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We would like to engage the transplant community and ask support for research about the causes of type 1 diabetes (T1D): we discuss here the critical need to facilitate allocation to research of pancreata from those rare organ donors with recent onset T1D or prediabetes.
First, it is key to recognize that our knowledge of T1D pathogenesis and etiological factors is severely limited by scarce access to the pancreas of patients. To address this shortcoming, the JDRF supported the institution of the Network for the Pancreatic Organ Donors with Diabetes (nPOD; www.JDRFnPOD.org). Working with U.S. Organ Procurement Organizations (OPOs) nPOD has recovered pancreata from over 100 organ donors with T1D since 2007. nPOD promotes collaborative research by providing specimens to qualified investigators, worldwide, as well as scientific leadership and coordination (1). Many novel discoveries have been made through the study of nPOD pancreata (1) about key elements of the autoimmune pathogenesis and additional mechanisms of disease, including chronic inflammation associated with beta cell stress and dysfunction, alterations of key extra-cellular matrix components in the islets, alteration of the exocrine tissue, and more. Growing evidence shows that the disease is more chronic than previously thought, as pathological signs and insulin-positive beta cells persist for many years, sometimes decades, after clinical diagnosis.
However, islet autoimmunity is more prominent around the time of diagnosis and there remains a clear need to study the pancreas from donors with recent onset T1D (2). Thanks to therapeutic advances, the mortality associated with complications of acute diabetic ketoacidosis at diagnosis is now extremely low. Because those rare patients who succumb to complications of ketoacidosis are not typically considered for organ donation, we are writing to promote awareness that such potential organ donors are of extreme value to T1D research. We advocate that whenever possible attempts should be made to recover their pancreas for research. The JDRF nPOD is ready to receive these pancreata 24/7 (1-866-731-6585).
There is also pressing need to recover pancreata from prediabetic donors, as these may hold the key to the earlier stages and possibly the triggers of the disease. Those who are destined to develop T1D can be identified by screening for several T1D-associated autoantibodies; the risk of future T1D is proportional to the number of autoantibodies detected. Between 2007–2015 nPOD and participating OPOs have screened 5,123 organ donors; 275 (5.4%) tested positive, 260 for a single autoantibody and 15 for multiple autoantibodies. Only 27 (<11%) of these autoantibody-positive donors were offered to nPOD, as the majority of these pancreata were allocated to transplant.
Of those recovered by nPOD, 21 donors expressed a single autoantibody (2); these did not typically carry T1D-associated HLA genes and do not appear to have insulitis, the autoimmune lesion affecting the pancreatic islets in T1D. However, 2/6 donors with multiple autoantibodies and 1 donor with a single autoantibody had insulitis and T1D-associated HLA types (2). Two other studies in Europe conducted autoantibody screening in organ donors: a) in one study, 62 autoantibody-positive donors (4.1%) were found among 1,507 tested of whom only 3 had multiple autoantibodies, among which 2 had insulitis in association with high-risk HLA variants (3); another screening identified 32 autoantibody-positive donors among 969 tested (3.3%): 9 expressed multiple autoantibodies but none carried high-risk HLA types and insulitis was not observed (4). In both studies most of the pancreas was used for islet isolation, allowing pathology examination only on small amounts of tissue. Thus, insulitis so far has been found in some but not all of the autoantibody-positive donors, especially those with multiple autoantibodies and HLA alleles associated with increased T1D risk, which represent a minority of the autoantibody-positive donors. We predict that future studies will confirm an association of insulitis with predisposing HLA genes and multiple autoantibodies. It is possible that insulitis may be found in those with high risk HLA genes in the presence of a single autoantibody.
Supporting these studies will help better define to what extent autoantibody-positivity in an organ donor identifies pancreata with ongoing autoimmunity and possibly significant damage. If transplanted, such pancreata may have poor outcome. We conducted the only study so far that retrospectively examined the potential impact of donor autoantibody-positivity on pancreas transplant outcomes; we found 4 (2.9%) donors with a single autoantibody (thus low risk) among 135 tested (5), and could not find evidence that positivity for a single autoantibody impact graft outcome. However, as discussed above, at least a subset of autoantibody-positive donors will have insulitis and variable degrees of beta cell loss. We believe there is also an opportunity for the transplant community to help addressing this question if a retrospective and ethically sound study could examine transplant outcome data for pancreata from autoantibody-positive donors, but such a study may require long term follow-up to be meaningful.
In closing, we appeal to the transplant and OPO communities to facilitate the allocation of pancreata from autoantibody-positive donors and donors with recent onset T1D to research. The nPOD mission is aligned with the notion that when allocating potentially life-saving organs transplant should always be given first priority. However, in situations of autoantibody-positive organ donors, particularly those with multiple T1D-related autoantibodies and/or with HLA associated with increased T1D risk, it appears to be in the best interest of both the academic community and the organ recipients to allocate pancreas tissues to research. We emphasize that non-diabetic autoantibody-positive donors are rare, representing about 3% of the overall organ donor pool (2); moreover, only 0.2% of the donors have multiple autoantibodies. Thus, the preferential allocation of these donors to research would have minimal impact on availability of organs for pancreas transplantation; we also note that the clinical impact would be minimized because the majority of potential organ recipients on the pancreas-kidney or islet donor lists are clinically stable. We encourage the transplant community to take an active role in helping find the causes of T1D and at the same time improve pancreas selection criteria for transplantation.
Studies by the authors related to this topic were supported by grants from the National Institutes of Health (R01 DK070011), the JDRF (research grants 25-2013-268, 17-2011-594), and The Leona M. and Harry B. Helmsley Charitable Trust (George Eisenbarth nPOD Award for Team Science, 2015PG-T1D052). We are indebted to Dr. Irina Kusmartseva and the nPOD Organ Procurement and Pathology Core staff members. Author contributions are as follows: GWB, AP and MAA conceived the study. AP, ALP and GWB wrote the manuscript, CHW and MAA contributed to discussion and reviewed/edited the manuscript.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.