A review of the medical literature suggests that type 1 diabetes in a bone marrow allograft donor may be transmitted to the recipient after a successful transplant (1,2). We report a 21-year follow-up after a successful allograft for aplastic anemia. The donor had type 1 diabetes at the time of transplant. The recipient has developed a number of antibodies against pancreatic islet cells, and although these have persisted for a number of years, she has not developed diabetes.
A 6-year-old Caucasian girl presented in 1976 with aplastic anemia. She showed a partial response to androgens, but this was not sustained, and in 1979 she received a bone marrow transplant (BMT) from her HLA-matched male sibling, who was 3 years older and had been diagnosed with type 1 diabetes 7 years earlier. Both patients were group O Rh (D) positive and HLA-A1, -2, -B8, and MLC nonreactive. The transplant procedure and the progress post-BMT have already been published (3). Full donor engraftment of the hemopoietic system has been documented on a number of occasions over the past 21 years.
Mild acute graft versus host disease (GVHD) was followed by chronic GVHD, which was severe in the mouth. There was also a mild but persistent patchy fibrosis of the skin. Oral GVHD eventually responded to dental clearance and immunosuppressive therapy. She required prednisone, usually 10 mg/day, from June 1979 to June 1987. Azathioprine, 100 mg/day, was started in August 1979 and stopped in January 1986. She has had no immunosuppressive therapy since June 1987. Evidence of hyposplenism judged by blood film appearances was noted in 1983, but she has not experienced any significant sepsis to date. At the time of this report, she remains well and has had two healthy children. Both pregnancies and deliveries were uneventful, and the children are in good health.
The recipient was negative for islet cell antibodies (ICAs) by indirect immunofluorescence until 1994, when a positive result of 10 Juvenile Diabetes Foundation units was recorded. The development of high titer anti-nuclear antibodies since 1996 has made the detection of ICAs by indirect immunofluorescence virtually impossible. Recipient sera revealed high titer anti-GAD antibodies, determined using Diaplets Anti-GADPLUS ELISA (Roche Diagnostics) in 1994, 1997, 1998, 1999, and 2000 (maximum 3,086 ng/ml, normal range 0–32). However, neither anti-IA-2 antibodies (determined using Diaplets Anti-IA-2 ELISA, Roche Diagnostics) nor insulin antibodies (measured by radioimmunoassay) were detected at any time during follow-up. Fasting glucose measurements in 1999 and 2000 were 4.0 and 5.4 mmol/l, respectively. The diabetic donor was ICA-negative at the time of transplant and was negative for ICA, anti-GAD, and anti-IA-2 on follow-up testing in 1999. Evidence of autoimmunity would be expected at or soon after diagnosis with type 1 diabetes but was predictably absent a long time after presentation. HLA-DQα and -β allele typing was performed using DNA extracted from buccal epithelial and white blood cells in the recipient and in DNA from white blood cells in the donor. The recipient showed HLA identity with the donor at these loci. Both individuals were characterized by 0103/0501 at the HLA-DQα locus and 0201/0602, three at the HLA-DQβ locus. Endomysial antibodies, anti-myeloperoxidase, tissue antibodies, and antibodies against proteinase-3 and double stranded DNA were not detected. Both IgG and IgA antibodies to Gliadin were positive in 1999 but were not detected at follow-up testing in 2000.
Transfer of type 1 diabetes by BMT from a donor with type 1 diabetes was first reported in 1993 (1). The recipient developed type 1 diabetes–associated antibodies and developed diabetes 4 years after BMT from an HLA-identical brother. Subsequently, a review of the International Bone Marrow Transplant Registry revealed that 15 transplants had been undertaken from bone marrow donors with diabetes, including nine donors with confirmed diagnoses of type 1 diabetes (2). Of the three patients who had completed more than 2 years follow-up, two recipients had progressed to type 1 diabetes, all having received transplants in 1989. This report describes a BMT that took place in 1979. The donor had been diagnosed with type 1 diabetes 7 years before the transplant and was negative for ICAs at the time of transplant. The recipient has over time developed ICAs and high levels of anti-GAD antibodies. HLA identity together with ICA and/or anti-GAD confer a high positive predictive value for development of type 1 diabetes in siblings of children with type 1 diabetes (4). However, the patient also had chronic GVHD, a condition in which multiple autoantibodies are commonly found (5). We cannot find any report that looked for ICAs, anti-GAD, or insulin autoantibodies in chronic GVHD. It is possible that these antibodies have developed in our patient as part of the spectrum that occurs secondary to GVHD and might not be related to the fact that the donor had type 1 diabetes. Alternatively, the autoimmune process observed in the recipient may have been modified by the Azathioprine therapy, which was in place for 6 years immediately post-transplant. Blood glucose measurements over the past 21 years have shown no evidence of type 1 diabetes. Follow-up of patients after BMT for >20 years is rare, and in particular, there is very little information on the long-term outcome in patients when the donor has type 1 diabetes. Follow-up is needed to ensure this individual remains glucose tolerant.