The first large-scale immunosuppressive trial in recent onset T1D studied cyclosporine A in the mid-1980s[27
]. Continuous treatment reduced the need for exogenous insulin; however renal toxicity necessitated cessation of therapy [28
]. After stopping treatment, endogenous insulin production diminished indicating immunologic tolerance to islet antigens was not induced. During the same time period, a pilot study administered horse antithymocyte globulin (ATG) and prednisone to new onset T1D individuals. Again, there was a reduction in insulin requirements; however, toxicity in the form of serum sickness and thrombocytopenia led to a discontinuation of ATG [30
]. A phase II trial using rabbit ATG in new onset T1D is currently ongoing through the Immune Tolerance Network to evaluate the ability of this therapy to slow beta cell loss.
Following extensive studies in animal models [31
] in 2002, Herold and colleagues reported the use of a humanized anti-CD3 monoclonal antibody (mutated in the IgG1 Fc chain to eliminate Fc receptor binding) in new onset T1D patients leading to sustained preservation of c-peptide production lasting up to five years following a single two week treatment () [33
]. Nevertheless after the first year of preservation of C-peptide, further loss of C-peptide appears to proceed in parallel to the slope of placebo treated patients. These results were confirmed by Keymeulen and coworkers with a different mutated anti-CD3 antibody (mutated to remove elimination of glycosylation sites in the Fc chain) reduced the loss of c-peptide in newly diagnosed T1D individuals [36
]. Clinically, A1c and insulin usage improved and there were no long lasting adverse effects. Cytokine release syndrome developed in a number of treated subjects and particularly in the Keymeulen trial there was evidence of EBV reactivation that resolved spontaneously [38
]. Circulating T cell levels returned to pretreatment levels one month following therapy. It is hypothesized that the preserved C-peptide following therapy is not only related to elimination of effector T cells but also the preservation of regulatory T cells. Studies in the NOD mouse, spontaneous animal model of autoimmune diabetes, reveal Tregs in pancreatic lymph nodes of these mice (which were lacking naturally occurring Tregs, CD28−/−
mice) able to inhibit immune responses through a TGF-β-dependent mechanism following anti-CD3 treatment [39
]. Tregs including IL-10 producing CD4+ cells have been isolated from humans treated with the monoclonal antibody [40
] and it is possible that CD8+ Tregs are induced as well [43
]. With the initial success of anti-CD3 monoclonal antibody treatment there are now clinical trials evaluating repeat dosing (AbATE) and use in T1D patients further removed from diagnosis, 4 months to 1 year, still producing c-peptide (DELAY). An anti-CD3 prevention trial is being considered for individuals with multiple islet autoantibodies but without hyperglycemia sponsored through the TrialNet organization [44
Anti-CD3 monoclonal antibody treatment delays loss of C-peptide in new onset patients with type 1 diabetes. From Herold et al Diabetes 54:1763-9, 2005.
T1D is a T cell mediated disease, however, B lymphocytes are implicated in disease pathogenesis as they have been identified in the pancreata of T1D individuals [45
] and likely act as antigen presenting cells. A new onset study with rituximab, an anti-CD20 monoclonal antibody, showed modest improvement in c-peptide production 3 months after therapy but after 6 months the rate of c-peptide loss was similar between the treated and placebo groups [46
]. Clinical responders could be differentiated from nonresponders by the amount of CD19+CD27+IgD+ cell depletion. Concerning was the fact that CD19+ levels did not return to pretreatment levels by one year post treatment and IgM levels remained depressed in the treated cohort. The applicability of this therapy must be weighed against the potential for chronic immune suppression.
There are a number of therapies currently in ongoing clinical trials or just beginning. CTLA4-Ig [47
] is being used to block T cell activation. Anti-CD2 monoclonal antibodies which deplete memory and NK T cells will be used in a new onset T1D trial [48
]. The anti-inflammatory pathway, specifically targeted to IL-1, will also be evaluated in T1D. Many chronic diseases have persistent inflammation such as neurodegenerative diseases, vascular disease, and metabolic diseases (type 2 diabetes) [49
]. Type 2 diabetic patients treated with anakinra, an IL-1 receptor antagonist, improved glycemic control, reduced inflammation, and increased insulin sensitivity [50
]. There appeared to be beneficial β-cells effects, in addition to reduced insulin resistance, as the treated patients had increased insulin:proinsulin ratios compared to controls [51
]. β-cells may produce IL-1 in response to hyperglycemia, thereby perpetuating the cycle of inflammation and lymphocyte recruitment to the pancreas and pancreatic lymph nodes. Trials evaluating IL-1 blockade with anakinra and a monoclonal antibody to IL-1, canikinumab, are underway. Other therapies being used in T1D include alpha-1 antitrypsin (Aralast NP), a serine protease inhibitor, with anti-inflammatory properties [52
] and Gleevec, a tyrosine kinase inhibitor used as a cancer drug to treat leukemia [53
] as well as a peptide of a heat shock protein DiaPep277 (This peptide initially was considered an autoantigen but further studies suggest that it may influence innate immunity)[54
]. Gleevec targets innate immune cells such as inflammatory macrophages involved in diabetes pathogenesis.
A trial of cyclophosphamide and ATG with autologous bone marrow transplantation is probably the most aggressive therapeutic regimen studied in new onset patients [55
]. Probably associated with the severity of immunosuppression there was dramatic improvement n C-peptide secretion lasting several years and a subset of patients were able to discontinue insulin(see section 5 below).