Targeting follicular helper T cells across multiple autoimmune diseases

There are more than 80 different autoimmune conditions and often people develop more than one at a time.

They can affect people of any age and last a life-time, potentially resulting in decades of ill health and medical costs.

On the face of it, these diseases seem very different from one another, with completely different symptoms affecting distinct parts of the body.

However at a mechanistic level, when we try to unpick the early events that trigger the development of these diseases we can find common ground. Long before any symptoms develop, there are changes in how cells of the immune system behave.

White blood cells called T cells play an important role in determining whether an immune response takes place – either against a part of our own body (an auto-immune response) or against an infection.

T cells that have the potential to cause autoimmune disease exist in all of us, but are normally tightly regulated so they don’t become activated – in particular they are prevented from interacting with another type of white blood cells, B cells.

Data from our lab and others suggests that when regulation starts to fail, one of the first things that happens is that T cells start to collaborate with B cells and immune responses begin to develop.

These interactions trigger autoantibodies to be produced – soluble proteins in the blood that can be measured clinically to test if someone is developing a particular condition. In type 1 diabetes, the presence of islet autoantibodies precedes the development of overt diabetes by many years. The T cells that collaborate with B cells are called follicular helper T cells, or Tfh.

Interestingly, the number and appearance of Tfh starts to change early on in multiple different autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, lupus, multiple sclerosis and many more. Data from animal models suggest that Tfh may be important in driving disease. Approaches to target these cells would be a novel way of intervening in relevant to multiple different conditions.

One problem is that there is no single marker that identifies Tfh so they are difficult to selectively target with drugs.

To overcome this, we have brought together 2 different scientific disciplines (cellular immunology and organic chemistry) to try and tackle this in a new way.

Using a new chemical approach, we can target 2 markers on a cell at the same time, opening up the possibility to deliver a toxic drug just to the Tfh cells.

We plan to test whether this approach can kill Tfh cells in plastic dishes and also in live animals (in 2 different mouse models of autoimmune disease). We also plan to start making the human equivalent of the drug and testing it on human cells in the lab.

Ultimately our goal is to deploy this as a new way to intervene across multiple autoimmune settings, early in disease and potentially prior to symptom development.