Prediction and prevention of type 1 diabetes: update on success of prediction and struggles at prevention

Abstract

Type 1 diabetes mellitus (T1DM) is the archetypal example of a T cell-mediated autoimmune disease characterized by selective destruction of pancreatic β cells. The pathogenic equation for T1DM presents a complex interrelation of genetic and environmental factors, most of which have yet to be identified. On the basis of observed familial aggregation of T1DM, it is certain that there is a decided heritable genetic susceptibility for developing T1DM. The well-known association of T1DM with certain human histocompatibility leukocyte antigen (HLA) alleles of the major histocompatibility complex (MHC) was a major step toward understanding the role of inheritance in T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (e.g., HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3/DQ2) or DRB1*04-DQB1*0302 (DR4/DQ8)]. In addition, the HLA allele DQB1*0602 is associated with dominant protection from T1DM in multiple populations. A concordance rate lower than 100% between monozygotic twins indicates a potential involvement of environmental factors on disease development. The detection of at least two islet autoantibodies in the blood is virtually pre-diagnostic for T1DM. The majority of children who carry these biomarkers, regardless of whether they have an a priori family history of the disease, will develop insulin-requiring diabetes. Facilitating pre-diagnosis is the timing of seroconversion which is most pronounced in the first 2 yr of life. Unfortunately the significant progress in improving prediction of T1DM has not yet been paralleled by safe and efficacious intervention strategies aimed at preventing the disease. Herein we summarize the chequered history of prediction and prevention of T1DM, describing successes and failures alike, and thereafter examine future trends in the exciting, partially explored field of T1DM prevention.

Keywords: autoantibodies; diabetes; prediction of type 1 diabetes; prevention of type 1; type 1 diabetes.

Figure 1

A: The rate of progression to T1DM development in relatives negative for ICA512bdc carrying GAD65 in the absence (dashed line) or presence (solid line) of autoantibodies reacting with IA-2 full length (IA-2FL) (amino acids 1–979) (log rank P = 0.016). In this subgroup of relatives, the cumulative risk of developing insulin requiring diabetes in IA-2 full length antibody positive FDR was strikingly high, being 100% by 11 years of follow-up in GAD65 antibody positives (log rank P = 0.026). B: This effect was also observed in FDR selected for being negative for ICA512bdc having at least 2 islet autoantibodies in the absence (dashed line) or presence (solid line) of autoantibodies reacting with IA-2 full length (IA-2FL) (amino acids 1–979) (log rank, P = 0.003). In these relatives the cumulative risk of progressing to overt diabetes was 100% by 10 years of follow-up (log rank P = 0.022) (20). (With permission from Endocrinology)

Figure 2

Schematic representation of initiation of the immunologic response to an autoantigen. The antigen binds to a groove in MHC class II molecules on antigen-presenting cells (APCs). This binding allows the antigen to be presented to antigen receptors on autoreactive CD4 inducer or helper T cells which, in T1DM, mediate immune-mediated injury to the pancreatic β cells. Furthermore, the respective binding of B7 proteins and lymphocyte functional antigen-3 (LFA-3) on APCs to CD28 and CD2 on T cells are important costimulatory pathways that further enhance T cell activation. Other molecules can also participate in the immune response, such as the binding of interleukin-2 to its receptor (IL-2R). Both regulatory (Treg) and effector T lymphocytes are produced and their balance is crucial for maintaining tolerance (183).

Figure 3

The trimolecular complex and therapies targeting each component. The trimolecular complex consists of a T cell receptor, self-peptide, and HLA class II molecule. Potential therapies include: (a) a small molecule (black circle) occupies a pocket in the HLA peptide binding groove thereby blocking peptide presentation and subsequent T cell activation or a small molecule induces a protective immune response (IL10 production), (b) a monoclonal antibody can bind a specific peptide/MHC complex to block T cell activation, or (c) a monoclonal antibody targets a specific T cell receptor α or β chain to deplete pathogenic T cells.

Figure 4

Monoclonal antibody mAb287 delays diabetes and islet lymphocyte infiltration in NOD mice. (A) Groups of 4-wk-old female NOD mice were treated weekly with PBS (n = 18; black squares), 0.1 mg of mouse IgG1 (n = 18; blue diamonds), 0.1 mg of mAb287 (n = 15; green circles), or 0.5 mg of mAb287 (n = 18; red triangles), and followed up to 30 wk. The percentages of diabetes free mice are shown. (B–D) Groups of eight mice were treated weekly from age 4–11 wk with 0.5 mg of control IgG1 (red bars) or mAb287 (blue bars) at which time pancreatic islets were pooled in each group. (B) The average number of live CD4 T cells, CD8 T cells, and 220⁺ B cells per pancreas. (C) The percentages of CD4 T cells specifically binding the IA^g7–R3:RE, IA^g7-R3:RGE or IA^g7-chromogranin A (ChgA) tetramers, or CD8 T cells specifically binding the K^d-IGRP tetramer. (D) Average number of islet-infiltrating tetramer-positive cells per pancreas were calculated from the data in B and C (179) (With permission from the Proceedings of the National Academy of Sciences).