Type 1 diabetes (T1D) is a chronic autoimmune disorder thought to be caused by pro-inflammatory autoreactive T cells which mediate the destruction of insulin-producing pancreatic β cells via both direct and indirect mechanisms leading to lifelong dependence on exogenous insulin (Atkinson and Eisenbarth, 2001
). Development of T1D is genetically controlled and thought to be initiated in susceptible individuals by environmental factors such as virus infections, although a viral cause has not been clearly identified (von Herrath, 2009
). While both humoral and cell-mediated immune mechanisms are active during diabetes, CD4+
T cells occupy a critical role in T1D pathology (Anderson and Bluestone, 2005
) as exemplified by the observation that the majority of the genes associated with elevated disease risk relate to the function of CD4+
Th cells [e.g.
a trio of MHC II alleles (Concannon et al., 2009
)]. Prior to diagnosis of overt T1D, the pancreatic islets are infiltrated by inflammatory cells including CD4+
T cells (Kent et al., 2005
) and antibodies to various β cell antigens are demonstrable in the sera of patients at risk (Achenbach et al., 2005
Because of the ocular, circulatory, cardiovascular and neurological risks associated with hyperglycemia, treatments which prevent the pathologic autoimmunity from destroying pancreatic tissue is preferable to long-term management of symptoms by insulin replacement therapy since use of exogenous insulin cannot match the precision of endogenous insulin secretion. Much of what is understood about the pathogenesis and regulation of T1D has emerged from the study of spontaneous disease in the non-obese diabetic (NOD) mouse. NOD studies have highlighted the critical role of adaptive immune responses in disease pathogenesis as well as identifying various targets which prevent diabetogenic autoimmune responses as prime therapeutic candidates (Atkinson and Leiter, 1999
; Shoda et al., 2005
). However, it is critical to understand that there are numerous differences in the pathogenic mechanisms driving the initiation and progression of disease in the NOD mouse vs. human type 1 diabetics, e.g.
major differences in the antigens targeted, the composition of inflammatory cell infiltrates in the two species, as well as greatly increased expression of MHC class I in humans (Gianani et al., 2010
Existing and emerging therapies aimed at regulating the autoimmune response largely involve broad-based immunoregulatory strategies, including the inhibition or deletion of lymphocytes subsets and/or use of agents proposed to induce or re-establish immune tolerance via activation of regulatory T cells (Tregs), e.g.
non-mitogenic anti-CD3 or anti-thymocyte globulin (Chatenoud, 2003
; Chatenoud et al., 2001
; Chung et al., 2007
; Kohm et al., 2005
). Some of these have shown efficacy in initial clinical trials, but there are risks with any of the broad approaches such as cytokine release and/or reactivation of latent viruses. A highly desired alternative approach is the attempted induction of antigen-specific tolerance to β cell antigens for prevention of disease development in patients at risk or in new onset patients. This review will discuss immunoregulatory strategies employed as monotherapies or in combination, including the use of antigen-specific tolerance strategies, which are under evaluation in clinical trials and/or are being developed based on demonstrated efficacy in preventing or ameliorating disease progression in the NOD mice.
There are numerous pitfalls to the translation of laboratory findings to the clinic. Trials of therapies that alter the natural history of T1D have been hampered by the lack of biomarkers of the immune processes that causes the disease. There are immunologic “readouts” that correlate with the presence of T1D, for instance, the presence of autoantibodies against islet cell antigens including glutamic acid decarboxylase 65 (GAD65), insulin, islet cell antigen 512 (ICA512), and more recently zinc transporter 8 (ZnT8) have supported the autoimmune nature of the disease and have clearly differentiated T1D from Type 2 diabetes where these markers are not found (Seyfert-Margolis et al., 2006
). More recently, cellular proliferation assays to islet specific proteins have distinguished responses in patients from normal control subjects (Herold et al., 2009
). Other assays have identified antigen-specific cells in the circulation (Pinkse et al., 2005
). However, the direct causal relationship between these measures and disease has not yet been established. For instance,
in studies in which glycemic control has been modified [e.g.
Cyclosporin A (CSA) or anti-CD3 monoclonal antibody (mAb)] there were no identified changes in titers of autoantibodies (Bougneres et al., 1988
; Herold et al., 2005
; Herold et al., 2002
; Keymeulen et al., 2005
). Thus, an assay that would reflect tolerance to the immune process in T1D is not currently available, but highly sought after.
Immunologic assays may be used as measures of the effects of immune therapies, but their relationship to the disease process remains speculative. One is left with metabolic parameters as endpoints. Although the relationship of these endpoints to the clinical situation is clearer, it is important to recognize that the most widely employed studies are functional, not anatomic. For example, in murine studies of treatment with CD3 mAb at the diagnosis of T1D in NOD mice, improvement in insulin secretion reflected the recovery of degranulated β cells rather than growth of new cells (Sherry et al., 2006
). Even the relationship between improved metabolic function and the sequelae of the disease is controversial, but clinical data have suggested a direct relationship between the two (Palmer et al., 2004