martens H. Thymus and T Cells. In: Adelman G, Smith BH (eds) Encyclopedia of Neuroscience 3rd Edition. New York; Elsevier 2003: in press
    Search in Google Scholar
  • 23 Geenen V, Achour I, Robert F, Vandersmissen E, Sodoyez J C, Defresne M P, Boniver J, Lefebvre P J, Franchimont P. Evidence that insulin-like growth factor-2 (IGF-II) is the dominant thymic peptide of the insulin superfamily.  Thymus. 1993;  21 115-127
    PubMedSearch in Google Scholar
  • 24 van Buul-Offers S C, de Haan K, Reijnen-Gresnigt M G, Meinsma D, Jansen M, Oei S L, Bonte E J, Sussenbach J S, Van den Brande J L. Overexpression of human insulin-like growth factor-II in transgenic mice causes increased growth of the thymus.   J Endocrinol. 1995;  144 491-502
    PubMedSearch in Google Scholar
  • 25 Van der Ven L TM, Roholl P JM, Reijnen-Gresnigt M G, Bloemen R J, van Buul-Offers S C. Expression of insulin-like growth factor II (IGF-II) and histological changes in the thymus and spleen of transgenic mice overexpressing IGF-II.  Histochem Cell Biol. 1997;  107 193-203
    CrossrefPubMedSearch in Google Scholar
  • 26 Kooijman R, van Buul-Offers S C, Scholtens L E, Schuurman H J, van den Brande L J, Zegers B JM. T-cell development in insulin-like growth factor-II transgenic mice.  J Immunol. 1995;  154 5736-5745
    PubMedSearch in Google Scholar
  • 27 Kecha O, Martens H, Franchimont N, Achour I, Hazée-Hagelstein M T, Charlet-Renard C, Geenen V, Winkler R. Characterization of the insulin-like growth factor axis in the human thymus.  J Neuroendocrinol. 1999;  11 435-440
    CrossrefPubMedSearch in Google Scholar
  • 28 Montecino-Rodriguez E, Clark R, Dorshkind K. Effects of insulin-like growth factor administration and bone marrow transplantation on thymopoiesis in aged mice.  Endocrinology. 1998;  139 4120-4126
    CrossrefPubMedSearch in Google Scholar
  • 29 Kecha O, Brilot F, Martens H, Franchimont N, Renard C, Greimers R, Defresne M P, Winkler R, Geenen V. Involvement of insulin-like growth factors in early T-cell development: a study using fetal thymic organ cultures.  Endocrinology. 2000;  141 1209-1217
    CrossrefPubMedSearch in Google Scholar
  • 30 Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.  Nat Immunol. 2001;  2 1032-1039
    CrossrefPubMedSearch in Google Scholar
  • 31 Egwuagu C E, Charukamnoetkanok P, Gery I. Thymic expression of autoantigens correlates with resistance to autoimmune disease.  J Immunol. 1997;  159 3109-3112
    PubMedSearch in Google Scholar
  • 32 Sospedra M, Ferrer-Francesch X, Dominguez O, Juan M, Foz-Sala M, Pujol-Borrell R. Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanism in tolerance towards peripheral antigens.  J Immunol. 1998;  161 5918-5929
    PubMedSearch in Google Scholar
  • 33 Vafiadis P, Bennett S T, Todd J A, Nadeau J, Grabs R, Goodyer C G, Wickramasinghe S, Colle E, Polychronakos C. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus.  Nat Genet. 1997;  15 289-292
    CrossrefPubMedSearch in Google Scholar
  • 34 Pugliese A, Zeller M, Fernandez A Jr, Zalcberg L J, Bartlett R J, Ricordi C, Pietropaolo M, Eisenbarth G S, Bennett S T, Patel D D. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes.  Nat Genet. 1997;  15 293-297
    CrossrefPubMedSearch in Google Scholar
  • 35 Zapf J, Walter H, Froesch E R. Radioimmunological determination of insulin-like growth factors I and II in normal subjects and in patients with growth disorders and extrapancreatic tumor hypoglycemia.  J Clin Invest. 1981;  68 1321-1330
    PubMedSearch in Google Scholar
  • 36 Naquet P, Ellis J, Tibensky D, Kenshole A, Singh B, Hodges R, Delovitch T L. T-cell autoreactivity to insulin in diabetic and related non-diabetic individuals.  J Immunol. 1988;  140 2569-2578
