Correspondence

Autoimmunity after Islet-Cell Allotransplantation

N Engl J Med 2006; 355:1397-1399September 28, 2006

Article

To the Editor:

A 52-year-old man with a 36-year history of type 1 diabetes mellitus complicated by hypoglycemia unawareness received two intrahepatic islet-cell allografts. The glycated hemoglobin value before transplantation was 9.3%. He received 400,000 islet equivalents in the first transplantation and 512,000 in the second transplantation, 5 months later. Grafts were prepared at the Joslin Diabetes Center in Boston. His immunosuppression regimen conformed to the Edmonton protocol.1

Three weeks after the second graft, exogenous insulin was discontinued. The stimulated C-peptide concentration was 2.89 ng per milliliter. The patient did not receive exogenous insulin for 3 months, but thereafter insulin was resumed. His glycated hemoglobin value was 7.2% near the end of year 3. He has since been treated with 9 U of insulin glargine and low-dose insulin lispro, and he has only occasional hypoglycemia.

Thirty-two months after the second islet graft, symptomatic cholelithiasis developed and the patient underwent elective cholecystectomy. His surgeon, aware of the previous transplantations, obtained informed consent to perform a liver biopsy during the procedure.

Histologic study of a wedge-biopsy specimen revealed a single heterotopic islet in a portal triad (Figure 1AFigure 1Liver-Biopsy Specimen.). A sparse T-cell lymphoid infiltrate surrounded the islet (Figure 1B). Immunohistochemical analysis of the islet revealed no insulin-containing cells (Figure 1C) but many glucagon-containing cells (Figure 1D).

The function of islet allografts may be compromised by many factors, including allograft rejection, drug-induced toxicity, and an unfavorable heterotopic environment. In addition, these allografts may fail owing to recurrent autoimmunity. Both syngeneic and allogeneic pancreatic grafts transplanted into patients with type 1 diabetes have been shown to fail as a result of the selective destruction of beta cells owing to recurrent autoimmunity.2,3 There is one previous report of islet-allograft biopsy in a human.4 The biopsy was performed 14 days after transplantation and appeared to show recurrent autoimmunity. In that case, however, the islets were placed in the subfascial compartment of a forearm muscle, and the immunosuppressive regimen used predated the Edmonton protocol.

In our case of successful islet transplantation for type 1 diabetes with the use of the Edmonton protocol, insulin independence was achieved briefly, but exogenous insulin was subsequently required. The liver-biopsy specimen showing a single heterotopic islet suggests that recurrent autoimmunity may have resulted in the progressive loss of transplanted beta cells. The clinical status of the patient can still be described as improved, but our observations suggest that newer strategies will be required to prevent recurrent autoimmunity, which can compromise the outcome.

The Worcester Human Islet Transplantation Group

Supported by the National Institutes of Health.

Source Information

Members of the Worcester Human Islet Transplantation Group were as follows: V. Sharma, D. Andersen, M. Thompson, B.A. Woda, J.S. Stoff, C. Hartigan, C. Rastellini, D. Phillips, J.P. Mordes, and A.A. Rossini. Dr. Thompson assumes full responsibility for the overall content and integrity of the letter.

4 References

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   Sutherland DE, Sibley R, Xu XZ, et al. Twin-to-twin pancreas transplantation: reversal and reenactment of the pathogenesis of type I diabetes. Trans Assoc Am Physicians 1984;97:80-87
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Citing Articles (12)

Citing Articles

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   Q. Shi, J. R. Lees, D. W. Scott, D. L. Farber, S. T. Bartlett. (2012) Endogenous Expansion of Regulatory T Cells Leads to Long-Term Islet Graft Survival in Diabetic NOD Mice. American Journal of Transplantationno-no
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2. 2

   Alberto Pugliese, Helena K Reijonen, Jerry Nepom, George W Burke. (2011) Recurrence of autoimmunity in pancreas transplant patients: research update. Diabetes Management 1:2, 229-238
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3. 3

   Li Bai-Feng, Liu Yong-Feng, Cheng Ying. (2010) Silencing inducible nitric oxide synthase protects rat pancreatic islet. Diabetes Research and Clinical Practice 89:3, 268-275
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4. 4

   Nicola Gagliani, Alessandra Ferraro, Maria Grazia Roncarolo, Manuela Battaglia. (2009) Autoimmune diabetic patients undergoing allogeneic islet transplantation: are we ready for a regulatory T-cell therapy?. Immunology Letters 127:1, 1-7
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5. 5

   Christian Toso, Kumiko Isse, Anthony J. Demetris, Parastoo Dinyari, Angela Koh, Sharleen Imes, Tatsuya Kin, Juliet Emamaullee, Peter Senior, A M. James Shapiro. (2009) Histologic Graft Assessment After Clinical Islet Transplantation. Transplantation 88:11, 1286-1293
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   David A. Baidal, Raquel N. Faradji, Shari Messinger, Tatiana Froud, Kathy Monroy, Camillo Ricordi, Rodolfo Alejandro. (2009) Early Metabolic Markers of Islet Allograft Dysfunction. Transplantation 87:5, 689-697
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   C. Toso, J. A. Emamaullee, S. Merani, A. M. J. Shapiro. (2008) The role of macrophage migration inhibitory factor on glucose metabolism and diabetes. Diabetologia 51:11, 1937-1946
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   Christian Toso, Véronique Serre-Beinier, Juliet Emamaullee, Shaheed Merani, Mathieu Armanet, Anne Wojtusciszyn, Domenico Bosco, Thierry Calandra, Thierry Roger, Philippe Morel, A M. James Shapiro, Thierry Berney. (2008) The Role of Macrophage Migration Inhibitory Factor in Mouse Islet Transplantation. Transplantation 86:10, 1361-1369
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   Tatiana Froud, Raquel N. Faradji, Antonello Pileggi, Shari Messinger, David A. Baidal, Gaston M. Ponte, Pablo E. Cure, Kathy Monroy, Armando Mendez, Gennaro Selvaggi, Camillo Ricordi, Rodolfo Alejandro. (2008) The Use of Exenatide in Islet Transplant Recipients with Chronic Allograft Dysfunction: Safety, Efficacy, and Metabolic Effects. Transplantation 86:1, 36-45
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10. 10

    Simona Marzorati, Antonello Pileggi, Camillo Ricordi. (2007) Allogeneic islet transplantation. Expert Opinion on Biological Therapy 7:11, 1627-1645
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11. 11

    Ankit Bharat, Deepti Saini, Nicholas Benshoff, Jeremy Goodman, Niraj M. Desai, William C. Chapman, Thalachallour Mohanakumar. (2007) Role of Intra-Islet Endothelial Cells in Islet Allo-Immunity. Transplantation 84:10, 1316-1323
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12. 12

    Michael R. Rickels, Ali Naji, Karen L. Teff. (2007) Acute Insulin Responses to Glucose and Arginine as Predictors of β-Cell Secretory Capacity in Human Islet Transplantation. Transplantation 84:10, 1357-1360
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