scholarly journals Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Noémie Corcos ◽  
Slobodan Culina ◽  
Claire Deligne ◽  
Cassandra Lavaud ◽  
Sylvaine You ◽  
...  
Keyword(s):  
Diabetes Prevention ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Fc Receptor ◽  
Antigen Delivery ◽  
Dependent Manner ◽  
Neonatal Fc Receptor ◽  
Central Tolerance ◽  
Antigen Presenting

Tolerogenic vaccinations using beta-cell antigens are attractive for type 1 diabetes prevention, but clinical trials have been disappointing. This is probably due to the late timing of intervention, when multiple auto-antibodies are already present. We therefore devised a strategy to introduce the initiating antigen preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy employs an oral administration of PPI-Fc, i.e. PPI fused with an IgG Fc to bind the intestinal neonatal Fc receptor (FcRn) that physiologically delivers maternal antibodies to the offspring during breastfeeding. Neonatal oral PPI-Fc vaccination did not prevent diabetes development in PPI T-cell receptor-transgenic G9C8.NOD mice. However, PPI-Fc was efficiently transferred through the intestinal epithelium in an Fc- and FcRn-dependent manner, was taken up by antigen presenting cells, and reached the spleen and thymus. Although not statistically significant, neonatal oral PPI-Fc vaccination delayed diabetes onset in polyclonal Ins2-/-.NOD mice that spontaneously develop accelerated diabetes. Thus, this strategy shows promise in terms of systemic and thymic antigen delivery via the intestinal FcRn pathway, but the current PPI-Fc formulation/regimen requires further improvements to achieve diabetes prevention.

Human mucosal-associated invariant T cells respond to Mucorales species in a MR1-dependent manner

2020 ◽  
Author(s):  
Sarah Böttcher ◽  
Susann Hartung ◽  
Florian Meyer ◽  
Silke Rummler ◽  
Kerstin Voigt ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Activation ◽  
Cell Receptor ◽  
Mucor Circinelloides ◽  
Dependent Manner ◽  
Rhizopus Microsporus ◽  
Mait Cells ◽  
Cd107a Expression ◽  
Invariant T Cells ◽  
Antigen Presenting

Abstract Activation of mucosal-associated invariant T cells (MAIT cells) by certain bacteria, viruses, and yeast is well studied, but the activation potential of filamentous moulds from the order Mucorales is not known. Here, we show a rapid response of human MAIT cells against the Mucorales species Mucor circinelloides, Rhizopus arrhizus, and Rhizopus microsporus. This activation included upregulation of CD69 and degranulation marked by increased CD107a expression, while intracellular perforin and granzyme A expression were reduced. Furthermore, blocking of the antigen-presenting molecule major histocompatibility complex class I-related abrogated MAIT cell activation demonstrating a T cell receptor-dependent stimulation by Mucorales.

Anti-α/β T cell receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in nonobese diabetic (NOD) mice

1991 ◽  
Vol 21 (5) ◽  
pp. 1163-1169 ◽  
Author(s):  
Pascal Sempé ◽  
Pierre Bédossa ◽  
Marie-Francoise Richard ◽  
Maria-Carme Villà ◽  
Jean-Francois Bach ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
T Cell Receptor ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Nonobese Diabetic ◽  
Receptor Monoclonal Antibody

scholarly journals Dendritic cell–expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice

2007 ◽  
Vol 204 (1) ◽  
pp. 191-201 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Lucine Petit ◽  
Xiaopan Zuo ◽  
Priscilla Toy ◽  
Xunrong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Suppressor T Cells ◽  
Nonobese Diabetic ◽  
Glucose Challenge ◽  
Infiltrating Lymphocytes

