Authors: Júlio C. Voltarelli, MD, PhD; Carlos E. B. Couri, MD, PhD; Ana B. P. L. Stracieri, MD, PhD; Maria C. Oliveira, MD, MSc; Daniela A. Moraes, MD; Fabiano Pieroni, MD, PhD; Marina Coutinho, MD, MSc; Kelen C. R. Malmegrim, PhD; Maria C. Foss-Freitas, MD, PhD; Belinda P. Simões, MD, PhD; Milton C. Foss, MD, PhD; Elizabeth Squiers, MD; Richard K. Burt, MD
Summary: Type 1 diabetes mellitus (DM) results from a cell-mediated autoimmune attack against pancreatic beta cells.1 The course of autodestruction is subclinical until the amount of beta-cell mass is insufficient to maintain glucose homeostasis. Thus, at the time of clinical diagnosis, approximately 60% to 80% of the beta-cell mass has been destroyed.2
Type 1 DM comprises only 5% to 10% of all diabetic etiologies but is associated with a high frequency of vascular complications and compromises quality and expectancy of life.3-4 Patients with type 1 DM depend on exogenous insulin administration for survival and for control of long-term complications. The best-established treatment is tight control of blood glucose achieved by frequent daily injections or continuous subcutaneous infusion of insulin, ie, intensive insulin therapy. This treatment reduces the risk of retinopathy, nephropathy, and neuropathy by 35% to 90% when compared with conventional therapy with 1 to 2 injections per day.5
Subgroup analysis of the Diabetes Control and Complications Trial showed that patients with a larger beta cell reserve demonstrable by serum C-peptide levels presented a slower decline of these levels during the study and experienced fewer microvascular complications than patients with low or undetectable C-peptide concentrations. Therefore, beta cell preservation is another important target in the management of type 1 DM and in the prevention of its related complications.6
Many clinical trials have evaluated the role of immunointervention in preventing residual beta cell loss by blocking the autoimmune response with prednisone,7 azathioprine,8-9 prednisone plus azathioprine,10 cyclosporine,11 antibodies against CD3,12-13 heat shock protein,14 and rabbit antithymocyte globulin.15 These therapies were shown to induce a slower decline or some improvement in C-peptide levels when compared with placebo groups. However, almost all patients required exogenous insulin use.
Since 1996, organ-threatening systemic lupus erythematosus16 and other autoimmune diseases17 have been successfully treated with high-dose immunosuppression followed by autologous nonmyeloablative hematopoietic stem cell transplantation (AHST). Organ function was salvaged and in many cases improved following AHST. In animal models, allogeneic bone marrow transplantation prevents both insulitis and the development of type 1 DM in susceptible strains of mice.18
On the basis of these observations, we initiated a phase 1/2 study in November 2003 analyzing the safety, metabolic effects, and ability of AHST to preserve beta cell function in patients with newly diagnosed type 1 DM. Here we report the first prospective trial, to our knowledge, of stem cell therapy in human DM. We describe 15 patients with type 1 DM, submitted to AHST, and observed from 7 to 36 months (mean 18.8 months) after treatment.
Source:
JAMA. No. 14, April 11, 2007, 2007;297:1568-1576.