Exp Clin Endocrinol Diabetes 2004; 112(4): 181-186
DOI: 10.1055/s-2004-817966
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

β-Cell Secretory Function and CD25 + Lymphocyte Subsets In the Early Stage of Type 1 Diabetes Mellitus

Z. Milicevic1 , J. Knezevic2 , A. Sabioncello3 , G. Roglic2 , B. Rocic2
  • 1Lilly Area Medical Center Vienna, Austria (2 until 1998)
  • 2University Clinic “Vuk Vrhovac”, Zagreb, Croatia
  • 3Institute for Immunology, Zagreb, Croatia
Further Information

Publication History

Received: January 10, 2003 First decision: May 14, 2003

Accepted: October 10, 2003

Publication Date:
04 May 2004 (online)

Abstract

Cellular immunologic tests have not been used for diagnostic purposes in individuals at risk for autoimmune insulitis or in patients with partial β-cell destruction because of a lack of studies that show their predictive value. In this study we initially evaluated 43 patients with recent-onset Type 1 diabetes (disease duration ≤ 6 months, 29 ICA positive) with regard to β-cell secretion stimulation test with glucagon and immunologic parameters, including CD4 +, CD8 +, CD4 + CD25 +, CD8 + CD25 + lymphocyte subsets. At baseline, C-peptide concentration 6 min after stimulation increased on average by 0.18 ± 0.27 µg/ml. The percentage of CD4 + cells was 42 ± 9,4 % (healthy controls 44 ± 7.3 %, p nonsig.) and percentage of CD8 + was 33 ± 8.6 % (healthy control 31 ± 8.3 %, p nonsig.). Relative size of CD4 + CD25 + subpopulation was 7 ± 5.4 % (healthy control 2 ± 2 %, p < 0.001). Percentage of activated CD8 + cell subset was also increased (2 ± 1.4 vs. 1.0 ± 1.0 %), but not significantly. Functional β-cell testing was repeated after 6 months and nineteen patients were eligible for analysis. Their response was weaker after 6 months (0.13 ± 0.1 µg/ml, p < 0.05 vs. baseline). The average change in C-peptide excursion from baseline to the endpoint was - 0.07 ± 0.17 µg/ml. There was no significant correlation between β-cell functional parameters at baseline (C-peptide6minbaseline) and the relative size of various T cell subpopulations. Results were identical for the 6-month β-cell functional data (C-peptide6min6month). The change in the excursion of C-peptide between baseline and follow-up visit (C-peptide6min6month-baseline) showed mild, negative correlation with relative size of the CD8 + CD25 + subpopulation (r = - 0.511, p = 0.025), which may indicate that the size of this cell subpopulation has predictive value in assessing future functional β-cell changes.

