Immune Development

Using stem cells to study aspects of immune cell development, how these cells contribute to disease and how they might be manipulated to provide new medical treatments.

Our group uses human stem cells to understand human immunity and autoimmune diseases. Led by Professor Ed Stanley, the group has a special interest in diseases of the endocrine and immune systems. These areas apply to diseases such as type 1 diabetes, an autoimmune disease in which the body destroys its own insulin-producing beta cells. Our lack of knowledge hinders our ability to treat diseases such as diabetes about how these diseases develop. Improving our understanding of what causes autoimmunity is critical for the development of new treatments and for disease prevention.

Insulin is the hormone that controls the amount of sugar in the bloodstream. Children with Type 1 diabetes have to inject themselves with insulin 3 or 4 times per day and must monitor the amount of sugar in their blood using a finger prick test. This treatment method has not changed in the last 100 hundred years. We desperately need new therapies in the area.  

How autoimmune disorders develop and why the immune system becomes overactive is poorly understood. Using induced pluripotent stem cells made from people with type 1 diabetes, we can create different human immune cells in the laboratory and observe their development and behaviour. This technology allows us to model autoimmunity and explore causes and cures.

The Immune Development Laboratory aims to better understand diseases such as type 1 diabetes, a disease commonly occurring during childhood, and for which current treatments are inadequate. This increased understanding will aid the development of new treatments and contribute to the goal of developing a cure for this lifelong condition.

More information

• Human immune cells produced in a dish in world's first

Our projects

Making insulin-producing cells in the laboratory

We are using stem cells from people with type 1 diabetes to make insulin-producing cells. Insulin is a hormone that controls the level of glucose (sugar) in the blood. People with type 1 diabetes need regular insulin injections as their immune system has attacked and killed the cells that make insulin. These cells can be replaced with tissue provided by organ donors, but there are never enough donors to satisfy demand as well as sufficiently match. This supply problem could be solved if it was possible to efficiently generate insulin-producing cells from stem cells.

Making immune cells from people with type 1 diabetes

We have created immune cells from stem cells that are made from people with Type 1 diabetes. It is believed that immune cells cause type 1 diabetes by attacking parts of the pancreas. The generation of immune cells in the laboratory will enable us to test if these cells are in any way defective, and if they are, whether such defects can be corrected using drugs or other interventions.

Making B-lymphocytes form pluripotent stem cells

B lymphocytes are a critical arm of the adaptive immune system. The in vitro generation of B cells from human pluripotent stem cells provides an opportunity to study normal immune development, model disease, and generate cells and products for potential therapeutic use. We have methods for making definitive human hematopoietic lineages from PSCs, enabling us to generate human B lymphocyte progenitors in vitro and in animal models.

Modelling COVID-19 using immune cells made from stem cells

The virus that causes COVID-19 is able to hide from the immune system using several specialised techniques. This immune evasion is key in its devastation of disease and its ability to often spread initially undetected. We are creating immune cells in the lab which are modified to contain some of these viral genes and so can mimic the way coronavirus prevents being detected. By doing this we can study how the virus works and discover potential treatments. This model can also be adapted to investigate other viruses and so may prove useful for the investigation of future outbreaks.

Funding

• The Novo Nordisk Foundation
• NHMRC Ideas grant 
• NHMRC Research Fellowship
• NHMRC Project grant
• CSL Limited

Collaborations

• Professor Andrew Elefanty (MCRI) and Elizabeth Ng (MCRI), Topic – Blood cell development
• Prof Fergus Cameron (MCRI/RCH) and Associate Professor Stuart Mannering (St Vincent’s Institute), Topic – Type 1 Diabetes
• Professor John Bateman (MCRI) and Dr Shireen Lamande (MCRI), Topic – Bone and Cartilage development
• CSL (Commercial Partner), Topic – Blood cell development

Featured publications

• Multipotent RAG1+ progenitors emerge directly from haemogenic endothelium in human pluripotent stem cell-derived haematopoietic organoids.
  Motazedian A, Bruveris FF, Kumar SV, Schiesser JV, Chen T, Ng ES, Chidgey AP, Wells CA, Elefanty AG, Stanley EG.Nat Cell Biol. 2020 Jan;22(1):60-73. doi: 10.1038/s41556-019-0445-8. Epub 2020 Jan 6.PMID: 31907413
  
  
• Induced pluripotent stem cell macrophages present antigen to proinsulin-specific T cell receptors from donor-matched islet-infiltrating T cells in type 1 diabetes.
  Joshi K, Elso C, Motazedian A, Labonne T, Schiesser JV, Cameron F, Mannering SI, Elefanty AG, Stanley EG.Diabetologia. 2019 Dec;62(12):2245-2251. doi: 10.1007/s00125-019-04988-6. Epub 2019 Sep 12.PMID: 31511930
  
  
• Differentiation of human embryonic stem cells to HOXA+ hemogenic vasculature that resembles the aorta-gonad-mesonephros.
  Ng ES, Azzola L, Bruveris FF, Calvanese V, Phipson B, Vlahos K, Hirst C, Jokubaitis VJ, Yu QC, Maksimovic J, Liebscher S, Januar V, Zhang Z, Williams B, Conscience A, Durnall J, Jackson S, Costa M, Elliott D, Haylock DN, Nilsson SK, Saffery R, Schenke-Layland K, Oshlack A, Mikkola HK, Stanley EG, Elefanty AG.Nat Biotechnol. 2016 Nov;34(11):1168-1179. doi: 10.1038/nbt.3702. Epub 2016 Oct 17.PMID: 27748754
  
  
• GAPTrap: A Simple Expression System for Pluripotent Stem Cells and Their Derivatives.
  Kao T, Labonne T, Niclis JC, Chaurasia R, Lokmic Z, Qian E, Bruveris FF, Howden SE, Motazedian A, Schiesser JV, Costa M, Sourris K, Ng E, Anderson D, Giudice A, Farlie P, Cheung M, Lamande SR, Penington AJ, Parish CL, Thomson LH, Rafii A, Elliott DA, Elefanty AG, Stanley EG.Stem Cell Reports. 2016 Sep 13;7(3):518-526. doi: 10.1016/j.stemcr.2016.07.015. Epub 2016 Sep 1.PMID: 27594589 
  
  
• INS(GFP/w) human embryonic stem cells facilitate isolation of in vitro derived insulin-producing cells.
  Micallef SJ, Li X, Schiesser JV, Hirst CE, Yu QC, Lim SM, Nostro MC, Elliott DA, Sarangi F, Harrison LC, Keller G, Elefanty AG, Stanley EG. Diabetologia. 2012 Mar;55(3):694-706. doi: 10.1007/s00125-011-2379-y. Epub 2011 Nov 26.PMID: 22120512