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

University of Colorado, Denver, Colorado, United States
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.21). 06/2006; 91(5):1855-61. DOI: 10.1210/jc.2005-1171
Source: PubMed


Type 1A diabetes is characterized by a long prodromal phase during which autoantibodies to islet antigens are present. Nevertheless, we lack data on the pancreatic pathology of subjects who are positive for islet autoantibodies (to islet autoantigens GAD65, insulin, and ICA512).
In this manuscript, we describe a novel strategy in obtaining pancreata and pancreatic lymph nodes from islet autoantibody-positive organ donors that involves careful coordination among the laboratory and the organ donor provider organization.
We developed a rapid screening protocol for islet autoantibodies measurement of organ donors to allow identification of positive subjects before organ harvesting. In this way we were able to obtain pancreata and pancreatic lymph nodes from subjects with and without islet autoimmunity.
The organ donors used in this study were obtained from the general community.
The population studied consisted of 112 organ donors (age range 1 month to 86 yr, mean age 39 yr).
The main outcome measure of this study consisted of evaluating the pancreatic histology and identify T cells autoreactive for islet antigens in the pancreatic lymph nodes.
To date we have identified three positive subjects and obtained the pancreas for histological evaluation from one of the autoantibody-positive donors who expressed ICA512 autoantibodies. Although this subject did not exhibit insulitis, lymphocytes derived from pancreatic lymph nodes reacted to the islet antigen phogrin.
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.

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Available from: Ronald Gill, Dec 28, 2013
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    • "It is somewhat better characterized today and we know that the most frequent cell types are CD8 lymphocytes, followed by macrophages, B cells and CD4 T cells (Willcox et al. 2009). However, only a few studies have been carried out in non-diabetic, autoantibody positive (Ab+) donors, with the majority of the donors showing no leukocytic infiltration or beta cell damage (Gianani et al. 2006; In't Veld et al. 2007; Wagner et al. 1994). The Network for Pancreatic Organ Donors with Diabetes (nPOD) has now opened up the unique possibility of investigating and characterizing the histopathological presentation of all the stages of the disease, from the pre-diabetic to the chronic state. "
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    ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells are destroyed in the islets of Langerhans. One of its main pathological manifestations is the hyper-expression of Major Histocompatibility Complex I (MHC-I) by beta cells, which was first described over 3 decades ago yet its cause remains unknown. It might not only be a sign of beta cell dysfunction but could also render the cells susceptible to autoimmune destruction; for example, by islet-infiltrating CD8 T cells. In this report, we studied pancreas tissue from a 22-year-old non-diabetic male cadaveric organ donor who had been at high risk of developing T1D, in which autoantibodies against GAD and IA-2 were detected. Pancreas sections were analyzed for signs of inflammation. Multiple insulin-containing islets were identified, which hyper-expressed MHC-I. However, islet density and MHC-I expression exhibited a highly lobular and heterogeneous pattern even within the same section. In addition, many islets with high expression of MHC-I presented higher levels of CD8 T cell infiltration than normal islets. These results demonstrate the heterogeneity of human pathology that occurs early during the pre-diabetic, autoantibody positive phase, and should contribute to the understanding of human T1D. © The Author(s) 2015.
    Journal of Histochemistry and Cytochemistry 08/2015; 63(8):626-36. DOI:10.1369/0022155415576543 · 1.96 Impact Factor
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    • "A key question posed when nPOD was established was whether individuals with autoantibody (single or multiple) would have insulitis in the pancreas [26, 48, 49]. To date, insulitis has been demonstrated in two of three non-diabetic donors with multiple autoantibodies but not in any of the 18 donors with a single autoantibody. "
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    ABSTRACT: The Juvenile Diabetes Research Foundation (JDRF) Network for Pancreatic Organ Donors with Diabetes (JDRF nPOD) was established to obtain human pancreata and other tissues from organ donors with type 1 diabetes (T1D) in support of research focused on disease pathogenesis. Since 2007, nPOD has recovered tissues from over 100 T1D donors and distributed specimens to approximately 130 projects led by investigators worldwide. More recently, nPOD established a programmatic expansion that further links the transplantation world to nPOD, nPOD-Transplantation; this effort is pioneering novel approaches to extend the study of islet autoimmunity to the transplanted pancreas and to consent patients for postmortem organ donation directed towards diabetes research. Finally, nPOD actively fosters and coordinates collaborative research among nPOD investigators, with the formation of working groups and the application of team science approaches. Exciting findings are emerging from the collective work of nPOD investigators, which covers multiple aspects of islet autoimmunity and beta cell biology.
    Current Diabetes Reports 10/2014; 14(10):530. DOI:10.1007/s11892-014-0530-0 · 3.08 Impact Factor
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    • "Studies on autoantibody-positive non-diabetic organ donors surprisingly showed only limited evidence of islet lesions and beta cell damage [29, 37, 57–59]. The cumulative data from these studies show that only two out of the 72 autoantibody-positive subjects showed diabetes-related histopathological changes [37]. "
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    ABSTRACT: Human type 1 diabetes (T1D) is considered to be an autoimmune disease, with CD8+ T-cell-mediated cytotoxicity being directed against the insulin-producing beta cells, leading to a gradual decrease in beta cell mass and the development of chronic hyperglycemia. The histopathologically defining lesion in recent-onset T1D patients is insulitis, a relatively subtle leucocytic infiltration present in approximately 10 % of the islets of Langerhans from children with recent-onset (<1 year) disease. Due to the transient nature of the infiltrate, its heterogeneous distribution in the pancreas and the nature of the patient population, material for research is extremely rare and limited to a cumulative total of approximately 150 cases collected over the past century. Most studies on the etiopathogenesis of T1D have therefore focused on the non-obese diabetic (NOD) mouse model, which shares many genetic and immunological disease characteristics with human T1D, although its islet histopathology is remarkably different. In view of these differences and in view of the limited success of clinical immune interventions based on observations in the NOD mouse, there is a renewed focus on studying the pathogenetic process in patient material.
    Seminars in Immunopathology 07/2014; 36(5). DOI:10.1007/s00281-014-0438-4 · 7.75 Impact Factor
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