Initial Results of Screening of Nondiabetic Organ Donors for Expression of Islet Autoantibodies

Gianani, Roberto; Putnam, Amy; Still, T.; Yu, Liping; Miao, Dongmei; Gill, Ronald G.; Beilke, Joshua; Supon, Patrick; Valentine, Anne; Iveson, A.; Dunn, Sue; Eisenbarth, George S.; Hutton, John C.; Gottlieb, Peter A.; Wiseman, Alexander C.

doi:10.1210/jc.2005-1171

Cited by 54 publications

(57 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Islet ductal complexes and isolated insulin-positive cells in ducts have also been reported in pancreases obtained from autopsy specimens and organ donors [21,37]. Similarly, we observed insulin-positive cells in ducts from all patient groups.…”

Section: Discussionsupporting

confidence: 87%

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis Recent histological analysis of pancreases obtained from patients with long-standing type 1 diabetes identified chronic islet inflammation and limited evidence suggestive of beta cell replication. Studies in rodent models also suggest that beta cell replication can be induced by certain inflammatory cytokines and by gastrin. We therefore tested the hypothesis that beta cell replication is observed in non-autoimmune human pancreatic disorders in which localised inflammation or elevated gastrin levels are present. Methods Resected operative pancreatic specimens were obtained from patients diagnosed with primary adenocarcinoma (with or without chronic severe pancreatitis) or gastrinoma. Additional pancreatic tissue was obtained from autopsy control patients. Immunohistochemistry was used to assess fractional insulin area, beta cell number and replication rate and differentiation factors relevant to beta cell development.Results Fractional insulin area was similar among groups. Patients with pancreatic adenocarcinoma and localised chronic severe pancreatitis displayed significant increases in the number of single beta cells, as well as increased beta cell replication rate and levels of neurogenic differentiation 1 in islets. Patients with gastrinoma demonstrated significant increases in the number of single beta cells, but the beta cell replication rate and islet differentiation factor levels were similar to those in the control group. Conclusions/interpretation These findings indicate that chronic severe pancreatic inflammation can be associated with significant effects on beta cell number or replication rate, depending on the distribution of the cells. This information may prove useful for attempts seeking to design therapies aimed at inducing beta cell replication as a means of reversing diabetes.

show abstract

Section: Discussionsupporting

confidence: 87%

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

et al. 2008

View full text Add to dashboard Cite

show abstract

“…As a matter of fact, in NOD mice using a pancreatectomy/islet transplantation model, Kimura et al (23) have reported that the triggering of the diabetogenic autoimmune process needs to take place during a specific window of time (preinsulitis age 7 weeks) and that the presence of a large islet mass is not required for the progression to clinical diabetes. Although these are provocative findings, there is a need to have access to pancreatic tissue and pancreatic lymph nodes from subjects at risk of developing type 1 diabetes to uncover the role for islet cell mass in the development of islet autoimmunity during the natural history of the human disease (24). Adaptive and innate immunity.…”

Section: Type 1 Diabetes: a Chronic Inflammatory Disease Of The Isletsmentioning

confidence: 99%

The Heterogeneity of Diabetes

2007

View full text Add to dashboard Cite

Diabetes is an emblematic example of a heterogeneous disease. Systemic inflammation has emerged as a prominent factor in the type 2 diabetes pathoetiology, but it remains ill-defined in type 1 diabetes. There is a wide spectrum of associations between inflammatory responses and diabetic syndromes. At one end of this spectrum, there is type 1 diabetes for which there is convincing evidence that chronic inflammation of pancreatic islets is a central aspect of disease pathogenesis. At the opposite end, is type 2 diabetes that is clearly associated with systemic inflammation, which could be either the cause or simply mark the underlying pathology. Accumulating evidence has substantiated that a subgroup of adult patients clinically diagnosed with type 2 diabetes exhibit autoantibody responses to islet autoantigens. The presence of these immunologic abnormalities is associated with a severe insulin secretory defect and the absence of signs of systemic inflammation as documented by plasma C-reactive protein and fibrinogen levels that are comparable with those of control populations. Islet autoantibody evaluation should be part of the diagnostic assessment for clinically diagnosed type 2 diabetes not only because it might predict the rate of progression to insulin requirement in adult populations but also to identify a pathogenically distinct disease phenotype characterized by the absence of systemic inflammation and its related disorders. A more appropriate characterization of this subgroup of clinically diagnosed type 2 diabetes, diabetes of autoimmune pathogenesis, will promote future research into the etiology, natural history, and treatment.

show abstract

“…Our prior studies indicate that insulin peptide B:9-23 is a key target of the immune pathogenesis of NOD diabetes, despite evidence for additional targets (21)(22)(23). The current study indicates that a conserved V␣/J␣-chain targeting the B:9-23 peptide is sufficient to drive the expression of high levels of insulin autoantibodies, even when only this TCR ␣-chain is expressed (C␣ knockout mice per retrogenic mice).…”

Section: Discussionmentioning

confidence: 62%

Conserved T cell receptor α-chain induces insulin autoantibodies

Kobayashi

Jasinski

Liu

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

A fundamental question is what are the molecular determinants that lead to spontaneous preferential targeting of specific autoantigens in autoimmune diseases, such as the insulin B:9 -23 peptide sequence in type 1 diabetes. Anti-insulin B:9 -23 T cell clones isolated from prediabetic NOD islets have a conserved V␣-segment/J␣-segment, but no conservation of the ␣-chain N region and no conservation of the V␤-chain. Here, we show that the conserved T cell receptor ␣-chain generates insulin autoantibodies when transgenically or retrogenically introduced into mice without its corresponding V␤. We suggest that a major part of the mystery as to why islet autoimmunity develops relates to recognition of a primary insulin peptide by a conserved ␣ chain T cell receptor.autoimmunity ͉ NOD mouse ͉ Type 1 diabetes ͉ retrogenic

show abstract

Initial Results of Screening of Nondiabetic Organ Donors for Expression of Islet Autoantibodies

Abstract: In summary, these results indicate that it is possible to screen organ donors in real time for antiislet antibodies, characterize pancreatic histology, and obtain viable T cells for immunological studies.

Cited by 54 publications

References 15 publications

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

The Heterogeneity of Diabetes

Conserved T cell receptor α-chain induces insulin autoantibodies

Contact Info

Product

Resources

About