Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects

Danke, Nancy A.; Yang, Junbao; Greenbaum, Carla J.; Kwok, William W.

doi:10.1016/j.jaut.2005.08.007

Cited by 86 publications

(72 citation statements)

References 27 publications

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“…These maturation characteristics distinguish autoreactive cells in T1D subjects from similar, potentially autoreactive, naïve cells, which are present in normal individuals [11][12][13], and identify potential biomarkers that may correlate with clinical status. Pancreas organ transplantation is offered as a treatment for T1D, particularly in the context of simultaneous kidney transplantation, when treatment with chronic immunosuppression is used to suppress organ rejection.…”

Section: Discussionmentioning

confidence: 96%

“…MHC tetramers have been used to detect autoreactive antigen-specific CD4+ T cells in human subjects associated with T1D, MS, pemphigus vulgaris, and celiac disease [2,4,6,11,[16][17][18][19]. Because construction of appropriate MHC tetramers requires knowledge both of the HLA restriction element and of a suitable peptide epitope, diseases that have dominant HLA gene associations and dominant autoantigen targets are well suited for application of this technology, whereas other autoimmune disorders with more heterogeneous genetics or antigen targets are less optimal.…”

Section: Discussionmentioning

confidence: 99%

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Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Laughlin

Burke

Pugliese

et al. 2008

Clinical Immunology

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CD4+ T cells specific for the diabetes-associated autoantigen GAD65 were analyzed using peripheral blood samples after pancreas transplantation in subjects with T1D with clinical evidence of recurrent autoimmune diabetes. MHC class II tetramers facilitated the identification and cloning of antigenspecific autoreactive cells, which were found at several time points over a multiyear span, in spite of chronic immunosuppression of the subjects. Comparisons of TCR clonotypes by cDNA sequencing revealed that identical T cells were present in the circulation, separated by long time intervals, consistent with a persistent memory response associated with recurrent autoimmunity.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Laughlin

Burke

Pugliese

et al. 2008

Clinical Immunology

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“…However, recent studies have suggested that emigration from islets to the periphery, and formation of the peripheral effector memory T cells pool, is a more likely outcome. T cells specific for GAD65 and preproinsulin displaying an effector memory phenotype have been detected in the peripheral blood of patients [55,150]. We have recently studied the formation of these cells in the NOD mouse.…”

Section: Post Beta-cell Destruction Eventsmentioning

confidence: 99%

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

et al. 2012

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Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4 + T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8 + T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of the disease. The majority of our knowledge of these pathogenic processes is derived from the NOD mouse model, although some processes are mirrored in the human disease. However, more work is required to translate the data from the NOD mouse to our understanding of human diabetes pathogenesis. New technology, especially MHC tetramers and modern imaging, will enhance our understanding of the pathogenic mechanisms.

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“…It is therefore still unclear to what extent all the data provided can be translated into evaluation of diabetes risk or disease condition. Moreover, autoreactive T-cells-specific responses for T1D self-antigens have been widely described in healthy individuals in stimulation assays with peptides from GAD65 [338,339] and insulin [100,102,327]. Several differences have been proposed between self-reactive T CD4+ T cells from T1D and controls.…”

Section: T Cellsmentioning

confidence: 99%

“…Several differences have been proposed between self-reactive T CD4+ T cells from T1D and controls. Only GAD65-reactive T cells from T1D subjects seem to be fully autoantigen-experienced in vivo and express the memory T-cell marker CD45RA [338,339] and are capable of activation in the absence of CD28/B7 costimulatory signals [248]. It was also recently proposed that CD4+ T cells from T1D subjects may have a lower threshold of activation, as compared to healthy controls [340].…”

Section: T Cellsmentioning

confidence: 99%

Immunology of β-Cell Destruction

Torre

Lernmark

2010

Advances in Experimental Medicine and Biology

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Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects

Cited by 86 publications

References 27 publications

Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

Immunology of β-Cell Destruction

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