Type 1 diabetes mellitus is one of the most prevalent diseases in childhood. In addition to its financial costs and the need for daily insulin injections for survival, the concerns of long term complications are paramount, since every individual suffers in some way from acute (e.g. hypoglycemia) or chronic complications (nephropathy, neuropathy) of the disease: a curative therapy is desperately needed. At present, efforts to prevent or reverse diabetes have been limited by the absence of immunosuppressive/tolerogenic drugs that can be used both safely and effectively. Various studies have shown that relatively non-specific therapies (anti-CD3, Thymoglobulin) can be efficacious, in contrast to other more specific antigen-specific therapies (DPT-1/Insulin). Importantly, two substantial findings have emerged from these studies: first, that short term immune regulation of T cells can have a long-term effect on disease progression; and second, that immunomodulatory anti-T cell agents, in both animal and human studies, induce a regulatory T cell subset that is likely to be responsible for the long lived efficacy.

The identification of regulatory T lymphocytes (Treg) and the discovery of their importance in the effective regulation of the basic processes that maintain tolerance have opened an important new means of therapeutic intervention in immunology. Impairment in the number and/or function of this specialized T cell population has been implicated in a variety of autoimmune diseases, where their presence can be instrumental in preventing disease progression. Moreover, Tregs have a unique and highly robust therapeutic profile: while requiring specific T cell receptor (TCR)-mediated activation to develop regulatory activity, their effector function appears to work by bystander suppression, regulating local inflammatory responses through a combination of cell-cell contact and suppressive cytokine production.

While it is certain that the potential of Tregs is now well-established in animal models, there have as yet been no clinical studies of adoptive immunotherapy with Tregs. Its application has thus far been limited by an inability to define antigenic specificities of Tregs, small numbers of circulating Treg cells and difficulties in expanding functional Treg populations in vitro. Indeed, many questions remain that will need to be answered as we move towards the clinic.

Can antigen-specific Tregs be identified and expanded from patients with T1D or are the cells defective as has been suggested? Can we define cell surface and intracellular markers of Tregs that will allow more effective identification and isolation, reducing the risk of effector cell contamination? Will the Tregs function normally in the recipients? Does the regulatory effect of these cells require antigen specificity or is it general for all immune responses? Is the effectiveness of Tregs determined by the Ag specificity, the activation state of the target cell, or particular phenotype of the regulated cell? What is the duration of their regulatory effect? What are the implications of using various immunotherapies alone or in combination with Tregs to induce tolerance in the setting of an ongoing autoimmune disease? Are other cell types (either T cells or non T cells) potential immune regulators that can complement or replace current Tregs? Can state-of-the-art technologies permit scaling up Treg production and clinical application in a safe and effective manner?

These critical questions and others will be addressed in the proposed JDRF COLLABORATIVE CENTER FOR CELL THERAPY. In fact, the investigators of the proposed center have begun laying the necessary groundwork for the clinical investigation of T regulatory cell therapy. Recently, our program members have developed new innovative methods for expanding polyclonal and antigen-specific Tregs. Importantly, the investigators in this Center have not only been at the forefront of developing tools to expand and differentiate potent Tregs in the diabetes setting, they have extensive, demonstrated experience in bringing novel immunotherapies to the T1D clinical arena. The JDRF COLLABORATIVE CENTER FOR CELL THERAPY will take advantage of long and productive research and organizational collaborations in regulatory cell immunobiology and T cell expansion to establish a clinical effort to translate regulatory T cell therapy into patients with Type 1 Diabetes.