Immunologic Research

, 12:115 | Cite as

Self-nonself discrimination and tolerance in T and B lymphocytes

  • J. F. A. P. Miller
Symposium

Abstract

The immune system must not only fight off infections, but also ensure that it does not react against its own body tissues. Since clones of lymphocytes have predetermined reactivities, some will be self-reactive and have the potential to cause damage. They should therefore be neutralized in some way. In a system as complex and important as that governing self-tolerance, many mechanisms must exist to neutralize autoaggressive lymphocytes. They may be classified under two main groups. In one the tolerant state arises from the physical or functional silencing of potentially autoaggressive lymphocytes after antigen encounter. This may involve clonal deletion, clonal abortion or clonal anergy. In the second, regulatory mechanisms of the immune system itself may hold autoreactive lymphocytes in check, for example through the operation of idiotypic network interactions and the action of specialized suppressor cells. Much evidence has accumulated for the physical deletion of autoreactive T cells as they mature in the thymus. The fate of any that escape thymus censorship has been the subject of recent research and is discussed here. Under certain conditions, self-tolerance must also be imposed at the B-cell level to prevent the production of potentially damaging autoantibodies. Although the mechanisms which silence self-reactive lymphocytes are very efficient, self-tolerance can break down, and autoimmunity will thus ensue. The main factors responsible for this are briefly described here.

Key Words

Autoimmunity Tolerance Thymus T cells B cells Transgenic mice Self Nonself Negative selection Positive selection Major histocompatibility complex T cell receptor 

