Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8<sup>+</sup> T‐cell priming to tolerance in autoimmune‐prone NOD mice

Reeves, Peta; Rudraraju, Rajeev; Wong, F. Susan; Hamilton‐Williams, Emma E.; Steptoe, Raymond J.

doi:10.1002/eji.201747089

Cited by 6 publications

(9 citation statements)

References 48 publications

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“…This approach enables the delivery of antigens to DCs under steady-state conditions and the induction of peripheral tolerance ( 143 , 144 ). Reeves et al have shown that APC-targeted proinsulin expression converted insulin-specific CD8+ T-cell priming to tolerance in autoimmune-prone NOD mice ( 145 ). Ettinger et al achieved prolonged survival of transgenic mouse skin grafts by utilizing an antibody recognizing the CD205 receptor to deliver the immunodominant domain of type XVII collagen to host DCs without inflammatory stimuli ( 146 ).…”

Section: In Situ Targeting Of Dcregsmentioning

confidence: 99%

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

Que

Guo

2020

Front. Immunol.

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Current organ transplantation therapy is life-saving but accompanied by well-recognized side effects due to post-transplantation systematic immunosuppressive treatment. Dendritic cells (DCs) are central instigators and regulators of transplantation immunity and are responsible for balancing allograft rejection and tolerance. They are derived from monocyte-macrophage DC progenitors originating in the bone marrow and are classified into different subsets based on their developmental, phenotypical, and functional criteria. Functionally, DCs instigate allograft immunity by presenting donor antigens to alloreactive T cells via direct, indirect, and semidirect recognition pathways and provide essential signaling for alloreactive T cell activation via costimulatory molecules and pro-inflammatory cytokines. Regulatory DCs (DCregs) are characterized by a relatively low expression of major histocompatibility complex, costimulatory molecules, and altered cytokine production and exert their regulatory function through T cell anergy, T cell deletion, and regulatory T cell induction. In rodent transplantation studies, DCreg-based therapy, by in situ targeting or infusion of ex vivo generated DCregs, exhibits promising potential as a natural, well-tolerated, organ-specific therapeutic strategy for promoting lasting organ-specific transplantation tolerance. Recent early-phase studies of DCregs have begun to examine the safety and efficacy of DCreg-induced allograft tolerance in living-donor renal or liver transplantations. The present review summarizes the basic characteristics, function, and translation of DCregs in transplantation tolerance induction.

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Section: In Situ Targeting Of Dcregsmentioning

confidence: 99%

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

Que

Guo

2020

Front. Immunol.

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“…The advantage of DC targeting is that non-myeloablative conditions permit substantial donor engraftment [526], as shown here, because the encoded neoantigen is not sensed before late DC differentiation. While no systematic comparisons of lineage-restricting promoters have been performed, more widely expressed and membrane-bound antigens appear to be more tolerogenic [247,255,567,636]. Other promoters that target other subsets of DC or APC may be equally effective as demonstrated elsewhere [528,548,549], indicating intrinsic differences in presentation that affect tolerogenic potential [538].…”

Section: Discussionmentioning

confidence: 99%

“…Analogous to the peripheral control of autoreactive B cells, T cells which escape negative selection are tolerised by deletion or functional inactivation in the periphery [245][246][247][248]. Chronic engagement with self-peptide-MHC presented by resting DC triggers clonal deletion [249,250].…”

Section: Peripheral T Cell Tolerance To Limit B Cell Responsivenessmentioning

confidence: 99%

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Defining B cell tolerance checkpoints and their modulation by immunotherapy

