Immune therapy in type 1 diabetes mellitus

Abstract

(200 words) Type 1 diabetes mellitus (T1D) is an autoimmune disorder directed against the pancreatic islet β cells. The genetic risk for the disease is linked to HLA-DQ genotypes and unknown environmental triggers. In most countries, only 10-15% of newly diagnosed T1D children or young adults have a first degree relative with the disease. Autoantibodies against insulin, GAD65, IA-2 or ZnT8 transporter mark islet autoimmunity. These islet autoantibodies may develop already at 1-2 years of age. Immune therapy in T1D is approached at three stages. Primary prevention is treatment of subjects at increased genetic risk. The TRIGR trial is testing if hydrolyzed casein milk formula may reduce T1D in genetically predisposed infants. Secondary prevention is in subjects with persistent islet autoantibodies. On-going trials are either non-autoantigen (BCG, CD3 monoclonal antibodies) or autoantigen (oral and nasal insulin or Alum-formulated GAD65) specific. Intervention at diabetes onset include non-autoantigen (CD3 monoclonal antibodies, IL-2 receptor antibodies, Il-1b receptor inhibitor, Il-1b antibodies, BCG, ATG, DiaPep277) and autoantigen (proinsulin peptides) specific therapy. Although preserved beta-cell function long term has been difficult to achieve in many prior studies, considerable progress is being made through controlled clinical trials and animal investigations to uncover mechanisms of beta-cell destruction. Novel therapies that would prevent islet autoimmunity or halt progressive beta-cell destruction need to be designed.

Impact of anti-glutamic acid decarboxylase-65, anti-insulin and anti-tyrosine phosphatase autoantibodies on disease activity in type 1 diabetes patients

“…Type 1 diabetes (T1D) is a chronic autoimmune disease in which insulin-producing β-cells are located in the pancreatic islets of Langerhans, which are gradually destroyed by autoreactive T cells [2,3,9]. Prospective studies with pre-T1D patients have shown that the process of β-cell degeneration can take more than 3 years before the clinical manifestation and the disease progression occurs in waves or in cycles [24].…”

“…The main effector mechanism is clearly an autoimmune reaction, which is also evident at time of clinical diagnosis. This implies two concepts for clinical treatment: the first one is the knowledge of the cause is more critical for prevention than for at-onset therapy, and the other is at/near-onset therapy requires an immune silencing [2,10,11]. All these debates clearly indicate that several silent immune events occur before the appearance of clinical symptoms in T1D, which strongly suggest that immunological events play a fundamental role in the onset as well as in the progression of T1D.…”

“…Understanding and mapping the precise kinetics of the immune response to the disease has implications for the design of immunomodulatory therapeutics, and the regulatory immune components of T1D could be therapeutically exploited to ultimately suppress the progression of T1D [33][34][35]. However, the temporal and compositional details of the immune regulation that are associated with the onset and progress of T1D remain controversial [2,36]. Autoantibodies are currently the most robust biomarkers of T1D and are frequently used to establish entry criteria for the participation of genetically at-risk individuals in secondary prevention/intervention clinical trials.…”

“…The precise etiology remains uncertain; however, there is a general consensus that T1D is a T-cell mediated disorder that results from immune dysfunctions, with subsequent loss of tolerance to β cell antigens and destructive lymphocytic infiltration of the islets. This, in turn, leads to hyperglycemia [2]. Although unlikely to be intrinsically diabetogenic, circulating autoantibodies targeting pancreatic β cell proteins have been defined [3].…”

“…Although unlikely to be intrinsically diabetogenic, circulating autoantibodies targeting pancreatic β cell proteins have been defined [3]. Monitoring such systemic autoantibodies is currently the most reliable biomarker in the prodromal phase of T1D, since their appearance typically precedes overt T1D onset for years [1,2]. This provides a window for therapeutic intervention, and considerable effort has been devoted for identification of autoantigens as biomarkers of T1D.…”