References

  1. 1.
    Davis MM, Bjorkman PJ: T-cell antigen receptor genes and T-cell recognition. Nature 1988;334:395.PubMedCrossRefGoogle Scholar
  2. 2.
    Burnet FM: The Clonal Selection Theory of Acquired Immunity. London, Cambridge University Press, 1959.Google Scholar
  3. 3.
    Miller JFAP: Immunological function of the thymus. Lancet 1961;ii:748.CrossRefGoogle Scholar
  4. 4.
    Miller JFAP, Mitchell GF: The thymus and the precursors of antigen-reactive cells. Nature 1967;216:659.PubMedCrossRefGoogle Scholar
  5. 5.
    Berek C, Milstein C: The dynamic nature of the antibody repertoire. Immunol Rev 1988;105:5.PubMedCrossRefGoogle Scholar
  6. 6.
    Fink PJ, Matis A, McElligott DL, Bookman M, Hendrick SM: Correlations between T-cell specificity and the structure of the antigen receptor. Nature 1986;321:219.PubMedCrossRefGoogle Scholar
  7. 7.
    Zinkernagel RM, Doherty DC: MHC-restricted cytotoxic T cells: Studies on the biological role of polymorphic major transplantation antigens determining T cell restriction-specificity function and responsiveness. Adv Immunol 1979;27:51.PubMedGoogle Scholar
  8. 8.
    Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC: The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 1987;329:512.PubMedCrossRefGoogle Scholar
  9. 9.
    Braciale TJ, Morrison LA, Sweetser MT, Sambrook J, Gething MJ, Braciale VL: Antigen presentation pathways to class I and class II MHC-restricted T lymphocytes. Immunol Rev 1987;98:95.PubMedCrossRefGoogle Scholar
  10. 10.
    Basten A: Self-tolerance: The key to autoimmunity. Proc R Soc Lond [Biol] 1989;238:1.CrossRefGoogle Scholar
  11. 11.
    Sinclair NRStC: Autoreactions and autoimmunity: Rules for self-nonself discrimination. In preparation.Google Scholar
  12. 12.
    Scollay R, Bartlett P, Shortman K: T cell development in the adult murine thymus: Changes in the expression of the surface antigens Ly2, L3T4 and B2A2 during development from early precursor cells to emigrants. Immunol Rev 1984;82:79.PubMedCrossRefGoogle Scholar
  13. 13.
    Fowlkes BJ, Edison L, Mathieson BJ, Chusel TM: Early T lymphocytes. Differentiation in vivo of adult intrathymic precursor cells. J Exp Med 1985;162:802.PubMedCrossRefGoogle Scholar
  14. 14.
    Smith L: CD4+ murine T cells develop from CD8+ precursors in vivo. Nature 1987;326:798.PubMedCrossRefGoogle Scholar
  15. 15.
    Kisielow P, Blüthmann H, Staerz UD, Steinmetz M, von Boehmer M, von Boehmer H: Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 1988; 333:742.PubMedCrossRefGoogle Scholar
  16. 16.
    McPhee D, Pye J, Shortman K: The differentiation of T lymphocytes. V. Evidence for intrathymic death of most thymocytes. Thymus 1979;1:151.PubMedGoogle Scholar
  17. 17.
    Sha WC, Nelson CA, Newberry RD, Kranz DM, Russell JH, Loh D: Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature 1988;336:73.PubMedCrossRefGoogle Scholar
  18. 18.
    Scott B, Blüthmann H, Teh HS, von Boehmer H: The generation of mature T cells requires interaction of the αβ T-cell receptor with major histocompatibility antigens. Nature 1989;338:591.PubMedCrossRefGoogle Scholar
  19. 19.
    Burnet FM, Stone JD, Edney M: The failure of antibody production in the chick embryo. Aust J Exp Biol Med Sci 1950;28:291.PubMedCrossRefGoogle Scholar
  20. 20.
    Burnet FM, Fenner E: The Production of Antibodies. London, Macmillan, 1949, p 126.Google Scholar
  21. 21.
    Traub E: Factors influencing the persistence of choriomeningitis virus in the blood of mice after clinical recovery. J Exp Med 1938;68:229.CrossRefGoogle Scholar
  22. 22.
    Owen RD: Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945; 102:400.PubMedCrossRefGoogle Scholar
  23. 23.
