Insulin-dependent diabetes mellitus is an autoimmune diseasein which the beta cells of the islets of Langerhans are selectivelydestroyed.1 In a patient with this disease, a transplanted pancreasshould be as susceptible to the autoimmune process as the nativepancreas. Indeed, insulin-dependent diabetes mellitus can recurin an immunocompetent or minimally immunosuppressed recipientof a pancreatic transplant from an identical twin or HLA-identicalsibling.2 Usually, however, the degree of immunosuppressionrequired to prevent rejection is sufficient to prevent autoimmunedamage to the pancreatic graft.3 We report on two patients whounderwent pancreatic transplantation with poor HLA matchingand in whom the beta cells in the transplants were subsequentlydestroyed despite standard immunosuppressive therapy.
Case Reports
Patient 1
A 34-year-old man with insulin-dependent diabetes mellitus underwentcombined renal and pancreatic transplantation with cadavericgrafts because of end-stage diabetic nephropathy. The donor'sHLA haplotypes were HLA-A2,3; B12,15; and DR4,7; those of therecipient were HLA-A2; B5,27; and DR1,4. The pancreatic graftwas anastomosed to the common iliac artery and the vena cava.4The postoperative course was uneventful, and both grafts functionedwell. Maintenance immunosuppressive therapy consisted of cyclosporine,azathioprine, and prednisolone. The patient had no detectableC peptide in serum before transplantation but had high serumC-peptide concentrations both while fasting and postprandiallyafterward, indicating the systemic delivery of insulin.5
Twenty-nine months later, insulin therapy was resumed becauseof hyperglycemia, and although serum C peptide was still detectablein the fasting state, there was no increase in the concentrationtwo hours after a standard meal (Figure 1). The renal graftwas functioning well.
Figure 1. Fasting and Postprandial Serum C-Peptide Concentrations and Fasting Serum Glucose Concentrations in Two Recipients of Pancreatic and Kidney Transplants Who Had Recurrent Diabetes.
In Patient 1, serum C peptide was still detectable after the pancreatic transplant had been removed. However, the postprandial response (two hours after a standard meal) was abolished. In Patient 2, the pancreas was removed six years after the loss of beta-cell function. To convert the values for C peptide to nanomoles per liter, multiply by 0.331. To convert the values for glucose to millimoles per liter, multiply by 0.05551.
Three months later, the pancreatic graft was replaced. The excisedgraft looked normal, and histologic examination revealed almostnormal exocrine pancreatic tissue (Figure 2A). There was noevidence of rejection, such as mononuclear-cell infiltrationor endovasculitis.3 The islets, however, were infiltrated withmononuclear cells (i.e., insulitis was present). Immunohistochemicalstudies showed many cells with strong staining for glucagonand chromogranin A, but a smaller number of cells stained forinsulin, and the staining was weaker (Figure 2B, Figure 2C,and Figure 2D). Some cells that stained for common leukocyteantigen were seen in islets with weak staining for insulin.Tests for antibodies against islet cells6 and glutamic aciddecarboxylase7 were negative in serum obtained five months afterthe first transplantation (no earlier samples were available)but were positive in serum obtained two months before retransplantationand at the time of retransplantation. The second pancreatictransplant had to be removed after six weeks because of a seriousinfection. Microscopical evaluation of that graft did not revealany signs of beta-cell destruction.
Figure 2. Photomicrographs of Sections of the Pancreatic Graft Removed from Patient 1.
Panel A shows a slight lymphocytic inflammation in and adjacent to islets (arrows) — that is, insulitis — but only a minimal increase in interstitial fibrous tissue and no signs of rejection, such as diffuse parenchymal mononuclear-cell infiltration or endovasculitis (hematoxylin and eosin, x31). Panels B, C, and D show the results of immunoperoxidase staining of an islet with polyclonal antibodies against human glucagon, chromogranin A, and insulin, respectively (Dakopatts, Copenhagen, Denmark) (x125). In Panel B, many cells are stained with antibodies against glucagon. In Panel C, about the same number of cells are stained with antibodies against chromogranin A. In Panel D, a moderate number of cells are stained with antibodies against insulin, but the intensity of the staining is lower than in normal islets.
Patient 2
A 34-year-old woman with insulin-dependent diabetes mellitusunderwent combined transplantation with cadaveric renal andpancreatic grafts because of end-stage diabetic nephropathy.The donor's HLA haplotypes were HLA-A2,11; B12,40; and DR5,6;those of the recipient were HLA-A1,9; B8,16; and DR1,3. Maintenanceimmunosuppressive therapy consisted of cyclosporine, azathioprine,and prednisolone. The patient had no detectable C peptide inserum before transplantation. Afterward, the serum C-peptideconcentration ranged between 3 and 6 ng per milliliter (1 and2 nmol per liter) (normal range, 0.9 to 5.1 ng per milliliter[0.3 to 1.7 nmol per liter]) in the fasting state and increasedafter a standard meal (Figure 1).
