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Using hematopoietic stem cell gene therapy to induce immune tolerance in type 1 diabetes


Project Description

Hematopoietic stem cells (HSC) are increasingly being considered as important tools for clinically-relevant approaches to gene therapy. This project explores cutting-edge use of HSC-mediated gene therapy in humanized mouse models to: i) provide important fundamental information on the nature of T-cell tolerance in humans, ii) the potential of HSC-mediated gene therapy as a component of the pathway to a ‘cure’ for type 1 diabetes, and iii) develop non-toxic recipient treatments that enable gene-engineered to effectively engraft and grow in treated individuals.

Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic beta-cells. Despite use of life-saving insulin injections imperfect blood glucose control leads to substantial morbidity. As T1D results from destructive T-cell responses that target insulin-secreting pancreatic beta cells, the ultimate goal for an effective cure and ultimately prevention of T1D is development of an effective and safe immunotherapy to control the destructive T-cell responses.

We have pioneered application of hematopoietic stem cell-mediated gene therapy for T1D and other diseases of immune regulation and have made extensive progress in the understanding of this therapy in pre-clinical models. As a precursor to translation of these studies to clinical application we will now use humanized mice to explore the immunological mechanism by which hematopoietic stem cell-mediated gene therapy modulates human immune function, and how this might be applied in humans using clinically-applicable approaches.

This project is embedded in the application of hematopoietic stem cell-mediated gene therapy for immunotherapy and will provide a strong grounding for the successful applicant across immunology, hematopoiesis, HSC transplantation and gene therapy. Depending on the specific interests of the student, studies undertaken with this scholarship could be focused towards studies of either gene-therapy induced immune tolerance or modulation of recipient hematopoiesis to facilitate successful gene-therapy.


Techniques and areas studied may include:
• humanized mouse models
• immunology and T-cell tolerance
• therapy of type 1 diabetes
• hematopoiesis
• hematopoietic stem cell transplantation
• gene therapy


The preferred educational background for this project is BSc with Honours or Masters Degree in Science as a minimum and preferably with 1-2 years work experience or equivalence.

The Diamantina Institute within the University of Queensland offers a supportive environment for student development through strong mentoring, career development programs and attractive travel awards schemes.

https://di.uq.edu.au/

http://researchers.uq.edu.au/researcher/1361

https://future-students.uq.edu.au/study/program/Doctor-of-Philosophy-7501






Funding Notes

This scholarship is funded by the Commonwealth Government to provide financial assistance to students during completion of a PhD and is aligned with recently awarded Category 1 NHMRC project grant. The scholarship provides a living stipend of $27,596 per annum (2019 rate, indexed annually), tuition fees, and Overseas Student Health Cover (OSHC).

References

Underlying principles of the gene therapy approach is outlined in: Coleman MA, Steptoe RJ. Induction of antigen-specific tolerance through hematopoietic stem cell-mediated gene therapy: the future for therapy of autoimmune disease? Autoimm Rev. (2012) 12(2):195-203. doi: 10.1016/j.autrev.2011.08.012

Other relevant references:

Brooks JF, Davies JM, Wells JW, Steptoe RJ. Re-educating the immune system in allergy: The potential for hematopoietic stem cell-mediated gene therapy. J Mol Med. (2017) 96(1), 21-30. doi: 10.1007/s00109-017-1611-8

Reeves PS, Rudraraju R, Wong FS, Hamilton-Williams EE, Steptoe RJ. APC-targeted proinsulin expression inactivates insulin-specific memory CD8+ T cells in NOD mice. Immunol Cell Biol. (2017) 95:765-774. doi: 10.1038/icb.2017.48

AL-Kouba J, Wilkinson A, Starkey MR, Rudraraju R, Werder R, Horvat JC, Law S-C, Liu T, Brooks JF, Hill GR, Phipps S, Davies, JM, Hansbro PM, Steptoe RJ. Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation. JCI Insight. (2017) 2(11):e85742. doi:10.1172/jci.insight.85742

Coleman MA, Jessup CF, Bridge JA, Overgaard NH, Penko D, Walters S, Borg DJ, Galea R, Forbes JM, Thomas R, Wells JW, Steptoe RJ. Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection. Diabetes. (2016) 65(5):1328–1340. doi: 10.2337/db15-1418

Steptoe RJ, Ritchie JM, Harrison LC. Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes. J Clin Invest. (2003) 111:1357-1363.


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