    Billingham RE, Brent L, Medawar PO: Actively acquired tolerance of foreign cells. Nature 1953;172:603.PubMedCrossRefGoogle Scholar
  24. 24.
    Scollay R, Butcher E, Weissman I: Thymus migration: Quantitative studies on the rate of migration of cells from the thymus to the periphery in mice. Eur J Immunol 1980; 10:210.PubMedCrossRefGoogle Scholar
  25. 25.
    Osmond DG: Population dynamics of bone marrow B lymphocytes. Immunol Rev 1986;93:103.PubMedCrossRefGoogle Scholar
  26. 26.
    Lederberg J: Genes and antibodies. Science 1959;129:1649.PubMedCrossRefGoogle Scholar
  27. 27.
    Nossal GJV: The immunological response of foetal mice to influenza virus. Aust J Exp Biol Med Sci 1957; 35:549.PubMedCrossRefGoogle Scholar
  28. 28.
    Kinutani M, Cotley M, le Douarin NM: Postnatal development of a demyelinating disease in avian spinal cord chimeras. Cell 1986;45:307.PubMedCrossRefGoogle Scholar
  29. 29.
    Dresser DW, Mitchison NA: The mechanism of immunological paralysis. Adv. Immunol 1968;8:129.PubMedGoogle Scholar
  30. 30.
    Roelants GE, Goodman JW: Tolerance induction by an apparently non-immunogenic molecule. Nature 1970;227:175.PubMedCrossRefGoogle Scholar
  31. 31.
    Gershon RK: T-cell control of antibody production. Contemp Top Immunobiol 1974;3:1.PubMedGoogle Scholar
  32. 32.
    Loblay RH, Pritchard-Briscoe H, Basten A: Memory in suppressor T cells. Nature 1978;272:620.PubMedCrossRefGoogle Scholar
  33. 33.
    Möller G: Do suppressor T cells exist? Scand J Immunol 1988;27:247.PubMedCrossRefGoogle Scholar
  34. 34.
    Müler JFAP, Morahan G, Allison J: Extra-thymic acquisition of tolerance by T lymphocytes: Is suppression involved? Proc Immunol 1989; 7:882.Google Scholar
  35. 35.
    Kappler JW, Roehm M, Marrack P: T cell tolerance by clonal elimination in the thymus. Cell 1987;49:273.PubMedCrossRefGoogle Scholar
  36. 36.
    Kappler JW, Staerz U, White J, Marrack P: Self tolerance eliminates T cells specific for the Mis modified products of the major histocompatibility complex. Nature 1988;332:35.PubMedCrossRefGoogle Scholar
  37. 37.
    MacDonald HR, Sneider R, Lees RK, Howe RC, Acha-Orbea H, Fetenstein H, Zinkernagel RM, Hengartner H: T cell receptor Vβ use predicts reactivity and tolerance to Mlsα-encoded antigens. Nature 1988;332:40.PubMedCrossRefGoogle Scholar
  38. 38.
    Mitchison NA. The dosage requirements for immunological paralysis by soluble proteins. Immunology 1968;15:509.PubMedGoogle Scholar
  39. 39.
    Sprent J, Webb SR: Function and specificity of T cell subsets in the mouse. Adv Immunol 1987;41:39.PubMedGoogle Scholar
  40. 40.
    von Boehmer H, Hafen K: Minor but not major histocompatibility antigens of thymus epithelium tolerize precursors of cytolytic T cells. Nature 1986;320:626.CrossRefGoogle Scholar
  41. 41.
    Lo D, Sprent J: Identity of cells that imprint H-2 restricted T-cell specificity in the thymus. Nature 1986; 319:672.PubMedCrossRefGoogle Scholar
  42. 42.
    Salaün J, Bandeira A, khazaai I, Calman F, Cotley M, Coutinho A, Le Douarin NM: Thymic epithelium tolerizes for histocompatibility antigens. Science 1990;247:1471.PubMedCrossRefGoogle Scholar
  43. 43.
    Shimonkevitz RP, Bevan MJ: Split tolerance induced by the intrathymic adoptive transfer of thymocyte stem cells. J Exp Med 1988; 168:143.PubMedCrossRefGoogle Scholar
  44. 44.
    Rammensee HG: Veto function in vitro and in vivo. Int Rev Immunol 1989;4:175.PubMedCrossRefGoogle Scholar
  45. 45.
    Miller JFAP, Watson JD: Intracellalar recognition events eliminate self-reactive T cells. Scand J Immunol 1988;28:389.PubMedCrossRefGoogle Scholar
  46. 46.
    Lafferty KJ, Gill RG, Babcock SK, Wang Y: Active and passive antigen presentation: Its role in the induction of tissue immunity and allograft tolerance. Prog Immunol 1986;6:1040.Google Scholar
