Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes.

Follicular helper T (T) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether T cells were decreased by costimulation blockade using the CTLA-4-immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS) T cells and other ICOS populations, including peripheral helper T cells, were highly sensitive to costimulation blockade.

Assessing effector T cells in type 1 diabetes.

Purpose Of Review: The role of T cells specific for islet autoantigens is proven in pathogenesis of type 1 diabetes. Recently, there has been rapid expansion in the number of T-cell subsets identified, this has coincided with an increase in the repertoire of reported islet antigens mainly through the discovery of novel epitopes. A discussion of how these marry together is now warranted and timely.

Costimulation Blockade Disrupts CD4 T Cell Memory Pathways and Uncouples Their Link to Decline in β-Cell Function in Type 1 Diabetes.

We previously reported that costimulation blockade by abatacept limits the decline of β-cell function and the frequency of circulating CD4 central memory T cells (T) (CD45ROCD62L) in new-onset type 1 diabetes. In human subjects receiving placebo, we found a significant association between an increase in CD4 T cells and the decline of β-cell function. To extend and refine these findings, we examined changes in human CD4 and CD8 naive and memory T cell subsets at greater resolution using polychromatic flow and mass cytometry.

Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes.

The signal peptide region of preproinsulin (PPI) contains epitopes targeted by HLA-A-restricted (HLA-A0201, A2402) cytotoxic T cells as part of the pathogenesis of β-cell destruction in type 1 diabetes. We extended the discovery of the PPI epitope to disease-associated and (risk) and and (protective) alleles, revealing that four of six alleles present epitopes derived from the signal peptide region. During cotranslational translocation of PPI, its signal peptide is cleaved and retained within the endoplasmic reticulum (ER) membrane, implying it is processed for immune recognition outside of the canonical proteasome-directed pathway.

New insights into non-conventional epitopes as T cell targets: The missing link for breaking immune tolerance in autoimmune disease?

The mechanism by which immune tolerance is breached in autoimmune disease is poorly understood. One possibility is that post-translational modification of self-antigens leads to peripheral recognition of neo-epitopes against which central and peripheral tolerance is inadequate. Accumulating evidence points to multiple mechanisms through which non-germline encoded sequences can give rise to these non-conventional epitopes which in turn engage the immune system as T cell targets.

T cells in type 1 diabetes: Instructors, regulators and effectors: A comprehensive review.

Type 1 diabetes was one of the earliest disorders to be associated with the phenomenon of autoimmunity and is one of the most studied organ-specific autoimmune diseases at the epidemiologic, immunologic and genetic level. Despite this, and the emergence of a plethora of strategies for trying to intervene in, or prevent the disease, it remains at some distance from being reliably and safely tractable by immunotherapy, a source of great frustration in this research field. In this article we review some of the key concepts that might impact upon this lack of success in the clinic going forward.

Heterogeneity in the Locomotory Behavior of Human Monocyte Subsets over Human Vascular Endothelium In Vitro.

Human monocytes comprise three distinct subsets, defined by their relative expression of CD14 and CD16. These subsets appear to have different functional roles within homeostasis and inflammation, but little is known about the manner in which they interact with macro- and microvascular endothelial cells, a key enabling component for the fulfillment of their functional roles. In the present study, we examined the locomotory behavior of the three major human monocyte subsets over human endothelial monolayers subjected to physiologically relevant levels of shear flow in vitro.

β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure.

Autoreactive CD8 T cells play a central role in the destruction of pancreatic islet β-cells that leads to type 1 diabetes, yet the key features of this immune-mediated process remain poorly defined. In this study, we combined high-definition polychromatic flow cytometry with ultrasensitive peptide-human leukocyte antigen class I tetramer staining to quantify and characterize β-cell-specific CD8 T cell populations in patients with recent-onset type 1 diabetes and healthy control subjects. Remarkably, we found that β-cell-specific CD8 T cell frequencies in peripheral blood were similar between subject groups.

Human β-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly granule-mediated with the potency dependent upon T-cell receptor avidity.

The end-stage immunopathology of type 1 diabetes resulting in β-cell destruction appears to be strongly dominated by cytotoxic CD8 T lymphocytes (CD8 T cells). However, the mechanism of cytotoxicity used by autoreactive CD8 T cells in the human setting remains unknown. Using type 1 diabetes patient-derived preproinsulin-specific CD8 T-cell clones recognizing either an HLA-A2 (A*0201) or HLA-A24 (A*2402)-restricted epitope (peptide of preproinsulin [PPI](15-24), ALWGPDPAAA; or PPI(3-11), LWMRLLPLL), we assessed the use of conventional mediators of cytotoxicity in the destruction of human β-cells in vitro compared with virus-specific cytotoxic CD8 T-cell clones.

Circulating preproinsulin signal peptide-specific CD8 T cells restricted by the susceptibility molecule HLA-A24 are expanded at onset of type 1 diabetes and kill β-cells.

Type 1 diabetes results from T cell-mediated β-cell destruction. The HLA-A*24 class I gene confers significant risk of disease and early onset. We tested the hypothesis that HLA-A24 molecules on islet cells present preproinsulin (PPI) peptide epitopes to CD8 cytotoxic T cells (CTLs).

Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

Background: The activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab combined with oxaliplatin/leucovorin/5-fluorouracil (FUFOX) was assessed in first-line metastatic gastric and oesophago-gastric junction (OGJ) cancer in a prospective phase II study showing a promising objective tumour response rate of 65% and a low mutation frequency of KRAS (3%). The aim of the correlative tumour tissue studies was to investigate the relationship between EGFR gene copy numbers, activation of the EGFR pathway, expression and mutation of E-cadherin, V600E BRAF mutation and clinical outcome of patients with gastric and OGJ cancer treated with cetuximab combined with FUFOX.

Methods: Patients included in this correlative study (n = 39) were a subset of patients from the clinical phase II study.