Biomarkers for immune intervention trials in type 1 diabetes

Mallone, Roberto; Roep, Bart O.

doi:10.1016/j.clim.2013.02.009

Cited by 27 publications

(25 citation statements)

References 79 publications

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“…The same problem is encountered in prevention trials. Despite absence of clinical disease, selection of at-risk patients based on positivity for multiple autoantibodies (auto-Abs) underscores the presence of an autoimmune reaction that has already spread to several Ags (5). Prospective cohorts of genetically at-risk children further highlighted that b-cell autoimmunity initiates very early, possibly already during fetal life, as the median age at auto-Ab seroconversion is only 9-18 months (6,7).…”

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confidence: 99%

Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes

et al. 2015

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The first signs of autoimmune activation leading to b-cell destruction in type 1 diabetes (T1D) appear during the first months of life. Thus, the perinatal period offers a suitable time window for disease prevention. Moreover, thymic selection of autoreactive T cells is most active during this period, providing a therapeutic opportunity not exploited to date. We therefore devised a strategy by which the T1D-triggering antigen preproinsulin fused with the immunoglobulin (Ig)G Fc fragment (PPI-Fc) is delivered to fetuses through the neonatal Fc receptor (FcRn) pathway, which physiologically transfers maternal IgGs through the placenta. PPI-Fc administered to pregnant PPI B15-23 T-cell receptor-transgenic mice efficiently accumulated in fetuses through the placental FcRn and protected them from subsequent diabetes development. Protection relied on ferrying of PPI-Fc to the thymus by migratory dendritic cells and resulted in a rise in thymic-derived CD4 + regulatory T cells expressing transforming growth factor-b and in increased effector CD8 + T cells displaying impaired cytotoxicity. Moreover, polyclonal splenocytes from nonobese diabetic (NOD) mice transplacentally treated with PPI-Fc were less diabetogenic upon transfer into NOD.scid recipients. Transplacental antigen vaccination provides a novel strategy for early T1D prevention and, further, is applicable to other immune-mediated conditions.Islet destruction by autoreactive T cells is the hallmark of type 1 diabetes (T1D). Intense research efforts are therefore ongoing to develop immunotherapies aimed at blunting islet autoimmunity. Antigen (Ag)-specific immunotherapies are particularly attractive due to their selectivity and safety (1) but have met with limited success. Several attempts have focused on tolerogenic vaccination with b-cell Ags derived from preproinsulin (PPI) (2), which is the target initiating the autoimmune cascade in nonobese diabetic (NOD) mice (3) and likely also in humans (2). A recent clinical trial employing intranasal insulin in slow-onset T1D patients did not result in C-peptide preservation, despite successful induction of insulin-specific immune tolerance (4). These results suggest that the timing of intervention may be too late and that the Ag spreading that follows early b-cell destruction leads to a diversification of autoimmune reactions beyond insulin, thus making tolerance restoration to this sole Ag insufficient. The same problem is encountered in prevention trials. Despite absence of clinical disease, selection of at-risk patients based on positivity for multiple autoantibodies (auto-Abs) underscores the presence of an autoimmune reaction that has already spread to several Ags (5). Prospective cohorts of genetically at-risk children further highlighted that b-cell autoimmunity initiates very early, possibly already during

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Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes

et al. 2015

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“…pancreatic lymph nodes and spleen) from donors with T1D . This resource will greatly facilitate future translational studies designed to exploit β ‐cell‐reactive CD8 T cells as therapeutic targets and biomarkers to monitor autoimmune activity in at‐risk individuals, islet transplant patients, or those being considered for, or undergoing, intervention protocols …”