Brooks¹

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B cells that recognise self-antigens are thought to be deleted from the emerging repertoire and those which escape deletion are instead locked in an anergic state. Autoimmunity develops when this process breaks down. This paradigm was established almost three decades ago in mouse models where all B cells recognise a single model antigen. Since then, very little about B cell tolerance has been learned from polyclonal settings where mice express a normal endogenous repertoire. This is because we have lacked tools to dissect B cell tolerance within a physiological repertoire in fine detail. This thesis aimed to understand polyclonal B cell tolerance and ways to modulate it. To study B cell tolerance, I took advantage of mouse models that express membranebound ovalbumin (OVA) as a model self-antigen. Three models were used where OVA was expressed ubiquitously, by MHC class II-expressing cells, or by CD11c+ dendritic cells. I generated fluorescent OVA tetramers that could probe for OVA-specific B cells in a polyclonal repertoire in both naïve mice and following immunization. Surprisingly, at steady-state, self-reactive OVA-specific B cells populated OVA-expressing mice in a manner that suggested deletion during B cell development does not occur. Instead, the large number of self-reactive B cells in the peripheral repertoire are maintained as anergic cells. This anergic state largely prevented responses to self-antigen when mice were immunized with OVA in the presence of different immunogenic stimuli. Of the small number of self-reactive cells that became activated in OVA-expressing mice, these were rapidly deleted from germinal centres and OVA-specific antibody production was transient. Providing a source of T cell help, either cognate or from bystander T cells, failed to reverse anergy, indicating that anergy was B cell-intrinsic and not as a consequence of T cell tolerance. Collectively, these studies demonstrated checkpoints that maintain robust peripheral B cell tolerance in a polyclonal repertoire. As a way to modify an existing repertoire, I transplanted OVA-encoding bone marrow and tested whether OVA-specific responsiveness could be modulated following engraftment. OVA-specific B cells could be edited from the repertoire and rendered anergic by OVA expression as a neo-self-antigen, demonstrating an approach that could harness peripheral tolerance to control B cells. These studies refine our current understanding of B cell tolerance. Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, financial support and any other original research work used or reported in my th...

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“…[268]. Furthermore, other reports indicate that early intervention prevents pathogenic cells from expansion and acquisition of a memory phenotype [269,270] However, s.c. treatment of young 5-week-old mice did not delay the progression of T1D.…”

Section: Dmentioning

confidence: 99%

Antigen-specific peptide immunotherapy for treatment and prevention of type 1 diabetes

Buckle¹

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Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic β cells, involving CD4 + and CD8 + T cells. Currently, there is no treatment for T1D, and disease management relies on insulin replacement therapy associated with major complications. Therefore, there is an urgent need for an effective T1D therapy without the need for systemic immunosuppression. The ideal immunotherapy would be safe, cheap and specifically inactivate or eliminate pathogenic islet-specific T cells and/or increase isletspecific regulatory T cells (Tregs). To this end, I have investigated the utility of liposome delivered antigen-specific therapy for T1D. Using the non-obese diabetic (NOD) mouse model of T1D, the Hamilton-Williams lab has shown previously that liposomes co-encapsulating a CD4-targeted islet antigen and NF-kB inhibitor induced antigen-specific induction of regulatory CD4 + T cells in mice and delay disease progression. As islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is a major CD8-T cells diabetogenic antigen in NOD mice, I now aimed to test the efficacy of an IGRP-specific immunotherapy targeting CD8+ T cells for inducing tolerance and protecting from disease. For this current model, I have used liposomes co-delivering the CD8 epitope IGRP206-214 and NF-kB inhibitor calcitriol to treat NOD mice. Liposome delivered peptide was presented by antigen-presenting cells to T cells as IGRP-specific CD8 + transgenic 8.3 T cells proliferated in draining lymph nodes after treatment. IGRP-specific 8.3 T cells expanded at day 4 and then contracted by day 10 following delivery of IGRP206-214 only and IGRP206-214 /D3 liposomes. Furthermore, the upregulation of activation and anergy markers such as CD44, LAG-3 and PD-1 on the 8.3 T cells following the liposomal treatment was observed. In contrast, endogenous IGRP-specific CD8 + population did not increase in frequency or upregulate of activation markers after one liposomal treatment. However, after two treatments the endogenous IGRP-specific cells significantly upregulated CD44 and PD-1. Consistent with the cells gaining a tolerogenic phenotype, IFN-g production was suppressed in endogenous IGRP-specific CD8 + T cells following IGRP206-214 /D3 but not IGRP206-214 only liposome treatment. These data suggest that endogenous IGRP-specific CD8 + T cells get activated in response to the liposome delivered antigen, but they gain an unresponsive phenotype. I then tested the efficacy of the therapy firstly using an accelerated transfer model of diabetes. IGRP206-214/D3 subcutaneous liposomal treatment significantly delayed the Publications during candidature Research papers

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Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice

Cited by 6 publications

References 48 publications

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

Defining B cell tolerance checkpoints and their modulation by immunotherapy

Antigen-specific peptide immunotherapy for treatment and prevention of type 1 diabetes

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Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8+ T‐cell priming to tolerance in autoimmune‐prone NOD mice

Cited by 6 publications

References 48 publications

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

Defining B cell tolerance checkpoints and their modulation by immunotherapy

Antigen-specific peptide immunotherapy for treatment and prevention of type 1 diabetes

Contact Info

Product

Resources

About

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice