Greet Verstichel, M.D., Ph.D.

From mouse to man, towards a cure for autoimmune diseases

FUNDED: JANUARY 2020
FUNDED BY: the generosity of Barbara Donnell, Bill Passey & Maria Silva,
and 2019-20 Various Donors

Our immune system is very important in protecting us from infection, but for some people this immune protection comes at a very high cost. When the immune system can no longer discriminate between dangerous intruders like viruses and their own healthy cells, they suffer from autoimmune disease. More than 50 million Americans have been diagnosed with autoimmune disease and, for reasons unknown, these numbers are rising at alarming rates. Current treatment options are focused merely on dampening the immune response in an attempt to decrease the damage inflicted by an out-of-control immune system. Unfortunately, this is not a cure and it does not address the fundamental question in autoimmune disease: why in the first place does the immune system attack “self”?

During an infection, immune cells, particularly B and T cells, mediate pathogen-specific inflammatory immune responses. However, in patients with autoimmune disease pathogenic T cells mount an inappropriate response against the body’s own cells. I hypothesize that some immature T cells are already prone to attack self-antigens during their development in the thymus. I studied non-obese diabetic mice (NOD) that have a genetic predisposition to develop Type 1 diabetes and identified several defects that associate with abnormal T cell development in the thymus and the generation of pathogenic self-reactive T cells.

The objective of the current pilot study is to test if the same defects are also causing human autoimmune diseases. In order to do so, I want to set up a novel advanced human thymic organoid culture system to support normal human T cell development that closely mimics the conditions of a human body. My goal with the SPARK funding is to set up this physiologic in vitro human T cell system here at LJI. This will allow me to understand how human disease-causing cells develop and ultimately provide opportunities for translational research to cure or intervene even before the self-destructive disease is evident.

Six-Month Project Update

I’m studying the disturbed development of T cells in autoimmune disease using human samples. In partnership with Rady Children’s Hospital, I received thymus samples from patients undergoing heart surgery in which the surgeon needs to remove some of the thymus tissue. This was previously discarded but now with our collaboration and patient consent it can be used for research. So far I’ve processed and tested the viability of the samples when stored in liquid nitrogen, and also extracted stem cells from the total thymus pool that will be used for the cultures. For the second arm of the study, I’ve validated the growth of the bone marrow cell line that supports the development of human T cells and verified that the cell line expresses required ligands for the T cells to properly mature. Next I’ll set up the organoids by mixing the stem cells and bone marrow cells and assess their ability to mature to functional T cells. I’ll also experiment with interfering with the metabolism of the cells at certain stages of their development to see if that changes the ultimate profile and potential of the T cells. In particular, I’m testing if it predisposes the cells to recognize and attack self-antigens, which is what happens in autoimmune disease.