January 28, 2022
The investigators from The Accelerated Medicines Partnership® Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP® RA/SLE) Program, in collaboration with Drs. Chaim Putterman from the Albert Einstein College of Medicine and Chandra Mohan from the University of Houston, and the biotechnology company Equillium have discovered an immune pathway that plays an important role in the development of lupus nephritis (the lupus kidney disease caused by inflammation in the kidney). This finding may lead to new therapies for patients with lupus nephritis. The study, published in the Journal of Clinical Investigation, was funded in part by the Lupus Research Alliance (LRA).
Approximately half of the patients with systemic lupus erythematosus (SLE) experience a serious complication called lupus nephritis. Despite improvements in treatment, 10% of patients with lupus nephritis develop end-stage kidney disease, which can result in premature death.
While the causes of lupus remain incompletely understood, it is known that overactive immune cells that attack the body’s own organs are a key characteristic of the disease. One group of immune cells, called T cell, are central to the development of lupus nephritis. However, researchers and healthcare providers have found it difficult to specifically target only the “bad” T cells that contribute to the development of lupus. That’s why the more broad-spectrum immunosuppressive drugs remain the current treatment. This latest research may shed light into new molecules that could be targeted to treat lupus nephritis.
An Immune Pathway Gone Awry
All cells have special molecules which guide their activities throughout the body. These molecules interact with those released from or present on the surface of other cells. The interactions stimulate the cells to perform their intended activities. The AMP investigators, Dr. Putterman, Dr. Mohan, and Equillium in their latest finding show that one molecule in particular is responsible for stimulating T cells to cause damage in lupus nephritis.
The same group of researchers had initially found that the molecule called activated leukocyte cell adhesion molecule (ALCAM) was increased in the urine of patients with active lupus nephritis. This observation suggested that ALCAM may be contributing to lupus nephritis. ALCAM is released from several types of cells, including kidney cells and interacts with a molecule CD6, which is present on the surface of T cells.
Normally, the interaction between CD6 and ALCAM allows T cells to travel to sites where their activity is needed to participate in immune responses. However, high levels of ALCAM cause T cells to become overactive, which contributes to lupus.
To investigate ALCAM in lupus nephritis patients, the investigators looked at the levels of ALCAM in urine samples from 1,000+ patients with SLE and lupus nephritis from five ethnically diverse groups. The investigators found that higher ALCAM levels were associated with more severe lupus nephritis among all ethnic groups. This finding suggests that the urine ALCAM levels may be a novel biomarker indicating lupus nephritis disease activity.
Blocking the CD6-ALCAM Interaction May Reduce the Severity of Lupus Nephritis
After discovering that high levels of ALCAM are linked to more severe lupus nephritis, the research team also found that blocking ALCAM-CD6 interactions led to far less inflammation and kidney disease in two different mouse models of lupus. While mouse models do not fully mirror human disease, the findings from two lupus mouse models strongly suggest that interactions between ALCAM and CD6 on T cells are critical for the progression of nephritis in patients with SLE.
LRA Chief Scientific Officer Dr. Teo Staeva said, “We are proud to be able to support research that leads to groundbreaking findings for the lupus patient community. The results reported in this publication point to a novel biomarker and possible targets that could be used to develop new therapies for lupus nephritis which could improve disease outcomes and quality of life for many.”
Additional information on the AMP® RA/SLE Program can be found here. The LRA is proud to support this program.
Accelerating Medicines Partnership and AMP are registered service marks of the U.S. Department of Health and Human Services.