References

  • 1 Abiru N, Eisenbarth G S. Multiple genes/multiple autoantigens role in type 1 diabetes.  Clin Rev Allergy Immunol. 2000;  18 27-40
  • 2 Al Sakkaf L, Pozzilli P, Bingley P J, Lowdell M W, Thomas J M, Bonifacio E, Gale E A, Bottazzo G F. Early T-cell defects in pre-type 1 diabetes.  Acta Diabetol. 1992;  28 189-192
  • 3 Binimelis J, Codina M, Oriola J, Amill B, Perez A, de Leiva A. Activated T-lymphocytes in newly diagnosed type I diabetic patients: relationship to residual beta cell function.  J Autoimmun. 1990;  3 579-585
  • 4 Bonifacio E, Bingley P J, Shattock M, Dean B M, Dunger D, Gale E A, Bottazzo G F. Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes.  Lancet. 1990;  335 147-149
  • 5 Bruining G J, Molenaar J, Tuk C W, Lindeman J. Bruining HA, Marner B. Clinical time-course and characteristics of islet cell cytoplasmatic antibodies in childhood diabetes.  Diabetologia. 1984;  26 24-29
  • 6 Buschard K, Ropke C, Madsbad S, Mehlsen J, Rygaard J. T lymphocyte subsets in patients with newly diagnosed type 1 (insulin-dependent) diabetes: a prospective study.  Diabetologia. 1983;  25 247-251
  • 7 Di Bonito P, De Bellis A, Capaldo B, Turco S, Corigliani G, Pace E, Bizzarro A. Soluble CD8 antigen, stimulated C-peptide and islet cell antibodies are predictors of insulin requirement in newly diagnosed patients with unclassifiable diabetes.  Acta Diabetol. 1996;  33 220-224
  • 8 Durinovic-Bello I, Schendel D J, Kastelan A, Segurado O G. A novel diabetes-susceptibility HLA haplotype is present in the Croatian population.  Tissue Antigens. 1993;  41 107-109
  • 9 Eisenbarth G. Prediction and prevention strategies in type I diabetes.  Mt Sin J Med. 1991;  58 74-79
  • 10 Fox R I, Theofilopoulos A N, Altman A. Production of interleukin 2 (IL 2) by salivary gland lymphocytes in Sjogren's syndrome. detection of reactive cells by using antibody directed to synthetic peptides of IL 2.  J Immunol. 1985;  135 3109-3115
  • 11 Ghabanbasani M Z, Buyse I, Legius E, Decorte R, Marynen P, Bouillon R, Cassiman J J. Possible association of CD3 and CD4 polymorphisms with insulin-dependent diabetes mellitus (IDDM).  Clin Exp Immunol. 1994;  97 517-521
  • 12 Giordano C, De Maria R, Todaro M, Stassi G, Mattina A, Richiusa P, Galluzzo G, Panto F, Galluzzo A. Study of T-cell activation in type I diabetic patients and pre-type I diabetic subjects by cytometric analysis: antigen expression defect in vitro.  J Clin Immunol. 1993;  13 68-78
  • 13 Hehmke B, Michaelis D, Gens E, Laube F, Kohnert K D. Aberrant activation of CD8 + T-cell and CD8 + T-cell subsets in patients with newly diagnosed IDDM.  Diabetes. 1995;  44 1414-1419
  • 14 Hitchcock C L, Riley W J, Alamo A, Pyka R, Maclaren N K. Lymphocyte subsets and activation in prediabetes.  Diabetes. 1986;  35 1416-1422
  • 15 Hooks J J, Chan C C, Detrick B. Identification of the lymphokines, interferon-gamma and interleukin-2, in inflammatory eye diseases.  Invest Ophthalmol Vis Sci. 1988;  29 1444-1451
  • 16 Jeppsson J O, Jerntorp P, Sundkvist G, Englund H, Hylund V. Measurement of hemoglobin A1c by a new liquid-chromatographic assay: methodology, clinical utility, and relation to glucose tolerance evaluated.  Clin Chem. 1986;  32 1867-1872
  • 17 Johnston C, Alviggi L, Millward B A, Leslie R D, Pyke D A, Vergani D. Alterations in T-lymphocyte subpopulations in type I diabetes. Exploration of genetic influence in identical twins.  Diabetes. 1988;  37 1484-1488
  • 18 Jordan M S, Boesteanu A, Reed A J, Petrone A L, Holenbeck A E, Lerman M A, Naji A, Caton A J. Thymic selection of CD4 + CD25 + regulatory T cells induced by an agonist self-peptide.  Nature Immunol. 2001;  2 301-306
  • 19 Khoury S J, Guttmann C R, Orav E J, Kikinis R, Jolesz F A, Weiner H L. Changes in activated T cells in the blood correlate with disease activity in multiple sclerosis.  Arch Neurol. 2000;  57 1183-1189
