Skip to main content
SpringerLink
Log in

Immunoregulatory dysfunctions in type I diabetes: Natural and antibody-dependent cellular cytotoxic activities

  • Original Articles
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Peripheral blood lymphocytes from 13 patients with established insulin-dependent diabetes mellitus (IDDM) and 2 prediabetic patients were examined for natural killer (NK) and antibody-dependent cellular cytotoxic activities (ADCC), lectin-dependent cellular cytotoxicity (LDCC), interferon- and interleukin-2-induced cytotoxicity, and concanavalin A-induced suppressor-cell activities in comparison with age-matched normal controls. IDDM patients demonstrated normal levels of NK and ADCC activities against K562 and antibody-coated SB target cells, respectively, compared to controls. IDDM patients showed normal levels of LDCC activity. Notable deviations from control values were, however, observed with diabetic lymphocytes in the following systems. Interferon-and interleukin-2-induced NK activities were significantly higher with IDDM lymphocytes than with control cells. IDDM lymphocytes precultured with concanavalin A demonstrated lower NK and ADCC activities than control cells and manifested decreased suppressor effects on the NK activity of normal allogeneic lymphocytes. Lymphocytes from one of two prediabetic patients showed increased NK, ADCC, and LDCC activities in comparison to controls. The increased interferon- and interleukin-2-induced enhancement of NK activity and reduced suppressor activity of lymphocytes from IDDM patients may be involved in the pathogenesis of the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Gepts W: Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14:619–633, 1965

    Google Scholar 

  2. Bottazzo GF, Florin-Christensen A, Doniach D: Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2:1279–1281, 1974

    Google Scholar 

  3. Rittenhouse HG, Oxender DL, Pek S, Ar D: Complement mediated cytotoxic effects in pancreatic islets with sera from diabetic patients. Diabetes 29:317–322, 1980

    Google Scholar 

  4. Yoon JW, Austin M, Onodera T, Notkins AL: Virus induced diabetes mellitus in man. N Engl J Med 300:1173–1179, 1979

    Google Scholar 

  5. Alviggi L, Johnston C, Hoskins PJ, Tee DE, Pyke DA, Leslie LD, Vergani D: Pathogenesis of insulin-dependent diabetes. A role for activated T lymphocytes. Lancet 2:4–6, 1984

    Google Scholar 

  6. Sensi M, Pozzilli P, Gorsuch AN, Bottazo GF, Cudworth AG: Increased killer cell activity in insulin dependent (Type I) diabetes mellitus. Diabetologia 20:106–109, 1981

    Google Scholar 

  7. Huang SW, MacLaren NK: Insulin-dependent diabetes: A disease of autoaggression. Science 192:64–66, 1976

    Google Scholar 

  8. Nerup J, Anderson OO, Bendixen G, Egeberg J, Gunnarsson R, Kromann H, Paulsen JE: Cell mediated immunity in diabetes mellitus. Proc R Soc Med 67:506–513, 1974

    Google Scholar 

  9. MacCuish AC, Jordan J, Campbell CJ, Duncan LPJ, Irvine WJ: Cell mediated immunity in diabetes mellitus. Lymphocyte transformation by insulin and insulin fragments in insulin treated and newly diagnosed diabetics. Diabetes 24:36–43, 1975

    Google Scholar 

  10. Herberman RB: NK and Other Natural Effector Cells. New York, Academic Press, 1980

    Google Scholar 

  11. Cudkowicz G, Hochman PS: Do natural killer cells engage in regulated reactions against self to ensure homeostasis? Immunol Rev 44:13, 1979

    Google Scholar 

  12. Nair MPN, Fernandes G, Onoe K, Day NK, Good RA: Inhibition of effector cell functions in natural killer cell activity (NK) and antibody-dependent cellular cytotoxicity (ADCC) in mice by normal and cancer sera. Int J Cancer 25:667–677, 1980

    Google Scholar 

  13. Boyum A: Isolation of mononuclear cells and granulocytes from human blood. Isolation of mononuclear cells by one centrifugation and of granulocytes by combining centrifugation and sedimentation. J Clin Lab Invest 21 (Suppl 97):77, 1968

