October 8, 2020
People with lupus often develop complications in major organs such as the kidneys, called Lupus Nephritis (LN). By taking pictures of the kidneys with a special microscope, Dr. Janos Peti-Peterdi and his team at Keck School of Medicine of University of Southern California (USC) found a chain of molecules that leads to LN. They also found that treating the kidneys with a protein called hyaluronidase was able to stop these molecules and preserve kidney function. Funded by the LRA, these newly published study results open the door to targeting these molecules to treat LN in the future.
Over half of systemic lupus patients develop LN-related kidney disease, which currently does not have an effective treatment. In autoimmune diseases such as lupus, immune cells do not work properly, leading them to attack other harmless cells in the body. Researchers have shown that these immune cells may contribute to LN. One type of cell in the immune system called T cells play a key role in the body’s long-term response to a threat. T cells are able to kill sick cells and activate other immune cells. However, studying how T cells interact with the kidney cells in a living body has proven difficult without the appropriate tools.
Dr. Peti-Peterdi’s group used a special type of tool, called intravital imaging with multiphoton microscopy, to visualize cells in living kidneys and in collaboration with Dr. Chaim Jacob also at USC pinpoint the specific cell types involved in LN. The researchers wanted to see if kidney cells and immune cells from a specific part of the kidney (i.e. glomerular endothelial glycocalyx) work together to trigger T cells to travel and home to the kidneys. By using a mouse model that mimics LN, they showed that the number of active T cells was linked to the severity of LN in female mice (which may play a role in the sex difference seen in lupus); LN progression was measured by how healthy the kidney tissue was, tracked by changes in urine and inflammation in the kidneys.
To figure out which cell types are involved in LN, Dr. Peti-Peterdi and Dr. Jacob’s team first identified the immune cells seen in two kidney regions. Most of the immune cells (65-80%) across the two areas were T-cells. Dr. Peti-Peterdi and colleagues used a special mouse model with immune cells that behave like those in lupus and has kidneys that can be imaged in the living mouse. They saw the same T cell accumulation in the kidneys. The scientists also injected these diseased mice with T cells and showed that these T cells travelled to the kidneys; in contrast in healthy mice, these same T cells did not move to the kidneys.
However, researchers were able to stop the movement of the T cells to the kidneys by treating the diseased mice with hyaluronic acid before injecting the T cells. This suggests that T cells may attach or bind to hyaluronic acid and respond by changing their movements. Knowing that a layer on the kidney tissue called the glomular endothelial glycocalyx is the first point of contact for immune cells, the researchers tested a protein called hyaluronidase, which breaks down the glycocalyx, to see if it could stop the T cells from moving to the kidneys. When treated with hyaluronidase, diseased mice displayed fewer T cells in kidneys and improved kidney health, as shown by less leakage of proteins into the urine. With five days of hyaluronidase treatment, the number of T cells in the kidneys greatly decreased.
Ultimately, this study sheds light on the glomerular endothelial glycocalyx as a promising new target for LN therapies, as highlighted in an article in Nature Reviews Rheumatology commenting on the study. The review emphasizes that the hyaluronidase treatment in Peti-Peterdi et al.’s study not only improved T cell movement to the kidneys, but also improved kidney function. This study provided valuable insight into the proteins that contribute to LN and thus potential new treatments.
Dr. Peti-Peterdi commented, “I am extremely grateful for the grant support of the Lupus Research Alliance, which was absolutely essential to make this new discovery regarding the identification of a new lupus target. We couldn’t be more excited to continue our work towards therapeutic translation, and as the first step we will validate this newly identified mechanism in the human kidney in the next phase of research.”