  • 20 Kontiainen S, Scheinin T, Londei M, Feldmann M. Selective activation of blood T cells in children with newly diagnosed insulin dependent diabetes mellitus.  Autoimmunity. 1994;  19 63-66
  • 21 Kreuwel H T, Sherman L A. The role of Fas-FasL in CD8 + T-cell-mediated insulin-dependent diabetes mellitus (IDDM).  J Clin Immunol. 2001;  21 15-18
  • 22 Lemm G, Warnatz H. Evidence for enhanced interleukin 2 (IL-2) secretion and IL-2 receptor presentation by synovial fluid lymphocytes in rheumatoid arthritis.  Clin Exp Immunol. 1986;  64 71-79
  • 23 Morel P A, Dorman J S, Todd J A, McDevitt H O, Trucco M. Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study.  Proc Natl Acad Sci USA. 1988;  85 8111-8115
  • 24 Nagata M, Santamaria P, Kawamura T, Utsugi T, Yoon J W. Evidence for the role of CD8 + cytotoxic T cells in the destruction of pancreatic beta-cells in nonobese diabetic mice.  J Immunol. 1994;  152 2042-2050
  • 25 Neufeld M, Maclaren N K, Riley W J, Lezotte D, McLaughlin J V, Silverstein J, Rosenbloom A L. Islet cell and other organ-specific antibodies in U. S. Caucasians and Blacks with insulin-dependent diabetes mellitus.  Diabetes. 1980;  29 589-592
  • 26 Peakman M, Leslie R D, Alviggi L, Hawa M, Vergani D. Persistent activation of CD8 + T-cells characterizes prediabetic twins.  Diabetes Care. 1996;  19 1177-1184
  • 27 Peakman M, Warnock T, Vats A, McNab G L, Underhill J, Donaldson P T, Vergani D. Lymphocyte subset abnormalities, autoantibodies and their relationship with HLA DR types in children with type 1 (insulin-dependent) diabetes and their first degree relatives.  Diabetologia. 1994;  37 155-165
  • 28 Report of a WHO Consultation .Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. World Health Organisation 1999
  • 29 Rohane P W, Shimada A, Kim D T, Edwards C T, Charlton B, Shultz L D, Fathman C G. Islet-infiltrating lymphocytes from prediabetic NOD mice rapidly transfer diabetes to NOD-scid/scid mice.  Diabetes. 1995;  44 550-554
  • 30 Sempe P, Ezine S, Marvel J, Bedossa P, Richard M F, Bach J F, Boitard C. Role of CD4 + CD45RA+ T cells in the development of autoimmune diabetes in the non-obese diabetic (NOD) mouse.  Int Immunol. 1993;  5 479-489
  • 31 Smerdon R A, Peakman M, Hussain M J, Alviggi L, Watkins P J, Leslie R D, Vergani D. Increase in simultaneous coexpression of naive and memory lymphocyte markers at diagnosis of IDDM.  Diabetes. 1993;  42 127-133
  • 32 Stephens L A, Mason D. CD25 is a marker for CD4 + thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25 + and CD25 - subpopulations.  J Immunol. 2000;  165 3105-3110
  • 33 Tarn A C, Smith C P, Spencer K M, Bottazzo G F, Gale E A. Type I (insulin dependent) diabetes: a disease of slow clinical onset?.  Br Med J Clin Res Ed. 1987;  294 342-345
  • 34 Vassiliadis S, Dragiotis V, Protopapadakis E, Athanassakis I, Mitlianga P, Konidaris K, Papadopoulos G K. The destructive action of IL-1 alpha and IL-1 beta in IDDM is a multistage process: evidence and confirmation by apoptotic studies, induction of intermediates and electron microscopy.  Mediators Inflamm. 1999;  8 85-91
  • 35 Winearls B C, Bodmer J G, Bodmer W F, Bottazzo G F, McNally J, Mann J I, Thorogood M, Smith M A, Baum J D. A family study of the association between insulin dependent diabetes mellitus, autoantibodies and the HLA system.  Tissue Antigens. 1984;  24 234-246
  • 36 Winter W E, House D V, Schatz D. Pharmacological approaches to the prevention of autoimmune diabetes.  Drugs. 1997;  53 943-956

Dr. Zvonko Milicevic

Lilly Area Medical Center Vienna

Barichgasse 40 - 42

1030 Vienna

Austria

Phone: + 43171178236

Fax: + 43 1 71 17 82 59

Email: milicevic_zvonko@lilly.com

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