  47. 47.
    Loughnan MS, Nossal GJV: Interleukin 4 and 5 control expression of IL-2 receptor on murine B cells through independent induction of its two chains. Nature 1989;340:76.PubMedCrossRefGoogle Scholar
  48. 48.
    Bretscher PA, Cohn M: A theory of self-nonself discrimination: Paralysis and induction involve the recognition of one and two determinants on an antigen, respectively. Science 1970;163:1042.CrossRefGoogle Scholar
  49. 49.
    Lamb JR, Skidmore BJ, Green N, Chiller JM, Feldmann M: Induction of tolerance in influenza virus-immune T lymphocyte clones with syngeneic peptides of influenza hemaglutinin. J Exp Med 1983;157:1434.PubMedCrossRefGoogle Scholar
  50. 50.
    Essery G, Feldmann M, Lamb JR: Interleukin-2 can prevent and reverse antigen-induced unresponsiveness in cloned human T lymphocytes. Immunology 1988;64:413.PubMedGoogle Scholar
  51. 51.
    Schwartz RH: A cell culture model for T lymphocyte clonal anergy. Science 1990;248:1349.PubMedCrossRefGoogle Scholar
  52. 52.
    Weaver CT, Unanue ER: The costimulatory function of antigen-presenting cells. Immunol Today 1990; 11:49.PubMedCrossRefGoogle Scholar
  53. 53.
    Gross JA, St John T, Allison JP: The murine homologue of the T lymphocyte antigen CD28. Molecular cloning and cell surface expression. J Immunol 1990;144:3201.PubMedGoogle Scholar
  54. 54.
    Allison J, Campbell IL, Morahan G, Mandal TE, Harrison L, Miller JFAP: Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic β cells. Nature 1988; 333:529.PubMedCrossRefGoogle Scholar
  55. 55.
    Morahan G, Allison J, Miller JFAP: Tolerance of class 1 histocompatibility antigens expressed extra-thymically. Nature 1989;339:622.PubMedCrossRefGoogle Scholar
  56. 56.
    Morahan G, Brennan F, Bhathal PS, Allison J, Cox KO, Miller JFAP: Expression in transgenic mice of class I histocompatibility antigens controlled by the metallothionein promoter. Proc Natl Acad Sci USA 1989;86:3782.PubMedCrossRefGoogle Scholar
  57. 57.
    Miller JFAP, Morahan G, Allison J: Extra-thymic acquisiton of tolerance by T lymphocytes. Cold Spring Harbor Symp Quant Biol 1989;54:807.PubMedGoogle Scholar
  58. 58.
    Miller JFAP, Morahan G, Allison J, Bhathal P, Cox K, Brennan F: T cell tolerance in transgenic mice expressing major histocompatibility class I molecules in defined tissues. Immunol Rev 1989;107:109.PubMedCrossRefGoogle Scholar
  59. 59.
    Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart SE, Stewart TA: Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 1988;52:773.PubMedCrossRefGoogle Scholar
  60. 60.
    Lo D, Burkly LC, Flavell RA, Palmiter RD, Brinster RL: Tolerance in transgenic mice expressing class II major histocompatibility complex on pancreatic acinar cells. J Exp Med 1989;170:87.PubMedCrossRefGoogle Scholar
  61. 61.
    Lo D, Burkley LC, Widera G, Cowing C, Flaveli RA, Palmiter RD, Brinster RL: Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell 1988;53:159.PubMedCrossRefGoogle Scholar
  62. 62.
    Murphy KM, Weaver CT, Elish M, Allen PM, Loh DY: Peripheral tolerance to allogeneic class II histocompatibility antigens expressed in transgenic mice: Evidence against a clonal-deletion mechanism. Proc Natl Acad Sci USA 1989;86:10034.PubMedCrossRefGoogle Scholar
  63. 63.
    Miller J, Daitch L, Rath S, Selsink E: Tissue-specific expression of allogeneic class II MHC molecules induces neither tissue reaction nor clonal inactivation of alloreactive T cells. J Immunol 1990;144:334.PubMedGoogle Scholar
  64. 64.
    Jones-Youngblood SL, Wieties K, Forman J, Hammer RE: Effect of the expression of a hepatocyte-specific MHC molecule in transgenic mice on T cell tolerance. J Immunol 1990;144:1187.PubMedGoogle Scholar
  65. 65.