    Google Scholar 

  14. Nair MPN, Schwartz SA: Effect of histamine and histamine antagonists on natural and antibody dependent cellular cytotoxicity of human lymphocytes in vitro. Cell Immunol 81:45–60, 1983

    Google Scholar 

  15. Kadish AS, Doyle AT, Steinhaner EH, Ghossein NA: Natural cytotoxicity and interferon production in human cancer: deficient natural killer activity and normal interferon production in patients with advanced disease. J Immunol 127:1817–1822, 1981

    Google Scholar 

  16. Nair MPN, Schwartz SA, Menon M: Association of decreased natural and antibody-dependent cellular cytotoxicity and production of natural killer cytotoxic factor and interferon in neonates. Cell Immunol 94:159–171, 1985

    Google Scholar 

  17. Nair MPN, Schwartz SA: Suppression of natural killer activity and antibody dependent cellular cytotoxicity by cultured human lymphocytes. J Immunol 126:2221–2229, 1981

    Google Scholar 

  18. Pozzilli P, Zuccarini O, Iavicoli M, Andreeni D, Sensi M, Spencer KM, Bottazzo GF, Beverley PCL, Kyner JL, Cudworth AG: Monoclonal antibodies defined abnormalities of T lymphocytes in type I (insulin-dependent) diabetes. Diabetes 32:91–94, 1983

    Google Scholar 

  19. Jackson RA, Morris MA, Haynes GV, Eisenbach GS: Increased circulating Ia antigen bearing T cells in type I diabetes mellitus. N Engl J Med 306:785–788, 1982

    Google Scholar 

  20. Horila M, Suzuki H, Onodera T, Ginsberg-Fellner F, Fauci AS, Notkins AL: Abnormalities of immunoregulatory T cell subsets in patients with insulin-dependent diabetes mellitus. J Immunol 129:1425–1429, 1982

    Google Scholar 

  21. Pozzilli P, Sensi M, Gorsuch A, Bottazzo GF, Cudworth AG: Evidence for raised K cell levels in type I diabetes. Lancet 2:173–175, 1979

    Google Scholar 

  22. Charles A, Suzuki M, Waldeck N, Dodson LE, Slater L, Ong K, Kershnar A, Buckingham B, Golden M: Immune islet killing mechanisms associated with insulin dependent diabetes. In vitro expression of cellular and antibody mediated islet cell cytotoxicity in humans. J Immunol 130:1189–1194, 1983

    Google Scholar 

  23. Harold KC, Huen A, Gould L, Traisman H, Rubenstein AH: Alterations in lymphocyte subpopulations in type I (insulin-dependent) diabetes mellitus. Exploration of possible mechansims and relationships to auutoimmune phenomena. Diabetologia 27 (Suppl):102–105, 1984

    Google Scholar 

  24. Chandy KG, Charles MA, Ruckingham B, Waldeck N, Kershnar A, Gupta S: Deficiency of monoclonal antibody (Leu 7) defined NK cells in newly diagnosed insulin dependent diabetes mellitus. Immunol Lett 8:89–91, 1984

    Google Scholar 

  25. Kohler E, Kuospe S, Woltanski G, Maciejewski R, Salzsieder C, Rjasanowski I, Stress J, Michaelis D: Antibody dependent cell mediated cytotoxicity of mononuclear cells against Langerhans islets of Wistar rats in normal man and in patients at diabetic risk. Biomed-Biochem Acta 43(5):627–633, 1984

    Google Scholar 

  26. Galluzzo A, Giordano C, Rubin G, Bompiani GD: Immuno-regulatory T-lymphocyte subset deficiency in newly diagnosed Type I (insulin dependent) diabetes mellitus. Diabetologia 26:426–430, 1984

    Google Scholar 

  27. Brunda M, Varesio L, Herberman RB, Holden HT: Interferon independent, lectin-induced augmentation of murine natural killer cell activity. Int J Cancer 29:299, 1982

    Google Scholar 

  28. Spits H, Borst J, Terhorst C, DeVris JE: The role of T cell differentiation markers in antigen-specific and lectin dependent cellular cytotoxicity mediated by T8+ and T4+ human cytotoxic T cell clones directed at class I and class II MHC antigens. J Immunol 129:1563, 1982