    PubMedSearch in Google Scholar
  • 37 Like A A, Kislaukis E, Williams R M, Rossini A A. Neonatal thymectomy prevents spontaneous diabetes mellitus in the BB:W rat.  Science. 1982;  216 644-646
    PubMedSearch in Google Scholar
  • 38 Georgiou H M, Bellgrau D. Thymus transplantation and disease prevention in the diabetes-prone Bio-Breeding rat.  J Immunol. 1989;  142 3400-3405
    PubMedSearch in Google Scholar
  • 39 Georgiou H M, Mandel T E. Induction of insulitis in athymic (nude) mice. The effect of NOD thymus and pancreas transplantation.  Diabetes. 1995;  44 49-59
    PubMedSearch in Google Scholar
  • 40 Hosaka N, Nose M, Kyogoku M, Nagata N, Miyashima S, Good R A, Ikehara S. Thymus transplantation, a critical factor for correction of autoimmune disease in aging MRL/+ mice.  Proc Natl Acad Sci USA. 1996;  93 8558-8562
    CrossrefPubMedSearch in Google Scholar
  • 41 Thomas-Vaslin V, Damotte D, Coltey M, Le Douarin N M, Coutinho A, Salaün J. Abnormal T-cell selection on NOD thymic epithelium is sufficient to induce autoimmune manifestations in C57BL/6 athymic nude mice.  Proc Natl Acad Sci USA. 1997;  94 4598-4603
    CrossrefPubMedSearch in Google Scholar
  • 42 Savino W, Carnaud C, Luan J J, Bach J F, Dardenne M. Characterization of the extracellular matrix-containing giant perivascular spaces in the NOD mouse thymus.  Diabetes. 1993;  42 134-140
    PubMedSearch in Google Scholar
  • 43 Doukas J, Mordes J P, Swymer C, Niedzwiecki D, Mason R, Rozing J, Rossini A A, Greiner D L. Thymic epithelial defects and predisposition to autoimmune disease in BB rats.  Am J Pathol. 1994;  145 1517-1525
    PubMedSearch in Google Scholar
  • 44 Kecha-Kamoun O, Achour I, Martens H, Collette J, Lefebvre P J, Greiner D L, Geenen V. Thymic expression of insulin-related genes in an animal model of type 1 diabetes.  Diabetes/Metab Res Rev. 2001;  17 146-152
    PubMedSearch in Google Scholar
  • 45 Brimnes M K, Jensen T, Jorgensen T N, Michelsen B K, Troelsen J, Werdenlin O. Low expression of insulin in the thymus of non-obese diabetic mice.  J Autoimmun. 2002;  19 203-213
    CrossrefPubMedSearch in Google Scholar
  • 46 Chentoufi A A, Polychronakos C. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes.  Diabetes. 2002;  51 1383-1390
    PubMedSearch in Google Scholar
  • 47 Thebault-Baumont K, Dubois-Laforgue D, Krief P, Briand J P, Halbout P, Vallon-Geoffroy K, Morin J, Laloux V, Lehuen A, Carel J C, Jami J, Muller S, Boitard C. Acceleration of type 1 diabetes in proinsulin 2 deficient mice.  J Clin Invest. 2003;  111 851-857
    CrossrefPubMedSearch in Google Scholar
  • 48 Kaufman D L, Clare-Salzler M C, Tian J, Forsthuber T, Ting G SP, Robinson P, Atkinson M A, Sercarz E E, Tobin A J, Lehmann P V. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes.  Nature. 1993;  366 69-72
    CrossrefPubMedSearch in Google Scholar
  • 49 Diez J, Park Y, Zeller M, Brown D, Garza D, Ricordi C, Hutton J, Eisenbarth G S, Pugliese A. Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen.  Diabetes. 2001;  50 895-900
    PubMedSearch in Google Scholar
  • 50 Nagamine K, Peterson P, Scott H S, Kudoh J, Minoshima S, Heino M, Krohn K JE, Lalioti M D, Mullis P E, Antonorakis S E, Kawasaki K, Asakawa S, Ito F, Shimizu N. Positional cloning of the APECED gene.  Nat Genet. 1997;  17 393-398
    CrossrefPubMedSearch in Google Scholar
  • 51 Rossier M L, Heino M, Peterson P, Krohn K J, Gos A, Morris M A, Kudoh J, Shimizu N, Antonarakis S E, Scott H S. Isolation and characterization of the mouse Aire gene.  Biochem Biophys Res Commun. 1999;  255 483-490
    CrossrefPubMedSearch in Google Scholar
  • 52 Pitkänen J, Peterson P. Autoimmune regulator: from loss of function to autoimmunity.  Genes and Immunity. 2003;  4 12-21
