Reducing organ fibrosis by targeting a novel pro-fibrotic CLEC4D expressing myeloid subset.

Patients with kidney and liver disease lose their normal organ tissue as it is progressively replaced by scar tissue, resulting in a reduction in organ function. Eventually, this may lead to organ failure and the need for patients to undergo chronic dialysis therapy or kidney/liver transplantation. Despite these life-saving therapies, kidney and liver disease are the 11th and 12th leading causes of death.

Unfortunately, the number of patients with kidney and liver disease is continuing to rise and treatment options remain limited, therefore it is vitally important that researchers identify novel therapies that slow progression of disease.

Regardless of the underlying cause of the injury, damage to the kidneys and liver results in recruitment of white blood cells to the injured organs. These cells are part of the body's immune system that is important for fighting infection, however during organ injury they may promote further damage and scarring. We know that drugs that prevent recruitment of these immune cells to injured organs can slow, but not stop, progression of liver and kidney disease.

However, some subsets of the immune cells may be beneficial as they are required for normal tissue functions and to promote repair. Hence, blocking all immune cells from reaching the damaged organ is not advisable and a more targeted approach to inhibit specifically those subsets that promote injury is likely to be more beneficial.

In order to identify the specific immune cell subsets that promote organ injury, we have employed a state-of-the art technology called single-cell RNA sequencing in models of kidney and liver disease. This enabled us to determine which genes were switched on or off in individual immune cells. This revealed that there were many more immune cell subsets than we were previously aware of.

By analysing the genes that are activated in each cell, we have identified a subset of immune cells that expresses many genes that promote inflammation and scarring, leading us to suspect that this subset may promote kidney and liver injury. The immune cells in this subset have a specific protein called CLEC4D on their surface and we believe that targeting this CLEC4D molecule may prevent organ injury in a more precise manner than current therapies.

In this project we will use surplus tissue from biopsies from patients with liver and kidney disease to examine which molecular pathways are activated in the immune cells that express CLEC4D. This knowledge will help us develop new drugs that can prevent these cells causing inflammation and scarring.

Our collaborators have developed an antibody that binds to and neutralises the action of CLEC4D. We will use pre-clinical models of kidney and liver injury to test whether this antibody prevents the activation of immune cells, thereby preventing development of scar tissue in the organs. If successful, this could be used to prevent the development of scarring in the organs of patients with kidney and liver disease.

In addition, we have found a specific biochemical pathway is activated in the CLEC4D+ immune cells, which we believe contributes to inflammation and scarring. We will use genetic tools to block this pathway in the immune cells to test this hypothesis in models of kidney and liver disease. This will indicate whether blockade of this pathway by administration of a drug might be an alternative method of preventing kidney and liver scarring.

In summary, our studies will determine whether a number of complementary strategies focused on inhibition of a specific subset of immune cells could reduce inflammation and scarring in organs including kidney and liver to prevent organ failure.