    Google Scholar 

  29. Helderman H, Raskin P: The T lymphocyte insulin receptor in diabetes and obesity. An intrinsic binding defect. Diabetes 29:551–557, 1980

    Google Scholar 

  30. Helderman JH, Edwards L: Role of insulin in the intermediary metabolism of activated thymic-derived lymphocytes. J Clin Invest 67:1636–1642, 1981

    Google Scholar 

  31. Quinou-Debrie MC, Debray-Sachs M, Dardenne M, Czernichow P, Assan R, Bach JF: Anti-islet cellular and humoral immunity, T cell subsets, and thymic function in type I diabetes. Diabetes 34:373–379, 1985

    Google Scholar 

  32. Bishop GA, Schwartz SA: Enhancement of human natural killer cells by interferon requires DNA and protein synthesis. Clin Immunol Immunopathol 25:374–385, 1982

    Google Scholar 

  33. Herberman RR, Ortaldo JR, Bonnard GD: Augmentation by interferon of human natural and antibody-dependent cell-mediated cytotoxicity. Nature 277:221–223, 1979

    Google Scholar 

  34. Lattim EC, Pecoraro GA, Stutman O: The activity of natural cytotoxic cells is augmented by interleukin 2 and interleukin 3. J Exp Med 157:1070–1075, 1983

    Google Scholar 

  35. Saksela E, Timonen T, Cantell K: Human natural killer cell activity is augmented by interferon via recruitment of “pre-NK” cells. Scand J Immunol 10:257, 1979

    Google Scholar 

  36. Perussia B, Trinchieri G: Inactivation of natural killer cell cytotoxic activity after interaction with target cells. J Immunol 126:754–758, 1981

    Google Scholar 

  37. Ortaldo JR, Pestka S, Slease RB, Rubinstein MI, Herberman RB: Augmentation of human NK-cell activity with interferon. Scand J Immunol 12:365–369, 1980

    Google Scholar 

  38. Pearlstein KT, Palladino MA, Welte K, Vilcek J: Purified human interleukin 2 enhances induction of immune interferon. Cell Immunol 80:1–9, 1983

    Google Scholar 

  39. Svedersky LP, Shepard HM, Spencer SA, Shalaby MR, Palladino MA: Augmentation of human natural cell-mediated cytotoxicity by recombinant human interleukin 2. J Immunol 133:714–718, 1984

    Google Scholar 

  40. Hayward AR, Herberger M: Phenotype of activated T-cells from patients with type I diabetes mellitus. Diabetes 33(4):319–323, 1984

    Google Scholar 

  41. 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 4:424–428, 1984

    Google Scholar 

  42. Zier KS, Leo MM, Spielman RS, Baker L: Decreased synthesis of interleukin 2 (IL2) in insulin dependent diabetes mellitus. Diabetes 33(6):552–555, 1984

    Google Scholar 

  43. Horowitz SD, Borcherding W, Bargman GJ: Suppressor T cell function in diabetes mellitus. Lancet 2:1291, 1977

    Google Scholar 

  44. Buschard K, Madsbad S, Rygaard J: Depressed suppressor cell activity in patients with newly diagnosed insulin-dependent diabetes mellitus. Clin Exp Immunol 41:25–32, 1980

    Google Scholar 

  45. Fairchild RS, Kyner JL, Abdou NI: Specific immunoregulation abnormality in insulin dependent diabetes mellitus. J Lab Clin Med 99:175–185, 1982

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, The University of Michigan, 48109, Ann Arbor, Michigan

    Madhavan P. N. Nair & Stanley A. Schwartz

  2. Department of Epidemiology, The University of Michigan, 48109, Ann Arbor, Michigan

    Madhavan P. N. Nair & Stanley A. Schwartz

  3. Department of Internal Medicine, The University of Michigan, 48109, Ann Arbor, Michigan

    Eric W. Lewis

Authors
  1. Madhavan P. N. Nair
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric W. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stanley A. Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nair, M.P.N., Lewis, E.W. & Schwartz, S.A. Immunoregulatory dysfunctions in type I diabetes: Natural and antibody-dependent cellular cytotoxic activities. J Clin Immunol 6, 363–372 (1986). https://doi.org/10.1007/BF00915375

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00915375

Key words

Search

Navigation