    Nossal GJV: Cellular mechanism of immunologic tolerance. Annu Rev Immunol 1983;1:33.PubMedCrossRefGoogle Scholar
  66. 66.
    Jenkins MK, Schwartz R: Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med 1987; 165:302.PubMedCrossRefGoogle Scholar
  67. 67.
    Waldmann H, Cobbold SP, Qin S: Tolerance induction using CD4 and CD8 monoclonal antibodies. Prog Immunol 1989;7:147.Google Scholar
  68. 68.
    Rammensee HG, Kreschewski R, Frangouiis B: Clonal anergy induced in mature V6+ Y lymphocytes on immunizing, Mls-Ib mice with Mls-Ia expressing cells. Nature 1989; 339:541.PubMedCrossRefGoogle Scholar
  69. 69.
    Dailman MJ, Shiho O, Page TH, Wood KJ, Morris PJ: Peripheral tolerance to alloantigen results from altered regulation of the interleukin pathway. J Exp Med 1991;173:79.CrossRefGoogle Scholar
  70. 70.
    Simon JC, Tigelaar RE, Bergstresser PR, Edelbaum D, Cruz PD Jr: Ultraviolet B radiation converts Langerhans cells from immunogenic to tolerogenic antigen-presenting cells. Induction of specific clonal anergy in CD4+ T helper I cells. Immunol 1991;146:485.Google Scholar
  71. 71.
    Schönrich G, Kalinke U, Momburg F, Malissen M, Semitt-Verhulst AM, Malissen B, Hämmerling GJ, Arnold B: Downregulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell 1991;65:1.CrossRefGoogle Scholar
  72. 72.
    Morahan G, Hoffmann M, Miller JFAP: A hon-deletional mechanism of peripheral tolerance in T cell receptor transgenic mice. Proc Natl Acad Sci USA 1991;88:11421.PubMedCrossRefGoogle Scholar
  73. 73.
    Heath WR, Allison J, Hoffmann MW, Schönrich G, Hämmerling G, Arnold B, Miller JFAP: Autoimmune diabetes as a consequence of locally produced interleukin-2. Nature 1992;359:547.PubMedCrossRefGoogle Scholar
  74. 74.
    Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H: Abiation of ‘tolerance’ and induction of diabetes by virus infection in viral antigen transgenic mice. 1991;65:305.Google Scholar
  75. 75.
    Oldstone MBA, Nerenberg M, Southern P, Price J, Lewicki H: Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: Role of anti-self (virus) immune response. Cell 1991; 65:319.PubMedCrossRefGoogle Scholar
  76. 76.
    Allison J, Malcolm L, Chosich N, Miller JFAP: Inflammation but not autoimmunity occurs in transgenic mice expressing constitutive levels of IL-2 in islet β cells. Eur J Immunol 1992;22:1115.PubMedCrossRefGoogle Scholar
  77. 77.
    Harris DE, Cairns L, Rosen FS, Borel Y: A natural model of immunological tolerance: Tolerance to murine C5 is mediated by T cells and antigen is required to maintain unresponsiveness. J Exp Med 1983; 156:567.CrossRefGoogle Scholar
  78. 78.
    Whiteley PJ, Poindexter NJ, Landon C, Kapp JA: A peripheral mechanism preserves self-tolerance to a secreted protein in transgenic mice. J Immunol 1990;145:1376.PubMedGoogle Scholar
  79. 79.
    Goodnow CC, Adelstein S, Basten A: The need for central and peripheral tolerance in the B cell repertoire. Science 1990;248:1373.PubMedCrossRefGoogle Scholar
  80. 80.
    Nossal GJV, Pike B: Clonal anergy: Persistence in tolerant mice of antigen-binding B lymphocytes incapable of responding to antigen or mitogen. Proc Natl Acad Sci USA 1980; 77:1602.PubMedCrossRefGoogle Scholar
  81. 81.
    Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Mason DY, Jorgensen H, Brink RA, Pritchard-Briscoe H, Loughnan M, Loblay RH, Trent RJ, Basten A: Clonal silencing of self-reactive B lymphoytes in a transgenic mouse model. Cold Spring Harbor Symp Quant Biol 1989;54:907.PubMedGoogle Scholar
  82. 82.
    Goodnow CC, Crosbie J, Jorgensen H, Brink RA, Basten A: Induction of self-tolerance in mature peripheral B lymphocytes. Nature 1989;342:385.PubMedCrossRefGoogle Scholar
  83. 83.