Most treatments that prevent autoimmune diabetes in nonobese diabetic (NOD) mice require intervention at early pathogenic stages, when insulitis is first developing. We tested whether dendritic cell (DC)–expanded, islet antigen–specific CD4+ CD25+ suppressor T cells could treat diabetes at later stages of disease, when most of the insulin-producing islet β cells had been destroyed by infiltrating lymphocytes. CD4+ CD25+ CD62L+ regulatory T cells (T reg cells) from BDC2.5 T cell receptor transgenic mice were expanded with antigen-pulsed DCs and IL-2, and were then injected into NOD mice. A single dose of as few as 5 × 104 of these islet-specific T reg cells blocked diabetes development in prediabetic 13-wk-old NOD mice. The T reg cells also induced long-lasting reversal of hyperglycemia in 50% of mice in which overt diabetes had developed. Successfully treated diabetic mice had similar responses to glucose challenge compared with nondiabetic NOD mice. The successfully treated mice retained diabetogenic T cells, but also had substantially increased Foxp3+ cells in draining pancreatic lymph nodes. However, these Foxp3+ cells were derived from the recipient mice and not the injected T reg cells, suggesting a role for endogenous T reg cells in maintaining tolerance after treatment. Therefore, inoculation of DC-expanded, antigen-specific suppressor T cells has considerable efficacy in ameliorating ongoing diabetes in NOD mice.

scholarly journals Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

2020 ◽  
Author(s):  
Heejoo Kim ◽  
Jelena Perovanovic ◽  
Arvind Shakya ◽  
Zuolian Shen ◽  
Cody N. German ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Target Genes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Glucose Levels ◽  
Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

scholarly journals Podocyte-specific knockout of the neonatal Fc receptor (FcRn) results in differential protection depending on the model of glomerulonephritis

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0230401
Author(s):  
James F. Dylewski ◽  
Pantipa Tonsawan ◽  
Gabriela Garcia ◽  
Linda Lewis ◽  
Judith Blaine
Keyword(s):  
Antigen Presentation ◽  
Fc Receptor ◽  
Differential Protection ◽  
Wild Type ◽  
Neonatal Fc Receptor ◽  
Crescent Formation ◽  
Immune Mediated ◽  
The Difference ◽  
Antigen Presenting ◽  
Mhcii Expression

Podocytes have been proposed to be antigen presenting cells (APCs). In traditional APCs, the neonatal Fc receptor (FcRn) is required for antigen presentation and global knockout of FcRn protects against glomerulonephritis. Since podocytes express FcRn, we sought to determine whether the absence of podocyte FcRn ameliorates immune-mediated disease. We examined MHCII and costimulatory markers expression in cultured wild type (WT) and FcRn knockout (KO) podocytes. Interferon gamma (IFNγ) induced MHCII expression in both WT and KO podocytes but did not change CD80 expression. Neither WT nor KO expressed CD86 or inducible costimulatory ligand (ICOSL) at baseline or with IFNγ. Using an antigen presentation assay, WT podocytes but not KO treated with immune complexes induced a modest increase in IL-2. Induction of the anti-glomerular basement membrane (anti-GBM) model resulted in a significant decrease in glomerular crescents in podocyte-specific FcRn knockout mouse (podFcRn KO) versus controls but the overall percentage of crescents was low. To examine the effects of the podocyte-specific FcRn knockout in a model with a longer autologous phase, we used the nephrotoxic serum nephritis (NTS) model. We found that the podFcRn KO mice had significantly reduced crescent formation and glomerulosclerosis compared to control mice. This study demonstrates that lack of podocyte FcRn is protective in immune mediated kidney disease that is dependent on an autologous phase. This study also highlights the difference between the anti-GBM model and NTS model of disease.

scholarly journals CCR4 promotes medullary entry and thymocyte–dendritic cell interactions required for central tolerance

2015 ◽  
Vol 212 (11) ◽  
pp. 1947-1965 ◽  
Author(s):  
Zicheng Hu ◽  
Jessica N. Lancaster ◽  
Chayanit Sasiponganan ◽  
Lauren I.R. Ehrlich
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
Time Lapse ◽  
Cell Receptor ◽  
Peripheral Tolerance ◽  
Central Tolerance ◽  
Self Tolerance ◽  
Thymic Medulla ◽  
Antigen Presenting

