Reduction of use of experimental mice in type 1 diabetes research through non-invasive, in vivo longitudinal imaging

Our laboratory studies the causes of type 1 diabetes (T1D), and methods for preventing or curing disease using the non obese diabetic (NOD) mouse. Until now we have always had to cull mice to excise the pancreas to examine events in the islets, and the variation in disease progression between individual mice has meant that group sizes have to be large to estimate differences between treatments. We propose to employ a completely novel method we have developed in collaboration with the University of Glasgow for imaging of transplanted islets in the pinna of the ear, to investigate and explore the efficacy of therapeutic intervention strategies for T1D. This method permits non-invasive, in vivo longitudinal imaging of immunological events in the islets, interrogating factors such as immune infiltration and beta cell mass repeatedly in the same mouse. This will enable us to further elucidate the mechanism(s) of protection from T1D afforded by various treatments, as well as explore possibilities of combining treatment with protocols that increase endogenous beta cell mass to achieve restoration of glucose control. Our preliminary studies support our proposal and suggest that this longitudinal in vivo imaging will provide insight into key events in the islet. This new technique will allow us to gain further insight into immune mediated destruction of beta cells and mechanisms for therapeutic protection, but also be a useful tool to investigate beta cell development, differentiation and function.

Recino A et al. (2019). Immunosuppression overcomes insulin- and vector-specific immune responses that limit efficacy of AAV2/8-mediated insulin gene therapy in NOD mice. Gene Therapy 26(1-2):40-56. doi: 10.1038/s41434-018-0052-5

Benson RA et al. (2018). Non-Invasive Multiphoton Imaging of Islets Transplanted Into the Pinna of the NOD Mouse Ear Reveals the Immediate Effect of Anti-CD3 Treatment in Autoimmune Diabetes. Frontiers in Immunology 9(1006) doi: 10.3389/fimmu.2018.01006

Kucia-Tran JA et al. (2018). Anti-oncostatin M antibody inhibits the pro-malignant effects of oncostatin M receptor overexpression in squamous cell carcinoma. The Journal of Pathology 244(3):283-295. doi: 10.1002/path.5010

De Riva A  et al. (2017). Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment. PloS one 12(8):e0181964. doi: 10.1371/journal.pone.0181964

Recino A et al. (2017). Hyperglycaemia does not affect antigen-specific activation and cytolytic killing by CD8 T cells. Bioscience reports 37(4). doi: 10.1042/BSR20171079

Thaker YR et al. (2017). Activated Cdc42-associated kinase 1 (ACK1) binds the sterile α motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines. The Journal of Biological Chemistry 292(15):6281-6290. doi: 10.1074/jbc.M116.759555

Wallberg M et al. (2017). Anti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacity. Immunology 151(2):248-260. doi: 10.1111/imm.12729

Gautam P et al. (2016). Promoter optimisation of lentiviral vectors for efficient insulin gene expression in canine mesenchymal stromal cells: potential surrogate beta cells. The Journal of Gene Medicine 18(10):312-21. doi: 10.1002/jgm.2900

 

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Project grant

Status:

Closed

Principal investigator

Dr Maja Wallberg

Institution

University of Cambridge

Co-Investigator

Professor Anne Cooke

Grant reference number

NC/M001083/1

Award date:

Sep 2014 - Dec 2017

Grant amount

£368,635

Primary 'R'

Reduction

Scientific Discipline

Infection, immunity and inflammation
Basic immunology

Technologies/approach

Imaging

Keywords

Diabetes
Mouse