    Adelstein S, Pritchard-Briscoe H, Anderson TA, Crosbie J, Gammon G, Loblay RH, Basten A, Goodnow CC: Induction of self-tolerance in T cells but not in B cells of transgenic mice expressing little self antigen. Science 1991;251:1223.PubMedCrossRefGoogle Scholar
  84. 84.
    Adams E, Basten A, Goodnow CC: Intrinsic B-cell hyporesponsiveness accounts for self-tolerance in lysozyme/antilysozyme double transgenic mice. Proc Natl Acad Sci USA 1990;87:5687.PubMedCrossRefGoogle Scholar
  85. 85.
    Nemazee DA, Bürki K: Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 1989; 337:562.PubMedCrossRefGoogle Scholar
  86. 86.
    Nemazee DA, Russell D, Arnold B, Hämmerling G, Allison J, Miller JFAP, Morahan G, Bürki K: Clonal deletion of autospecific B lymphocytes. Immunol Rev 1991;122:117.PubMedCrossRefGoogle Scholar
  87. 87.
    Ehrlich P: On immunity with special reference to cell life. Proc R Soc Lond [Biol] 1990;66:424.Google Scholar
  88. 88.
    Todd JA, Bell JI, McDevitt HO: HLA-DQ β gene contributes to susceptibility and resistance in insulin-dependent diabetes mellitus. Nature 1987;329:599.PubMedCrossRefGoogle Scholar
  89. 89.
    Bacelj A, Charlton B, Mandel TE: Prevention of cyclophosphamide-induced diabetes by anti-Vβ8 T-lymphocyte-receptor monoclonal antibody therapy in NOD/Wehi mice. Diabetes 1989;38:1492.PubMedCrossRefGoogle Scholar
  90. 90.
    Biddison WE, Beall SS, Concannon P, Charmley P, Gatti RA, Hood LE, McFarland HF, McFarlin DE: The germiine repertoire of T cell receptor β chain genes in patients with multiple sclerosis. Res Immunol 1989;140:212.PubMedCrossRefGoogle Scholar
  91. 91.
    Nishimoto H, Kikutani H, Yamamura K, Kishimoto T: Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. Nature 1987;328:432.PubMedCrossRefGoogle Scholar
  92. 92.
    Böhme J, Schuhbaur B, Kanagawa O, Benoist C, Mathis D: MHC-linked protection from diabetes dissociated from clonal deletion of T cells. Science 1990;249:293.PubMedCrossRefGoogle Scholar
  93. 93.
    Lund T, O'Reilly L, Hutchings P, Kanagawa O, Simpson F, Gravely R, Chandler P, Dyson J, Picard JK, Edwards A, Kicussis D, Cooke A: Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A β-chain or normal I-E α-chain. Nature 1990;345:727.PubMedCrossRefGoogle Scholar
  94. 94.
    Miyazaki T, Uno M, Uehira KM, Kikutani H, Kishimoto T, Kimoto M, Nishimoto H, Miyazaki J, Yamamura K: Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice. Nature 1990;345:722.PubMedCrossRefGoogle Scholar
  95. 95.
    Slattery R, Kjer-Nielsen L, Allison J, Charlton B, Mandel TE, Miller JFAP: Prevention of diabetes in NOD/Lt-I-Ak transgenic mice. Nature 1990;345:724.PubMedCrossRefGoogle Scholar
  96. 96.
    Reich EP, Sherwin RS, Kanagawa O, Janeway CA: An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. Nature 1989;341:326.PubMedCrossRefGoogle Scholar
  97. 97.
    Haskins K, McDuffie M: Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 1990;249:1433.PubMedCrossRefGoogle Scholar
  98. 98.
    Chariton B, Baceli A, Slattery RM, Mandel TE: Cyclophosphamide induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Diabetes 1989;38:441.CrossRefGoogle Scholar
  99. 99.
    Boitard C, Yasunami R, Dardenne M, Bach JF: T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J Exp Med 1989;169:1669.PubMedCrossRefGoogle Scholar
  100. 100.
    Chandy KG, Charles AM, Kershnar A, Buckingham B, Waldeck N, Gupta S: Autologous mixed lymphocyte reaction in man: XV. Cellular and molecular basis of deficient autologous mixed lymphocyte response in insulin-dependent diabetes mellitus. J Clin Immunol 1984;4:424.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1993

Authors and Affiliations

  • J. F. A. P. Miller
    • 1
  1. 1.Walter and Eliza Hall Institute of Medical ResearchRoyal Melbourne HospitalMelbourneAustralia

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