Cellular Therapy for Type 1 Diabetes: Title and subTitle BreakHas the Time Come?

Type 1 diabetes mellitus (DM) arises from selective immunologically mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans with consequent insulin deficiency.^{1 - 2} This occurs in genetically susceptible individuals and is a cellular-mediated process, presumably a specific reaction to 1 or more beta cell proteins (autoantigens), although probably initiated by some environmental factors. There is consequent progressive impairment of beta cell function and decline in beta cell mass.

The immunologic nature of the type 1 DM disease process was firmly established in humans by studies in the late 1980s and early 1990s demonstrating that immune intervention in patients with newly diagnosed type 1 DM resulted in a slower decline in beta cell function than in control groups.^{3 - 4} Over the last several years, there have been major efforts to interdict the type 1 DM disease process either in newly diagnosed patients^{5 - 6} or in relatives of individuals with type 1 DM in whom evidence of the disease process has been found to be under way.^{7 - 9} Although some promising studies have suggested better sustained beta cell function, no definitive intervention has resulted in an increase of beta cell function. To further the conduct of studies to interdict the type 1 DM disease process, the National Institutes of Health has created a clinical trials network entitled Type 1 Diabetes TrialNet¹⁰ to conduct randomized controlled trials both in patients with new-onset type 1 DM and in relatives at risk for the disease.

In this issue of JAMA, Voltarelli and colleagues¹¹ report provocative findings in a small group of patients who underwent autologous hematopoietic stem cell transplantation (AHSCT) within 6 weeks of receiving a type 1 DM diagnosis. The authors report that patients who underwent AHSCT had increased beta cell function as evidenced by an increment in C-peptide levels and by low levels of hemoglobin A_1c despite very low doses or frank discontinuation of insulin therapy.

The potential use of bone marrow transplantation (BMT) to alter the course of the type 1 DM disease process was first proposed in animal studies in 1985 using allogenic bone marrow.¹² Other animal studies supported the concept.¹³ Human studies in the 1990s suggested that type 1 DM could be transferred to recipients of allogenic BMT^{14 - 15} and that use of allogenic BMT for treatment of malignancy resulted in reversal of several autoimmune diseases including type 1 DM.¹⁶

In the 1990s, several groups examined the potential use of BMT for type 1 DM, particularly focusing on animal models to explore the mechanisms involved.^{17 - 18} Human experience with BMT, particularly in malignant diseases, was improving, such that by the early part of the 2000s, enthusiasm was increasing for testing BMT in humans with autoimmune diseases,^{19 - 20} including calls for BMT to be tested in type 1 DM.^{21 - 22} Meanwhile, use of AHSCT in patients with other autoimmune diseases showed promise—including systemic sclerosis,²³ rheumatoid arthritis,²⁴ refractory Crohn disease,²⁵ and systemic lupus erythematosus.²⁶ A recent review summarized the current status of AHSCT for autoimmune diseases²⁷ despite the lack of understanding of how AHSCT affects the pathological processes of autoimmune diseases.²⁸ Although the goal of AHSCT for patients with autoimmune diseases is to generate new self-tolerant lymphocytes after elimination of self-reactive or autoreactive lymphocytes, other mechanisms have not been excluded, such as generation of relatively larger numbers of regulatory lymphocytes or stem cell differentiation to new healthier cells within the organs being damaged by the autoimmune disease process.

Autologous human stem cell transplantation involves 3 steps: (1) stem cell mobilization of peripheral blood CD34+ cells, (2) conditioning (immune ablation) of the recipient to eliminate self-reactive lymphocytes within the body, and (3) reinfusion of the autologous human stem cells harvested in step 1 and stored in liquid nitrogen until use. Myeloablative conditioning, such as with total lymphoid irradiation, is not used for AHSCT. This 3-step approach was used by Voltarelli et al.¹¹

Voltarelli et al enrolled individuals with new-onset type 1 DM in contrast to the studies of AHSCT in other autoimmune diseases that enrolled individuals with refractory disease. At first blush this might appear to be inappropriate. However, there is demonstrable benefit from immunomodulatory therapies in other autoimmune diseases, whereas in type 1 DM there is not. Moreover, if the target of therapy with AHSCT is the type 1 DM disease process leading to beta cell destruction, this intervention should be applied when sufficient beta cells are available for salvage (ie, relatively early in the course of the disease). Thus, the timing of therapy seems appropriate. In addition, due to the measurement of a single autoantibody (anti-GAD) that may be present in as many as 10% of patients with type 2 DM,²⁹ another question is whether individuals with type 2 DM were inadvertently enrolled; however, the patients are sufficiently well characterized that this is not likely the case. All but 2 patients carried the type 1 DM high-risk HLA alleles DR3,DQB1*0201 or DR4,DQB1*0302, and the other 2 carried the type 1 DM moderate-risk allele DR1,DQB1*0501. All patients were young (aged 15-27 years), and all had a body mass index of less than 25, all presented with weight loss, and all but one presented with significant hyperglycemia; these characteristics are typical of type 1 DM.

Although the study demonstrates a significant improvement in beta cell function as measured by C-peptide levels, there are several important limitations. First, the study design did not include a randomized control group that either received no intervention or received only immunosuppression or immunomodulation. Second, the duration of follow-up for all patients who underwent AHSCT was insufficient to determine whether the apparent improvement in C-peptide levels was sustained. Third, it is not known whether the putative beneficial effects of AHSCT are due to immune reconstitution or otherwise altering the immune-mediated beta cell destruction that eventuates in the type 1 DM disease process or to regeneration of beta cells.³⁰ Fourth, there is the well-known honeymoon period of relative remission after the onset of type 1 DM that complicates interpretation of the results.³¹

Voltarelli et al¹¹ acknowledge these limitations stating “further follow-up is necessary to confirm the duration of insulin independence and the mechanisms of action of the procedure. In addition, randomized controlled trials and further biological studies are necessary to confirm the role of this treatment in changing the natural history of type 1 DM and to evaluate the contribution of hematopoietic stem cells to this change.” These appropriate cautionary notes deserve emphasis to avoid creating false hope based on the preliminary nature of the study results.

This study by Voltarelli et al¹¹ is the first of what likely will be many attempts at cellular therapy to interdict the type 1 DM disease process. Other approaches under consideration include infusion of dendritic cells,^{32 - 33} T-regulatory lymphocytes,³⁴ umbilical cord cells,³⁵ embryonic or adult stem cells,^{36 - 38} and allogenic BMT^{21 ,39} in addition to further studies with AHSCT. Research in this field is likely to explode in the next few years and should include randomized controlled trials as well as mechanistic studies. As these further studies confirm and build on the results of Voltarelli et al¹¹ —the time may indeed be coming for starting to reverse and prevent type 1 DM.