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Safer Conditioning for Antigen-Encoding Bone Marrow Transfer to Induce Immune Tolerance

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Safer Conditioning for Antigen-Encoding Bone Marrow Transfer to Induce Immune Tolerance Safer conditioning for antigen-encoding bone marrow transfer to induce immune tolerance Md Anayet Hasan BSc (Honors), MSc in Biotechnology https://orcid.org/0000-0003-3796-7031 A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in Year 2020 Faculty of Medicine i | P a g e Abstract Transplanting genetically-engineered hematopoietic stem cells (HSC) encoding antigen targeted to dendritic cells (DC) or other antigen presenting cells (APC) provides an efficient means to induce antigen-specific T-cell tolerance. Low-level, but stable HSC chimerism is sufficient for T-cell tolerance induction and prevention of autoimmune disease in animal models. A current limitation of this approach is, highly-toxic myeloablative and/or immunoablative pre-transfer recipient conditioning regimens are typically used to achieve high chimerism levels with the transferred engineered HSC. Whilst low doses of total body irradiation can be used in order to reduce toxicity, this is still genotoxic, leading to cell and DNA damage. Several alternatives to total body irradiation and other genotoxic (e.g. chemotherapy) approaches have been suggested. One alternative that has been reported is the use of a CD45-targeted immunotoxin (CD45-SAP) that has been shown to deplete >98% of HSC and facilitates 90% of donor chimerism when used at high doses in mice, but CD45- SAP is highly immunoablative at the explored high doses. To promote clinical applicability that might be achieved by avoiding immunodepletion and, as low-levels of stable donor chimerism are suitable to generate T-cell tolerance, I tested whether use of lower doses of CD45.2-SAP that might preserve immunity would be suitable as a low-toxicity conditioning regimen. Titrating the dose of CD45.2- SAP led to a dose-dependent depletion of phenotypically-defined long-term repopulating HSC (LT- HSC) in bone marrow. Dose-dependent CD45.2-SAP- mediated LT-HSC depletion was verified by competitive bone marrow transplantation. In contrast to high dose CD45.2-SAP, a lower dose (0.5 mg/kg) preferentially depleted approximately 45-50% of LT-HSC whereas peripheral leukocytes were largely preserved (approximately 80% retained). A moderate level of hematopoietic mixed chimerism (10-12%) and tolerance induction was achieved after transplanting antigen-encoding bone marrow using this non-genotoxic conditioning. It is also established that tolerance induction can be improved by transplanting large number of gene-modified bone marrow cells. These results were carried forward and hematopoietic stem and progenitor cells (HSPC) specific immunotoxin (2B8- SAP) was tested whether it induce T-cell tolerance without affecting recipients peripheral leukocytes. It is demonstrated that low dose 2B8-SAP (0.5mg/kg) depleted >90% of LT-HSC without depleting peripheral leukocytes and permits approximately 25-30% of donor chimerism which subsequently induce T-cell tolerance. Thus non-genotoxic conditioning approach through targeted immunotoxins (low dose CD45.2-SAP/2B8-SAP) could provide a useful alternative to toxic conditioning approaches for tolerance induction with gene-engineered bone marrow. ii | P a g e 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 thesis. The content of my thesis is the result of work I have carried out since the commencement of my higher degree by research candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from co-authors for any jointly authored works included in the thesis. iii | P a g e Publications included in this thesis No publication included Submitted manuscripts included in this thesis No manuscript submitted for publication Other publications during candidature Research papers No other publication. Oral*/Poster presentation ➢ Hasan MA, Pettit AR, Steptoe RJ (2019) “Transplanting antigen-encoding bone marrow under non-genotoxic conditioning facilitates hematopoietic chimerism and antigen-specific immune tolerance”- 48th Annual Scientific Meeting of The Australasian