Aberrant Activation of CD8+ T-cell and CD8+ T-Cell Subsets in Patients With Newly Diagnosed IDDM

Hehmke, B; D, Michaelis; Gens, Elke; Laube, F.; Kohnert, Klaus–Dieter

doi:10.2337/diab.44.12.1414

Cited by 21 publications

(18 citation statements)

References 27 publications

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“…Aberrant activation of CD8 cells in patients with newly diagnosed insulin-dependent diabetes mellitus was reported pre- (16). It has also been shown that type 1 diabetes of long standing is associated with activation of circulating T cells (9), corroborating our findings of increased activated T-cell phenotypes during the natural course of the disease, as shown in the placebo group.…”

Section: Discussionsupporting

confidence: 81%

Effect of Photopheresis on Lymphocyte Population in Children with Newly Diagnosed Type 1 Diabetes

Ernerudh

Ludvigsson

Berlin

et al. 2004

Clin Vaccine Immunol

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In recent years photopheresis has been claimed to be an effective form of immunomodulation. It has also been shown to have an effect on the disease process at the onset of type 1 diabetes. In a double-blind, placebo-controlled randomized study, we analyzed if the effect of photopheresis in children with newly diagnosed diabetes is related to changes in the balance of lymhocyte populations. We also analyzed if lymphocyte subsets were related to recent infection, mild or aggressive disease manifestations, heredity, or gender. Nineteen children received active treatment with photopheresis, while 21 children received sham pheresis (placebo group). No influence of a history of previous infection, heredity, or certain clinical parameters on lymphocyte subsets was found. At the onset of type 1 diabetes, girls showed a higher proportion and a larger number of T cells (CD3 ؉ ) and T-helper cells (CD4 ؉ ) and a higher proportion of naïve CD4 ؉ CD45RA ؉ cells. In the placebo group, an increase in the number of subsets with the activated phenotype in both the CD4 (CD29 ؉ ) and the CD8 (CD11a ؉ ) compartments was noted during the course of the study. These changes did not occur in the photopheresis group. No relation between lymphocyte subsets and clinical outcome was found 1 year after the treatment with photopheresis. In conclusion, we found no major effect of photopheresis on lymphocyte populations in a group of children with newly diagnosed type 1 diabetes. However, in the placebo group the proportions of activated CD4 and CD8 cells increased over time. Since these changes did not occur in the actively treated group, our findings suggest that photopheresis may have some suppressive effects.

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Section: Discussionsupporting

confidence: 81%

Effect of Photopheresis on Lymphocyte Population in Children with Newly Diagnosed Type 1 Diabetes

Ernerudh

Ludvigsson

Berlin

et al. 2004

Clin Vaccine Immunol

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“…The same applies to the observation of more marked HLA-DR expression on CD4 ϩ cells in DML, which seems to be restricted to memory cells, whereas at manifestation of IDDM it occurs in both memory (27) and naive T cells (27,28). HLA-DR expression was, however, not restricted to the CD45RA Ϫ compartment (21) of CD8 ϩ cells in DM, but, rather, favored the CD45RA ϩ subset.…”

Section: Discussionmentioning

confidence: 81%

“…ϩ T cells and their CD45RA ϩ subsets in patients with newly manifested IDDM than in HS (27,28 addition, a significantly greater expression of the early activation antigen CD69 is observed in DML than DM, but not vs. HS on CD4 ϩ (ϩ48%) and CD8 ϩ T cells (ϩ40%). This contrasts with the increased proportion of CD69 ϩ cells described among peripheral blood lymphocytes vs. HS in a group of 12 patients with DM and DML (16).…”

Section: Discussionmentioning

confidence: 99%

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Increased CD69 and Human Leukocyte Antigen-DR Expression on T Lymphocytes in Insulin-Dependent Diabetes Mellitus of Long Standing

