Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation

Al-Kouba, Jane; Wilkinson, A; Starkey, Malcolm R.; Rudraraju, Rajeev; Werder, Rhiannon B.; Liu, Xiao; Law, Soi Cheng; Horvat, Jay C.; Brooks, Jeremy F.; Hill, Geoffrey R.; Davies, Janet M.; Phipps, Simon; Hansbro, Philip M.; Steptoe, Raymond J.

doi:10.1172/jci.insight.85742

Cited by 15 publications

(14 citation statements)

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“…It would be interesting to determine the effect of co‐transferred activated islet‐antigen‐specific CD4 + T cells, or even other specificities of islet‐antigen‐specific CD8 + T cells, on tolerance induction to understand the influence of ‘help’ on tolerance induction and to understand the potential for tolerance induction in an ‘inflamed’ setting. Interestingly, we have recently showed that memory/effector Th2‐skewed CD4 + T cells are readily inactivated by enforced antigen expression in APC 50 and this could potentially extend to diabetogenic CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

APC‐targeted proinsulin expression inactivates insulin‐specific memory CD8⁺ T cells in NOD mice

et al. 2017

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Section: Discussionmentioning

confidence: 99%

APC‐targeted proinsulin expression inactivates insulin‐specific memory CD8⁺ T cells in NOD mice

et al. 2017

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“…Actin.mOVA (act.OVA) mice ubiquitously expressing membrane-bound ovalbumin (OVA) under the control of a β-actin promoter (15) in PBS and injected s.c. at the tail base. For adjuvant-free conditions, OVA was either injected alone or depleted of LPS as described (16) and 100μg injected s.c. at the tail base. Where shamimmunized controls were included, PBS and adjuvant was prepared and injected as described for OVA immunizations.…”

Section: Micementioning

confidence: 99%

Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific B-cell responses under strongly immunogenic conditions

Brooks

Murphy

Barber

et al. 2020

Preprint

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A series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached, however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy individuals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically-relevant B-cell responses, without the use of an engineered B-cell receptor. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. Here we use a strong adjuvant to provide bystander innate and adaptive signals that promote B-cell responsiveness, in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although autoreactive B cells are recruited into the germinal centre, their development does not proceed, possibly through rapid counter-selection. Consequently, differentiation of plasma cells is blunted, and autoantibody responses are transient and devoid of affinity maturation. We propose this approach and these tools can be more widely applied to track antigen-specific B cell responses to more disease relevant antigens, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell-mediated autoimmunity.

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“…Additionally, pathogenic memory cells that are resistant to conditioning, for example radioresistance in memory T cells [524], also drives susceptibility to relapse. As an additional step to overcome these issues, various groups including ours have combined gene engineering with autologous BMT [525][526][527][528][529][530][531]. In this setting, membrane-directed selfantigens (or allergens) are genetically encoded by donor stem cells and provide a strong source of cell-intrinsic tolerance following engraftment [526].…”

Section: Novel Therapeutic Strategies Using Antigen-encoding Bone Marmentioning

confidence: 99%

“…In this setting, membrane-directed selfantigens (or allergens) are genetically encoded by donor stem cells and provide a strong source of cell-intrinsic tolerance following engraftment [526]. This cell-intrinsic tolerance component overcomes tolerance defects endowed genetically [527] or by inflammation [525]. This principle takes advantage of the central and peripheral tolerance mechanisms discussed in earlier sections of this review.…”

Section: Novel Therapeutic Strategies Using Antigen-encoding Bone Marmentioning

confidence: 99%

“…This allows us to tailor transplantation protocols in a way that reduces conditioning requirements because overcoming immune-mediated rejection is no longer a challenge [515]. For example, in one approach, by targeting antigen for expression by DCs, only very mild irradiation is required to create space for donor cells and leaves the existing immune repertoire intact [525][526][527]. Not only does this selectively purge pathogenic cells involved in the unwanted immune response (via DC-mediated tolerance), it also preserves beneficial immunity in the host [525,527].…”

Section: Novel Therapeutic Strategies Using Antigen-encoding Bone Marmentioning

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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Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation

Cited by 15 publications

References 61 publications

APC‐targeted proinsulin expression inactivates insulin‐specific memory CD8⁺ T cells in NOD mice

APC‐targeted proinsulin expression inactivates insulin‐specific memory CD8⁺ T cells in NOD mice

Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific B-cell responses under strongly immunogenic conditions

Defining B cell tolerance checkpoints and their modulation by immunotherapy

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Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation

Cited by 15 publications

References 61 publications

APC‐targeted proinsulin expression inactivates insulin‐specific memory CD8+ T cells in NOD mice

APC‐targeted proinsulin expression inactivates insulin‐specific memory CD8+ T cells in NOD mice

Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific B-cell responses under strongly immunogenic conditions

Defining B cell tolerance checkpoints and their modulation by immunotherapy

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Product

Resources

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APC‐targeted proinsulin expression inactivates insulin‐specific memory CD8⁺ T cells in NOD mice

APC‐targeted proinsulin expression inactivates insulin‐specific memory CD8⁺ T cells in NOD mice