    CrossrefPubMedSearch in Google Scholar
  • 53 Zuklys S, Balciunaite G, Agarwal A, Farler-Kan E, Palmer E, Holländer G A. Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).  J Immunol. 2000;  165 1976-1983
    PubMedSearch in Google Scholar
  • 54 Heino M, Peterson P, Silanpää N, Guerin S, Wu L, Anderson G, Scott H S, Antonarakis S E, Kudoh J, Shimizu N, Jenkinson E J, Naquet P, Krohn K J. RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse.  Eur J Immunol. 2000;  30 1884-1893
    CrossrefPubMedSearch in Google Scholar
  • 55 Anderson M S, Venanzi E S, Klein L, Chen Z, Berzins S P, Turley S J, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D. Projection of an immunological self shadow in the thymus by the Aire protein.  Science. 2002;  298 1395-1301
    CrossrefPubMedSearch in Google Scholar
  • 56 Liston A, Lesage S, Wilson J, Peltonen L, Goodnow C C. Aire regulates negative selection of organ-specific T-cells.  Nat Immunol. 2003;  4 350-354
    CrossrefPubMedSearch in Google Scholar
  • 57 Burnet F M. A reassessment of the forbidden clone hypothesis of autoimmune diseases.  Aust J Exp Biol Med Sci. 1973;  50 1-9
    PubMedSearch in Google Scholar
  • 58 Gottlieb P A, Eisenbarth G S. Insulin-specific tolerance in diabetes.  Clin Immunol. 2002;  102 2-11
    CrossrefPubMedSearch in Google Scholar
  • 59 Liu E, Moriyama H, Abiru N, Miao D, Yu L, Taylor R M, Finkelman F D, Eisenbarth G S. Anti-peptide antibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9 - 23 and B: 13 - 23.  J Clin Invest. 2002;  110 1021-1027
    CrossrefPubMedSearch in Google Scholar
  • 60 Chaillous L, Lefevre H, Thivolet C, Boitard C, Lahlou N, Atlan-Gegner C, Bouhanick B, Mogenet A, Nicolino M, Carel J C, Lecomte P, Marchenaud R, Bougneres P, Charbonnel B, Sai P. Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomized controlled trial. Diabetes Insulin Oral Group.  Lancet. 2000;  356 545-549
    CrossrefPubMedSearch in Google Scholar
  • 61 Pozzilli P, Pitocco D, Visalli N, Cavallo M G, Buzzetti R, Crino A, Spera S, Suraci C, Multari G, Cervoni M, Manca Bitti M L, Matteoli M C, Marietti G, Ferrazzoli F, Cassone Faldetta M R, Giordano C, Sbriglia M, Sarugeri E, Ghirlanda G. No effect of oral insulin on residual beta-cell function in recent-onset type 1 diabetes.  Diabetologia. 2000;  43 1000-1004
    CrossrefPubMedSearch in Google Scholar
  • 62 DPT-Type 1 diabetes Study Group . Effects of insulin in relatives of patients with type 1 diabetes.  N Engl J Med. 2002;  346 1685-1691
    CrossrefPubMedSearch in Google Scholar
  • 63 Alleva D G, Crowe P D, Jin L, Kwok V W, Ling N, Gottschalk M, Conlon P J, Gottlieb P A, Putman A L, Gaur A. A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin.  J Clin Invest. 2001;  107 173-180
    PubMedSearch in Google Scholar
  • 64 Geenen V, Brilot F, Hansenne I, Louis C, Martens H, Wücherpfennig K, Gorus F. Thymus tolerance dysfunction in the development of the autoimmune diabetogenic response: a way for a novel type of vaccine/immunotherapy.  Diabetologia. 2003;  46 (suppl. 2) A10, abstract 22
    PubMedSearch in Google Scholar
  • 65 Nossal G JV. Vaccination and autoimmunity.  J Autoimmun. 2000;  14 13-15
    CrossrefPubMedSearch in Google Scholar
  • 66 Geenen V, Poulin J F, Dion M L, Martens H, Castermans E, Hansenne I, Moutschen M, Sekaly R P, Cheynier R. Quantification of T-cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology.  J Endocrinol. 2003;  176 305-311
    CrossrefPubMedSearch in Google Scholar
  • 67 Kong F K, Kong F, Chen C H, Cooper M D. Thymic function can be accurately monitored by the level of recent T-cell emigrants in the circulation.  Immunity. 1998;  8 97-104