Two years later, the patient's beta-cell function began to deteriorate,and exogenous insulin therapy was resumed. The serum creatinineconcentration ranged from 1.7 to 2.8 mg per deciliter (150 to250 µmol per liter). Six years later, the pancreatic graftwas removed because of recurrent acute episodes of abdominalpain with tenderness over the graft and high serum amylase concentrations.The pancreatic graft appeared normal on gross examination. Histologicexamination revealed essentially normal exocrine pancreatictissue, with no signs of rejection. The islets showed no signsof insulitis. Immunohistochemical studies showed staining forglucagon and chromogranin A but no staining for insulin (Figure 3A,Figure 3B, and Figure 3C). Cells stained for common leukocyteantigen were seen in the exocrine pancreatic tissue and in afew of the islets. Tests for antibodies against islet cellsand glutamic acid decarboxylase in serum samples obtained atthe time of transplantation, immediately afterward, six monthsafter the loss of endocrine function, and at the time of transplantremoval were all negative. A second transplantation was notperformed.
Figure 3. Photomicrographs of Sections of the Pancreatic Graft Removed from Patient 2.
Panels A, B, and C show the results of immunoperoxidase staining of an islet with polyclonal antibodies against human glucagon, chromogranin A, and insulin, respectively (Dakopatts) (x125). In Panel A, many cells are stained (although somewhat weakly) with antibodies against glucagon. In Panel B, many cells are stained with antibodies against chromogranin A. In Panel C, none of the cells are stained with antibodies against insulin.
Discussion
Many diseases treated by organ transplantation are believedto have an autoimmune origin, and theoretically, any transplantedorgan is as susceptible to the autoimmune process as the organbeing replaced. Indeed, in the early era of transplantation,it was feared that all transplanted organs would be affectedby the original disease. This has not proved to be the case,probably because the immunosuppressive therapy required to preventrejection is sufficient to prevent autoimmune damage to thegraft. If the donor is an identical twin and immunosuppressivetherapy is not needed to prevent rejection, however, the autoimmunedisease may rapidly recur.2 Thus, in patients with autoimmunedisease, the advantage of transplanting tissue from an identicaltwin is lost.
To our knowledge, there have been no reports of recurrent diabetesin patients with insulin-dependent diabetes mellitus who receivedcadaveric pancreatic grafts. The pattern of selective destructionof beta cells in our two patients, with the preservation ofalpha and delta cells, resembles that in pancreatic islets frompatients with long-standing insulin-dependent diabetes mellitus8and suggests that the autoimmune disease had recurred. Furthermore,there were no signs of acute rejection (diffuse parenchymalmononuclear-cell infiltration, endovasculitis, or both) or chronicvascular rejection (fibrous intimal proliferation in the arteries).3
The physiologic data support the same conclusion. In both patients,after long-term functioning of the pancreatic grafts, beta-cellfunction gradually decreased over a period of 6 to 12 months.The first sign of deterioration was a decline in the rise inthe serum C-peptide concentration after a meal, followed bya decrease in the serum C-peptide concentration in the fastingstate. This gradual decline in beta-cell secretory capacityis similar to that which occurs in adults with insulin-dependentdiabetes mellitus.9
Lastly, in Patient 1, serum tests for antibodies against isletcells and glutamic acid decarboxylase were initially negative,but both types of antibodies were detected at high titers atthe time of overt beta-cell dysfunction. Moreover, there washistologic evidence of insulitis in association with the recurrenceof markers for humoral autoimmunity. Hence, this patient hadthe characteristic features of insulin-dependent diabetes mellitusof recent onset.8 In Patient 2, neither of these antibodieswas detected, but several years had elapsed between the timewhen serum C peptide was last detected and the removal of thepancreas (when samples were obtained for the antibody tests).By the time the graft was removed, the islets were devoid ofbeta cells, and there were no signs of insulitis.
The incidence of selective beta-cell destruction after pancreatictransplantation is unknown. However, a possible associationbetween the reappearance of islet-cell antibodies and the failureof a cadaveric pancreatic graft has been suggested.10 In ourseries of 155 patients who received cadaveric pancreatic transplants,20 patients with recurrent diabetes under similar circumstances(a slow decline in insulin secretion after a prolonged periodof stable function) have undergone pancreatic biopsies or removalof the transplants. Of these 20 patients, only the 2 describedhere had a selective loss of beta cells. Eleven other patientshad pancreatic grafts that gradually failed after functioningfor several years, but since these patients did not undergobiopsy or graft removal, histologic studies were not performed.Some of these patients may have had recurrent autoimmune disease.
Our findings clearly suggest that selective destruction of betacells may occur despite sustained immunosuppressive therapywith cyclosporine, azathioprine, and prednisolone. Similarly,immunosuppressive therapy does not prevent progressive beta-celldysfunction in patients with insulin-dependent diabetes mellitusof recent onset.11 Finally, it has been suggested that a poorHLA match between donor and recipient may reduce the risk ofrecurrent autoimmune diabetes after pancreatic transplantation.2Our findings clearly demonstrate that the donor and recipientof a pancreatic graft do not have to share HLA alleles for autoimmunedestruction of the graft to occur.
Supported by the Swedish Medical Research Council and the KarolinskaInstitute.
We are indebted to Ms. Marie Larsson, Ms. Anita Lindström,and Ms. Christina Rosborn for expert technical assistance.
Source Information
From the Divisions of Transplantation Surgery (G.T.), Pathology (F.P.R.), and Medicine (J.B.), Karolinska Institute, Huddinge Hospital, Huddinge, and the Department of Endocrinology, Malmö University Hospital, Malmö (G.S.) — both in Sweden.
Address reprint requests to Dr. Tydén at the Division of Transplantation Surgery, Karolinska Institute, Huddinge Hospital, 141 86 Huddinge, Sweden.
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