ORCID Profile
0000-0002-0702-9784
Current Organisations
University of Queensland
,
University of Tasmania
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2020
DOI: 10.1101/2020.03.10.985127
Abstract: 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 in iduals 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.
Publisher: Wiley
Date: 07-2022
DOI: 10.1002/CPZ1.485
Abstract: The skin protects our body from external challenges, insults, and pathogens and consists of two layers, epidermis and dermis. The immune cells of the skin are an integral part of protecting the body and essential for mediating skin immune homeostasis. They are distributed in the epidermal and dermal layers of the skin. Under homeostatic conditions, the mouse and human skin epidermis harbors immune cells such as Langerhans cells and CD8 + T cells, whereas the dermis contains dendritic cells (DCs), mast cells, macrophages, T cells, and neutrophils. Skin immune homeostasis is maintained through communication between epidermal and dermal cells and soluble factors. This communication is important for proper recruitment of immune cells in the skin to mount immune responses during infection/injury or in response to external/internal insults that alter the local cellular milieu. Imbalance in this crosstalk that occurs in association with inflammatory skin disorders such as psoriasis and atopic dermatitis can lead to alterations in the number and type of immune cells contributing to pathological manifestation in these disorders. Profiling changes in the immune cell type, localization, and number can provide important information about disease mechanisms and help design interventional therapeutic strategies. Toward this end, skin cells can be detected and characterized using basic techniques like immunofluorescence, immunohistochemistry, and flow cytometry, and recently developed methods of multiplexing. This article provides an overview on the basic techniques that are widely accessible to researchers to characterize immune cells of the skin. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-07-2020
Abstract: A simple cut-and-paste reagent development method applicable to any species reveals checkpoint molecules on transmissible cancers.
Publisher: Elsevier BV
Date: 02-2021
DOI: 10.1016/J.DCI.2020.103882
Abstract: Immune checkpoint immunotherapy is a pillar of human oncology treatment with potential for non-human species. The first checkpoint immunotherapy approved for human cancers targeted the CTLA4 protein. CTLA4 can inhibit T cell activation by capturing and internalizing CD80 and CD86 from antigen presenting cells, a process called trans-endocytosis. Similarly, CD28 can capture CD80 and CD86 via trogocytosis and retain the captured ligands on the surface of the CD28-expressing cells. The wild Tasmanian devil (Sarcophilus harrisii) population has declined by 77% due to transmissible cancers that evade immune defenses despite genetic mismatches between the host and tumors. We used a live cell-based assay to demonstrate that devil CTLA4 and CD28 can capture CD80 and CD86. Mutation of evolutionarily conserved motifs in CTLA4 altered functional interactions with CD80 and CD86 in accordance with patterns observed in other species. These results suggest that checkpoint immunotherapies can be translated to evolutionarily ergent species.
Publisher: The American Association of Immunologists
Date: 09-2020
Abstract: 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 in iduals 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 BCR. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. In this study, 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 self-reactive B cells are recruited into the germinal center, their development does not proceed, possibly because of rapid counterselection. Consequently, differentiation of plasma cells is blunted, and Ab responses are transient and devoid of affinity maturation. We propose this approach, and these tools can be more widely applied to track Ag-specific B cell responses to more disease-relevant Ags, 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.
Publisher: Cold Spring Harbor Laboratory
Date: 12-06-2020
DOI: 10.1101/2020.06.11.145789
Abstract: Immune checkpoint immunotherapy is a pillar of human oncology treatment with potential for non-human species. The first checkpoint immunotherapy approved for human cancers targeted the CTLA4 protein. CTLA4 can inhibit T cell activation by capturing and internalizing CD80 and CD86 from antigen presenting cells, a process called trans-endocytosis. Similarly, CD28 can capture CD80 and CD86 via trogocytosis and retain the captured ligands on the surface of the CD28-expressing cells. The wild Tasmanian devil ( Sarcophilus harrisii ) population has declined by 77% due to transmissible cancers that evade immune defenses despite genetic mismatches between the host and tumours. We used a live cell-based assay to demonstrate that devil CTLA4 and CD28 can capture CD80 and CD86. Mutation of evolutionarily conserved motifs in CTLA4 altered functional interactions with CD80 and CD86 in accordance with patterns observed in other species. These results suggest that checkpoint immunotherapies can be translated to evolutionarily ergent species. Key immune checkpoint receptor-ligand interactions are conserved in marsupials. Live cell-based assays show Tasmanian devil CD28 and CTLA4 can capture CD80 and CD86 in trans from adjacent cells. Mutation of the conserved CTLA4 MYPPPY ligand binding motif to CTLA4 MYPPPA reduces binding to CD80 and intercellular protein transfer. Removal of conserved CTLA4 YVKM protein recycling binding motif in CTLA4 results in bidirectional intercellular protein transfer between CTLA4 and CD80. Highly successful human immune checkpoint immunotherapies have the potential to be translated for veterinary and conservation medicine.
Publisher: Cold Spring Harbor Laboratory
Date: 07-11-2020
DOI: 10.1101/831404
Abstract: Immune checkpoint immunotherapy has revolutionized medicine, but translational success for new treatments remains low. Around 40% of humans and Tasmanian devils ( Sarcophilus harrisii ) develop cancer in their lifetime, compared to less than 10% for most species. Additionally, devils are affected by two of the three known transmissible cancers in mammals. Unfortunately, little is known about of immune checkpoints in devils and other non-model species, largely due to a lack of species-specific reagents. We developed a simple cut-and-paste reagent development method applicable to any vertebrate species and show that immune checkpoint interactions are conserved across 160 million years of evolution. The inhibitory checkpoint molecule CD200 is highly expressed on devil facial tumor cells. We are the first to demonstrate that co-expression of CD200R1 can block CD200 expression. The evolutionarily conserved pathways suggest that naturally occurring cancers in devils and other species can serve as models for understanding cancer and immunological tolerance.
No related grants have been discovered for Peter Murphy.