    CrossrefPubMedSearch in Google Scholar
  • 68 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 of HIV infection.  Nature. 1998;  396 690-695
    CrossrefPubMedSearch in Google Scholar
  • 69 Poulin J F, Viswanathan M N, Harris J M, Kumanduri K V, Wieder E, Rinquette N, Jenkins M, McCune J M, Sekaly R P. Direct evidence for thymic function in adult humans.  J Exp Med. 1999;  190 479-486
    CrossrefPubMedSearch in Google Scholar
  • 70 McEndy D P, Boon M C, Furth J. On the role of thymus, spleen, and gonads in the development of leukemia in a high-leukemia stock of mice.  Cancer Res. 1944;  4 377-383
    PubMedSearch in Google Scholar
  • 71 Metcalf D. In: Outstanding Papers in Biology. London; Current Biology Ltd 1993: 117-124
    Search in Google Scholar
  • 72 Petridou E, Klimentopoulou A E, Moustaki M, Kostrikis L G, Hatzakis A, Trichopoulos D. Recent thymic emigrants and prognosis in T- and B-cell childhood hematopoietci malignancies.  Int J Cancer. 2002;  101 74-77
    CrossrefPubMedSearch in Google Scholar
  • 73 von Boehmer H, Aifantis I, Feinberg J, Lechner O, Saint-Ruf C, Walter U, Buer J, Azogui O. Pleiotropic changes controlled by the pre-T-cell receptor.  Curr Opin Immunol. 1999;  11 135-142
    CrossrefPubMedSearch in Google Scholar
  • 74 Jameson S, Bevan M. T-cell selection.  Curr Opin Immunol. 1998;  10 214-219
    CrossrefPubMedSearch in Google Scholar
  • 75 Bellavia D, Campese A F, Alesse E, Vacca A, Felli M P, Balestri A, Stoppacciaro A, Tiveron C, Tatangelo L, Giovarelli M, Gaetano C, Ruco L, Hoffman E S, Hayday A C, Lendahl U, Frati L, Gulino A, Screpanti I. Constitutive activation of NF-κB and T-cell leukemia/lymphoma in Notch3 transgenic mice.  EMBO J. 2000;  19 3337-3348
    CrossrefPubMedSearch in Google Scholar
  • 76 Bellavia D, Campese A F, Checquolo S, Balestri A, Biondi A, Cazzaniga G, Lendahl U, Fehling H J, Hayday A C, Frati L, von Boehmer H, Gulino A, Screpanti I. Combined expression of pToc and Notch3 in T-cell leukemia identifies the requirement of preTCR for leukemogenesis.  Proc Natl Acad Sci USA. 2002;  99 3788-2793
    CrossrefPubMedSearch in Google Scholar
  • 77 Amsen D, Kruisbeek A M. Thymocyte selection: not by TCR alone.  Immunol Rev. 1998;  165 209-229
    PubMedSearch in Google Scholar
  • 78 Pansky B, House E L, Cone L A. An insulin-like thymic factor. A preliminary report.  Diabetes. 1965;  14 325-332
    PubMedSearch in Google Scholar
  • 79 Silverstein M N, Wakim K, Bahn R C, Bayrd E D. A hypoglycemic factor in leukemic tumors.  Proc Soc Exp Biol Med. 1960;  103 824-826
    PubMedSearch in Google Scholar
  • 80 Zapf J, Hauri C, Waldvogel M, Froesch E R. Acute metabolic effects and half-lives of intravenously administered insulin-like growth factors I and II in normal and hypophectomised rats.  J Clin Invest. 1986;  77 1768-1775
    PubMedSearch in Google Scholar
  • 81 Kooijman R K, Scholtens L E, Rijkers G T, Zegers B J. Differential expression of type I insulin-like growth factor receptors in different stages of human T-cells.  Eur J Immunol.. 1995;  25 931-935
    PubMedSearch in Google Scholar
  • 82 Hansenne I, Rasier G, Charlet-Renard C, Defresne M P, Greimers R, Breton C, Legros J J, Geenen V, Martens H. Neurohypophysial receptor gene expression by thymic T-cell subsets and thymic T-cell lymphoma cell lines.  Dev Immunol. 2003;  in press
    PubMedSearch in Google Scholar
  • 83 Mason D Y. Seventh Workshop on Human Leukocyte Differentiation Antigens,. 2000
    Search in Google Scholar

V. Geenen M. D., Ph. D.

Research Director of Belgian NFSR and Director of CIL, Institute of Pathology CHU-B23

B-4000 Liege-Sart Tilman · Belgium

Phone: + 32 (4) 366 25 50

Fax: + 32 (4) 366 29 77 ·

Email: vgeenen@ulg.ac.be