Autoimmunity results from a breakdown in central or peripheral tolerance. To establish central tolerance, developing T cells must enter the thymic medulla, where they scan antigen-presenting cells (APCs) displaying a diverse array of autoantigens. If a thymocyte is activated by a self-antigen, the cell undergoes either deletion or diversion into the regulatory T cell (T reg) lineage, thus maintaining self-tolerance. Mechanisms promoting thymocyte medullary entry and interactions with APCs are incompletely understood. CCR4 is poised to contribute to central tolerance due to its expression by post-positive selection thymocytes, and expression of its ligands by medullary thymic dendritic cells (DCs). Here, we use two-photon time-lapse microscopy to demonstrate that CCR4 promotes medullary entry of the earliest post-positive selection thymocytes, as well as efficient interactions between medullary thymocytes and DCs. In keeping with the contribution of thymic DCs to central tolerance, CCR4 is involved in regulating negative selection of polyclonal and T cell receptor (TCR) transgenic thymocytes. In the absence of CCR4, autoreactive T cells accumulate in secondary lymphoid organs and autoimmunity ensues. These studies reveal a previously unappreciated role for CCR4 in the establishment of central tolerance.

Linkage on chromosome 3 of autoimmune diabetes and defective Fc receptor for IgG in NOD mice

Science ◽  
1993 ◽  
Vol 260 (5108) ◽  
pp. 695-698 ◽  
Author(s):  
J. Prins ◽  
J. Todd ◽  
N. Rodrigues ◽  
S Ghosh ◽  
P. Hogarth ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Fc Receptor ◽  
Chromosome 3

scholarly journals Targeting the Neonatal Fc Receptor for Antigen Delivery Using Engineered Fc Fragments

2008 ◽  
Vol 181 (11) ◽  
pp. 7550-7561 ◽  
Author(s):  
Wentao Mi ◽  
Sylvia Wanjie ◽  
Su-Tang Lo ◽  
Zhuo Gan ◽  
Beatrix Pickl-Herk ◽  
...  
Keyword(s):  
Fc Receptor ◽  
Antigen Delivery ◽  
Neonatal Fc Receptor

scholarly journals Single-chain Variable Fragment Albumin Fusions Bind the Neonatal Fc Receptor (FcRn) in a Species-dependent Manner

2013 ◽  
Vol 288 (33) ◽  
pp. 24277-24285 ◽  
Author(s):  
Jan Terje Andersen ◽  
Jason Cameron ◽  
Andrew Plumridge ◽  
Leslie Evans ◽  
Darrell Sleep ◽  
...  
Keyword(s):  
Fc Receptor ◽  
Dependent Manner ◽  
Single Chain Variable Fragment ◽  
Single Chain ◽  
Neonatal Fc Receptor

scholarly journals Revealing the specificity of regulatory T cells in murine autoimmune diabetes

2018 ◽  
Vol 115 (20) ◽  
pp. 5265-5270 ◽  
Author(s):  
Allyson Spence ◽  
Whitney Purtha ◽  
Janice Tam ◽  
Shen Dong ◽  
Youmin Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Activation Markers ◽  
Nonobese Diabetic ◽  
Organ Specific ◽  
Control Organ

Regulatory T cells (Tregs) control organ-specific autoimmunity in a tissue antigen-specific manner, yet little is known about their specificity in a natural repertoire. In this study, we used the nonobese diabetic (NOD) mouse model of autoimmune diabetes to investigate the antigen specificity of Tregs present in the inflamed tissue, the islets of Langerhans. Compared with Tregs present in spleen and lymph node, Tregs in the islets showed evidence of antigen stimulation that correlated with higher proliferation and expression of activation markers CD103, ICOS, and TIGIT. T cell receptor (TCR) repertoire profiling demonstrated that islet Treg clonotypes are expanded in the islets, suggesting localized antigen-driven expansion in inflamed islets. To determine their specificity, we captured TCRαβ pairs from islet Tregs using single-cell TCR sequencing and found direct evidence that some of these TCRs were specific for islet-derived antigens including insulin B:9–23 and proinsulin. Consistently, insulin B:9–23 tetramers readily detected insulin-specific Tregs in the islets of NOD mice. Lastly, islet Tregs from prediabetic NOD mice were effective at preventing diabetes in Treg-deficient NOD.CD28−/− recipients. These results provide a glimpse into the specificities of Tregs in a natural repertoire that are crucial for opposing the progression of autoimmune diabetes.

Sign in / Sign up

Export Citation Format

Share Document