title: Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus.
abstract: BACKGROUND
  Type 1 diabetes mellitus (DM) results from a cell-mediated autoimmune attack against pancreatic beta cells. Previous animal and clinical studies suggest that moderate immunosuppression in newly diagnosed type 1 DM can prevent further loss of insulin production and can reduce insulin needs.
  
  
  OBJECTIVE
  To determine the safety and metabolic effects of high-dose immunosuppression followed by autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) in newly diagnosed type 1 DM.
  
  
  METHODS
  A prospective phase 1/2 study of 15 patients with type 1 DM (aged 14-31 years) diagnosed within the previous 6 weeks by clinical findings and hyperglycemia and confirmed with positive antibodies against glutamic acid decarboxylase. Enrollment was November 2003-July 2006 with observation until February 2007 at the Bone Marrow Transplantation Unit of the School of Medicine of Ribeirão Preto, Ribeirão Preto, Brazil. Patients with previous diabetic ketoacidosis were excluded after the first patient with diabetic ketoacidosis failed to benefit from AHST. Hematopoietic stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (10 microg/kg per day) and then collected from peripheral blood by leukapheresis and cryopreserved. The cells were injected intravenously after conditioning with cyclophosphamide (200 mg/kg) and rabbit antithymocyte globulin (4.5 mg/kg).
  
  
  METHODS
  Morbidity and mortality from transplantation and temporal changes in exogenous insulin requirements (daily dose and duration of usage). Secondary end points: serum levels of hemoglobin A1c, C-peptide levels during the mixed-meal tolerance test, and anti-glutamic acid decarboxylase antibody titers measured before and at different times following AHST.
  
  
  RESULTS
  During a 7- to 36-month follow-up (mean 18.8), 14 patients became insulin-free (1 for 35 months, 4 for at least 21 months, 7 for at least 6 months; and 2 with late response were insulin-free for 1 and 5 months, respectively). Among those, 1 patient resumed insulin use 1 year after AHST. At 6 months after AHST, mean total area under the C-peptide response curve was significantly greater than the pretreatment values, and at 12 and 24 months it did not change. Anti-glutamic acid decarboxylase antibody levels decreased after 6 months and stabilized at 12 and 24 months. Serum levels of hemoglobin A(1c) were maintained at less than 7% in 13 of 14 patients. The only acute severe adverse effect was culture-negative bilateral pneumonia in 1 patient and late endocrine dysfunction (hypothyroidism or hypogonadism) in 2 others. There was no mortality.
  
  
  CONCLUSIONS
  High-dose immunosuppression and AHST were performed with acceptable toxicity in a small number of patients with newly diagnosed type 1 DM. With AHST, beta cell function was increased in all but 1 patient and induced prolonged insulin independence in the majority of the patients.
authors.affiliation: Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil. jcvoltar@fmrp.usp.br
authors.forename: Júlio C
authors.initials: JC
authors.lastname: Voltarelli
authors.forename: Carlos E B
authors.initials: CE
authors.lastname: Couri
authors.forename: Ana B P L
authors.initials: AB
authors.lastname: Stracieri
authors.forename: Maria C
authors.initials: MC
authors.lastname: Oliveira
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Moraes
authors.forename: Fabiano
authors.initials: F
authors.lastname: Pieroni
authors.forename: Marina
authors.initials: M
authors.lastname: Coutinho
authors.forename: Kelen C R
authors.initials: KC
authors.lastname: Malmegrim
authors.forename: Maria C
authors.initials: MC
authors.lastname: Foss-Freitas
authors.forename: Belinda P
authors.initials: BP
authors.lastname: Simões
authors.forename: Milton C
authors.initials: MC
authors.lastname: Foss
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Squiers
authors.forename: Richard K
authors.initials: RK
authors.lastname: Burt
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood; D002096:C-Peptide / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000628:therapy*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006442:Glycated Hemoglobin; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D007328:Insulin / Q000008:administration & dosage; D008297:Male; D011446:Prospective Studies; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous
chemical_list: D001323:Autoantibodies; D002096:C-Peptide; D005968:Glutamate Decarboxylase; D006442:Glycated Hemoglobin; D006454:Hemoglobins; D007328:Insulin; C517652:hemoglobin A1c protein, human