Gessl

Waldhäusl

1998

The Journal of Clinical Endocrinology &Amp; Metabolism

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To better define prevailing activation of circulating T cell subsets in insulin-dependent diabetes mellitus (IDDM) of recent onset (DM; n ϭ 31; median age Ϯ SD,, 28 Ϯ 6.9 yr) and of long standing (DML; n ϭ 27; age, 33 Ϯ 10.4 yr; median duration of disease, 105 months), CD4 ϩ and CD8 ϩ T cells were analyzed to determine their naive and memory subsets as well as their expression of human leukocyte antigen (HLA)-DR, interleukin-2 receptor ␣-chain (CD25), and CD69 by three-color flow cytometry. Twenty-six healthy subjects (HS; age, 32.0 Ϯ 8.2 yr) served as controls.No 2204 -2209, 1998)

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“…This includes differences, compared to healthy controls, in the proportion of T cells (alKassab & Raziuddin, 1990;Ilonen et al, 1991;Petersen et al, 1996) and also in their function (Hehmke et al, 1995;Spatz et al, 2003). In particular, there has been much conjecture over the frequency and function of Treg in T1D .…”

Section: Failure Of Immunological Tolerance In Human T1dmentioning

confidence: 99%

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

Reeves¹

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Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β cells. The current treatment for the fatal insulin-deficiency in T1D is injection of exogenous insulin. Despite the dramatic increase in survival from the use of exogenous insulin, complications develop from imperfect glycemic control and exogenous insulin does not rectify the underlying cause of disease, the diabetogenic autoimmune response. Hence, there is a need for an effective therapy that impedes the progress of the pathogenic autoimmune response. β cell-reactive CD8 + In the NOD mouse model of T1D, insulin is the primary β-cell antigen that elicits disease. As such, I have investigated T-cell tolerance to insulin in an adoptive transfer setting in which TCR transgenic (G9) CD8 + T cells specific for insulin B15-23 (InsB15-23) were transferred to transgenic mice over-expressing proinsulin in APC. Subsequently, I examined the effect of introducing transgenic proinsulin expression on diabetes development in wild type NOD mice.When transferred to mice transgenically expressing proinsulin, naïve G9 T cells proliferated extensively prior to undergoing rapid deletion. In proinsulin transgenic recipients, the remaining population of G9 T cells displayed reduced T-cell receptor (TCR) expression and bound less InsB15-23-loaded, H2-K d -tetramer compared to G9 T cells that had been transferred to non-transgenic NOD recipients. Interestingly, TCR down-regulation represented that which occurred for OVA-specific CD8 + T cells transferred to mice expressing OVA in APC in a non-autoimmune prone strain.Importantly, naïve G9 T cells did not expand or produce the important effector cytokine, interferon (IFN)-γ, in response to InsB15-23 immunisation after transfer to proinsulin transgenic mice. These data confirm naïve G9 T cells undergo rapid deletion and inactivation after transfer to mice transgenically-expressing proinsulin, despite genetic tolerance defects in NOD mice. Memory CD8 + T cells (Tmem) perpetuate β-cell autoimmunity and pose a distinct barrier to immunotherapy. It was pertinent to determine whether inactivation of insulin-specific CD8 + Tmem also occurs after transfer to mice expressing proinsulin in APC. To test inactivation of insulin-specific CD8 + Tmem, G9 Tmem were generated using an in vitro culture method. Cultured G9 Tmem were validated by assessing phenotypic markers and cytokine production. Similarly to naïve G9 T cells, G9 Tmem proliferated extensively and most G9 Tmem were rapidly deleted after transfer to mice overexpressing proinsulin in APC. The remaining, non-deleted population of G9 Tmem was infrequent ii and exhibited reduced TCR expression. Furthermore, G9 Tmem did not expand or produce IFN-γ in response to InsB15-23 immunisation, consistent with functional inactivation. These results demonstrate transgenic proinsulin expression in APC overcomes genetic defects in NOD mice to induce tolerance in insulin-specific CD8 + Tmem.From the data described above, transgenic proinsulin expression is tolerogenic for in...

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Aberrant Activation of CD8+ T-cell and CD8+ T-Cell Subsets in Patients With Newly Diagnosed IDDM

Cited by 21 publications

References 27 publications

Effect of Photopheresis on Lymphocyte Population in Children with Newly Diagnosed Type 1 Diabetes

Effect of Photopheresis on Lymphocyte Population in Children with Newly Diagnosed Type 1 Diabetes

Increased CD69 and Human Leukocyte Antigen-DR Expression on T Lymphocytes in Insulin-Dependent Diabetes Mellitus of Long Standing

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

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