Autoimmunity after Islet-Cell Allotransplantation
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《新英格兰医药杂志》
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 1A). 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).
Figure 1. Liver-Biopsy Specimen.
A single heterotopic islet is present in a portal triad stained with hematoxylin and eosin (Panel A). Immunoperoxidase staining shows a sparse population of CD3-positive T cells surrounding the islet (Panel B), with an absence of insulin-containing cells (Panel C) but many glucagon-containing cells (Panel D). The hepatic parenchyma was unremarkable, and there was no steatosis.
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
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.
Supported by the National Institutes of Health.
References
Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230-238.
Sibley RK, Sutherland DE, Goetz F, Michael AF. Recurrent diabetes mellitus in the pancreas iso- and allograft: a light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest 1985;53:132-144.
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.
Stegall MD, Lafferty KJ, Kam I, Gill RG. Evidence of recurrent autoimmunity in human allogeneic islet transplantation. Transplantation 1996;61:1272-1274.
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 1A). 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).
Figure 1. Liver-Biopsy Specimen.
A single heterotopic islet is present in a portal triad stained with hematoxylin and eosin (Panel A). Immunoperoxidase staining shows a sparse population of CD3-positive T cells surrounding the islet (Panel B), with an absence of insulin-containing cells (Panel C) but many glucagon-containing cells (Panel D). The hepatic parenchyma was unremarkable, and there was no steatosis.
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
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.
Supported by the National Institutes of Health.
References
Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230-238.
Sibley RK, Sutherland DE, Goetz F, Michael AF. Recurrent diabetes mellitus in the pancreas iso- and allograft: a light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest 1985;53:132-144.
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.
Stegall MD, Lafferty KJ, Kam I, Gill RG. Evidence of recurrent autoimmunity in human allogeneic islet transplantation. Transplantation 1996;61:1272-1274.