Humans of New York, the popular blog that uses images of New Yorkers to create a photographic census of the city, featured a scientist last week who caught our eye: She can put your entire immune system into the body of a mouse!
As she put it to Humans of New York, “I can take your immune system and transplant it into a mouse that I’ve genetically engineered to have no immune system of it’s [sic] own, so that I can model the genetics of your immune system and find immunoregulatory defects that will determine how you are going to respond to the cellular therapy needed to treat your disease.”
"That's a super hero right there," said one commenter on the Humans of New York Instagram account. The blog never reveals the names of its subjects, but we tracked her down: She's Nichole Danzi, an associate research scientist at Columbia University's Center for Translational Immunology. We talked to her about her work and how she became interested in this field. Unfortunately, she wouldn't disclose whether she has transferred her own immune system to any of the mice.
Below is a lightly edited and condensed transcript of our discussion.
When and how did it become possible to transplant the immune system of a human into a mouse?
Xenografting refers to the transplantation of cells from one species into another species ... In 2002, a strain of mice known as ‘NSG’ became available, which allows for the best engraftment and growth of human cells. These mice are used extensively by biomedical researchers to study human tumors, and in our lab at the Columbia Center for Translational Immunology, we use NSG mice to study the development of human immune systems.
It is relatively easy to take mature human blood cells from an adult and inject them into NSG mice. The human blood cells circulate and persist in these mice for a limited period of time. But T cells in the human immune cell graft will quickly recognize the mouse host as foreign and mount an attack. To prevent this graft versus host reaction, we grow the human immune system in mice from the ground up, starting from the most immature blood stem cells. To allow a functioning and self-tolerant immune system to develop, we must also surgically implant a piece of human thymus into the mouse. The thymus is like a classroom for T cells. The thymus contains highly specialized cells that foster T cell maturation from stem cells and selects/educates T cells that will react against foreign but not self molecules.
It turns out that preparation of the thymus tissue was the key to the success of the model, and we developed a method to cryopreserve and recover the tissue. In 2012 we published a series of experiments showing how to take stem cells from an adult’s bone marrow and essentially recreate that human’s immune system in NSG mice. These ‘personalized immune’ mice have B cells and T cells that are tolerant to cells from the mouse host and human donor, but can react against foreign molecules.
Do you have a mouse with your own immune system in it?
I can’t comment on this specific question. I can say that the principal investigator of my lab, Megan Sykes, was the first person to donate bone marrow and her blood stem cells did create mice with her immune system in them. In these early stages of the project she referred to the mouse model as the ‘mini-me’ model. With further discussion and input from a journal editor we changed the name to the ‘Personalized Immune Mouse,' as this was more accurate in describing the model.
Tell me a little about your background. How did you get into this particular field?
As a graduate student I studied the development of the thymus -- an organ that sits just above your heart and gradually involutes as you age. Within the thymus, immature T cells progressively mature, and as they mature they are carefully selected to react against foreign molecules and not self. This education/selection process is called central tolerance. Defects in this selection process lead to autoimmune disease. In my graduate studies, I exclusively used mouse models to study T cell and thymus development. You can learn a lot from studying the development of mouse immune systems.
However, I wanted to delve into the complexity of human immunology where individual variation in genetic makeup and environment all contribute to differences in immune function. The overarching purpose of my research at CCTI is to understand how tolerance becomes broken in patients with autoimmune diseases. The Personalized Immune Mouse Model that we developed combines strategies of central and peripheral tolerance induction and allows study of the genetic lesions that drive autoimmunity in humans.
What’s the biggest challenge you’ve faced in your work?
There was a steep learning curve as I transitioned from a basic researcher working exclusively with mice to a translational researcher where the research makes a direct connection with human patients. Our human subjects all agree to undergo genetic testing and a bone marrow biopsy. Control subjects must be genetically matched to patients with autoimmunity. We need to coordinate the busy schedules of our human donors with stem cell isolation procedures in our lab and delicate surgeries in our mice. In addition to the logistics, the ethical and regulatory issues surrounding this project are complex.
Having the direct connection to human patients, however, has been more rewarding than it has been challenging. If you look at many of the comments on the Humans of New York posting, you see that individuals who struggle with autoimmunity view this type of personalized research model as an important way forward in understanding their health problems.
Powered by funding from the [The National Institute of Diabetes and Digestive and Kidney Diseases], we have developed specialized resources for housing, grafting, post-op care and analysis of the personalized immune mice at the CCTI. Besides being surrounded by a highly skilled team of scientists at the CCTI, I’m very privileged to work with an awesome clinical team, first at the Naomi Berrie Diabetes Center and, more recently, in the rheumatology division. Our clinical collaborators have helped foster sensitivity, a real sense of purpose and connection to the individuals dealing with chronic disease and to all of the volunteers which participate in the study. As you can imagine, without a fully supportive clinical and research team, this type of study would not be possible.
What’s next for this research? Is there a particular goal you’d like to see accomplished?
Most autoimmune diseases have an important but complex genetic component. Each human with autoimmune disease has a unique set of genetically encoded traits that, by an unknown mechanism, disrupts regulation of the immune system to tip the balance from self-tolerance to autoimmunity.
Right now, we are trying to understand the underlying immunoregulatory problems in patients with Type 1 diabetes and rheumatoid arthritis. For our study, we need to basically take blood stem cells from the bone marrow of patients and healthy controls and use them to ‘reboot’ these individuals’ immune systems in the NSG mice. We then study the developing human immune systems in these mice over time and try to identify a specific immunoregulatory dysfunction that may have contributed to the disease. Unlike the human donors, the immune populations in the mice are not affected by disease or a lifetime of treatment.
Ultimately, I would like to see these personalized immune mice actively participating in patient care. We have much more work to do before we get to this point, but perhaps some day a specific immune dysfunction identified in a patient’s mouse might suggest a particular mode of immunotherapy or small molecule therapy.