and New Zealand Society for Immunology, Adelaide, Australia. ➢ Hasan MA, Pettit AR, Steptoe RJ (2019) “Transplanting antigen-encoding bone marrow under non-genotoxic conditioning facilitates hematopoietic chimerism and antigen-specific immune tolerance”- British Society for Immunology Congress, Liverpool, United Kingdom. ➢ Hasan MA, Pettit AR, Steptoe RJ (2019) “Transplanting antigen-encoding bone marrow under non-genotoxic conditioning facilitates hematopoietic chimerism and antigen-specific immune tolerance”- Institute of Medical Sciences, The University of Tokyo (IMSUT), Tokyo, Japan. * ➢ Hasan MA, Pettit AR, Steptoe RJ (2019) “Non-genotoxic conditioning facilitates tolerance induction through stable mixed hematopoietic chimerism of gene modified bone marrow”- 17th International Congress of Immunology, Beijing, China. ➢ Hasan MA, Pettit AR, Steptoe RJ (2019) “Non-genotoxic conditioning facilitates tolerance induction through stable mixed hematopoietic chimerism of gene modified bone marrow”- Princess Alexandra Hospital Health Symposium, Brisbane, Australia. iv | P a g e ➢ Hasan MA, Pettit AR, Steptoe RJ (2019) “Non-genotoxic conditioning facilitates tolerance induction through stable mixed hematopoietic chimerism of gene modified bone marrow”- Translational Research Institute Research Symposium, Brisbane, Australia. ➢ Hasan MA, Pettit AR, Steptoe RJ (2018) “Non-genotoxic conditioning facilitates stable mixed hematopoietic chimerism of gene modified bone marrow”- 47th Annual Scientific Meeting of The Australasian Society for Immunology, Perth, Australia. ➢ Hasan MA, Pettit AR, Steptoe RJ (2018) “Non-genotoxic conditioning facilitates stable mixed hematopoietic chimerism of gene modified bone marrow”- 18th Annual Brisbane Immunology Group Meeting, Gold Coast, Australia. ➢ Hasan MA, Pettit AR, Steptoe RJ (2018) “Non-genotoxic conditioning facilitates stable mixed hematopoietic chimerism of gene modified bone marrow”- Princess Alexandra Hospital Health Symposium, Brisbane, Australia. ➢ Hasan MA, Pettit AR, Steptoe RJ (2018) “Non-genotoxic conditioning facilitates stable mixed hematopoietic chimerism of gene modified bone marrow”- Translational Research Institute Research Symposium, Brisbane, Australia. v | P a g e Contributions by others to the thesis Associate Professor Raymond Steptoe contributed to the design and analysis of all experiments as well as the written portions of this thesis. Professor Allison Pettit contributed to the design of some experiments and some written portion of this thesis. In chapter 4 and 5, James Barber performed mice immunization (Figure 4.17 Figure 4.21 and Figure 5.11). Statement of parts of the thesis submitted to qualify for the award of another degree No works submitted towards another degree have been included in this thesis. Research involving human or animal subjects Experiments included in this thesis were approved in the following projects: TRI/UQDI/296/14/NHMRC TRI/UQDI/371/17/NHMRC vi | P a g e Acknowledgments First of all I wish to express my heartiest gratitude to my God for giving me the strength to carry out this work with enthusiasm and for being with me every steps of the way. My regards, gratitude, indebtedness and appreciation goes to my respected supervisor Associate Professor Raymond Steptoe for his supervision, constructive criticism, expert guidance, enthusiastic encouragement to pursue new ideas and a good sense of humour and never ending inspiration throughout the entire period of my research work. Without you, this thesis would have been in no way achievable. I know words are not enough to show how thankful I am. I am so lucky to have you as my supervisor. Thank you Ray. I would like to thank my co-supervisor Professor Allison Pettit for her supervision, support, invaluable advice and constructive criticism during my candidature. My thesis committee members, Associate Professor Graham Leggatt, Associate Professor Emma Hamilton-Williams and Dr Roberta Mazzieri, I thank you for your time and valuable feedback during my PhD milestones. I would like to extend my deepest gratitude to all the present and past members of the Autoimmunity and Tolerance Laboratory, and very special
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