Subscribe to RSS
DOI: 10.1055/s-2004-817966
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
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.
Key words
Type 1 diabetes - C-peptide - CD25 positive lymphocytes - CD4 positive lymphocytes - CD8 positive lymphocytes
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