Section: Discussionmentioning

confidence: 99%

Glucagon‐reactive islet‐infiltrating CD8 T cells in NOD mice

et al. 2015

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SummaryType 1 diabetes is characterized by T-cell-mediated destruction of the insulin-producing b cells in pancreatic islets. A number of islet antigens recognized by CD8 T cells that contribute to disease pathogenesis in nonobese diabetic (NOD) mice have been identified; however, the antigenic specificities of the majority of the islet-infiltrating cells have yet to be determined. The primary goal of the current study was to identify candidate antigens based on the level and specificity of expression of their genes in mouse islets and in the mouse b cell line MIN6. Peptides derived from the candidates were selected based on their predicted ability to bind H-2K d and were examined for recognition by islet-infiltrating T cells from NOD mice. Several proteins, including those encoded by Abcc8, Atp2a2, Pcsk2, Peg3 and Scg2, were validated as antigens in this way. Interestingly, islet-infiltrating T cells were also found to recognize peptides derived from proglucagon, whose expression in pancreatic islets is associated with a cells, which are not usually implicated in type 1 diabetes pathogenesis. However, type 1 diabetes patients have been reported to have serum autoantibodies to glucagon, and NOD mouse studies have shown a decrease in a cell mass during disease pathogenesis. Our finding of isletinfiltrating glucagon-specific T cells is consistent with these reports and suggests the possibility of a cell involvement in development and progression of disease.

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“…B cells are unable to prime naive T cells (41); the ability of B cells to act as APC largely depends on the capacity of B cells to take up autoantigens through Ag-specific autoantibodies on their surface, which requires help from activated T cells that are primed by DC. In T1D, B cells produce autoantibodies against several autoantigens, including insulin, IA-2, and GAD65, providing diagnostic and prognostic biomarkers for disease development (42,43). B cells not expressing Ag-specific autoantibodies are inefficient APC.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cells Guide Islet Autoimmunity through a Restricted and Uniquely Processed Peptidome Presented by High-Risk HLA-DR

Lummel

Veelen

et al. 2016

The Journal of Immunology

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Identifying T cell epitopes of islet autoantigens is important for understanding type 1 diabetes (T1D) immunopathogenesis and to design immune monitoring and intervention strategies in relationship to disease progression. Naturally processed T cell epitopes have been discovered by elution from HLA-DR4 of pulsed B lymphocytes. The designated professional APC directing immune responses is the dendritic cell (DC). To identify naturally processed epitopes, monocyte-derived DC were pulsed with preproinsulin (PPI), glutamic acid decarboxylase (65-kDa isoform; GAD65), and insulinoma-associated Ag-2 (IA-2), and peptides were eluted of HLA-DR3 and -DR4, which are associated with highest risk for T1D development. Proteome analysis confirmed uptake and processing of islet Ags by DC. PPI peptides generated by DC differed from those processed by B lymphocytes; PPI signal-sequence peptides were eluted from HLA-DR4 and -DR3/4 that proved completely identical to a primary target epitope of diabetogenic HLA-A2–restricted CD8 T cells. HLA-DR4 binding was confirmed. GAD65 peptides, eluted from HLA-DR3 and -DR4, encompassed two core regions overlapping the two most immunodominant and frequently studied CD4 T cell targets. GAD65 peptides bound to HLA-DR3. Strikingly, the IA-2 ligandome of HLA-DR was exclusively generated from the extracellular part of IA-2, whereas most previous immune studies have focused on intracellular IA-2 epitopes. The newly identified IA-2 peptides bound to HLA-DR3 and -DR4. Differential T cell responses were detected against the newly identified IA-2 epitopes in blood from T1D patients. The core regions to which DC may draw attention from autoreactive T cells are largely distinct and more restricted than are those of B cells. GAD65 peptides presented by DC focus on highly immunogenic T cell targets, whereas HLA-DR–binding peptides derived from IA-2 are distinct from the target regions of IA-2 autoantibodies.

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Biomarkers for immune intervention trials in type 1 diabetes

Cited by 27 publications

References 79 publications

Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes

Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes

Glucagon‐reactive islet‐infiltrating CD8 T cells in NOD mice

Dendritic Cells Guide Islet Autoimmunity through a Restricted and Uniquely Processed Peptidome Presented by High-Risk HLA-DR

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