However, studies in human populations have made it difficult to determine the extent to which APOL1 itself contributes to this risk independent of these other influences, says Menon.
To isolate the effects of APOL1, Menon’s team turned to genetically engineered mouse models carrying the G1 or G2 risk variants. This allowed the researchers to investigate whether the variants directly contribute to transplant rejection and to characterize the biological mechanisms involved.
They found that mice carrying the G1 or G2 variants showed heightened activation of T cells, immune cells that play an important role in transplant rejection. In transplant models, mice with the G1 variant also had greater immune cell infiltration into transplanted tissue and poorer graft survival.
The heightened immune response may reflect the evolutionary origins of these variants, says Menon. G1 and G2 are thought to have evolved in West and Central Africa because they provided protection against African sleeping sickness, a potentially fatal parasitic infection.
“These variants formed from a competitive evolutionary arms race between a parasite and a human,” Menon says. “In places such as the United States, where African sleeping sickness is not endemic, the variants no longer provide the same evolutionary advantage, while their effects on the immune system remain.”
The researchers also found that T cells carrying the G1 variant were less responsive to calcineurin inhibition, the pathway targeted by commonly used immunosuppressive medications for transplant patients.
Menon emphasizes that although further research is needed, future studies could test whether patients with these variants may benefit from different immunosuppressive strategies, including dose adjustments or the addition of alternative agents.
While people with African ancestry have long been known to experience higher rates of rejection and graft loss, or complete loss of function of the transplanted kidney, Menon hopes that identifying specific genetic and biological contributors to this risk could eventually allow clinicians to more precisely determine which patients are at increased risk and tailor their care accordingly.
“This kind of information is what’s going to help us come to true precision medicine,” he says.
The implications of these findings could also extend beyond transplantation, Menon says. APOL1 variants are strongly associated with non-diabetic kidney disease, yet most people who carry them never develop progressive disease, he says.
“One compelling idea is that how much the T cells are activated may have something to do with who progresses to kidney disease and who doesn’t,” Menon says. “The final cell that gets injured is the kidney cell, but the T cell may have something to do with how those cells are injured.”
Other Yale authors on this study include Shuta Ishibe, MD; Joseph Craft, MD; Irene Chernova, MD, PhD; Ashwani Kumar, PhD; Anand Reghuvaran, PhD; Stefan Somlo, MD; Mateus Guerra, PhD; Jordan Pober, MD, PhD; E. M. Tanvir, PhD; and John Pell.
Nephrology is one of 10 sections in the Yale Department of Internal Medicine. Committed to excellence in patient care, research, and education, the section’s faculty and trainees aim to be national and international leaders in academic nephrology. To learn more, visit Nephrology.