LAUSR

Nature reviews | Nephrology active and pathogenic, as determined by T cell depletion experiments. Kidneyinfiltrating T cells from these mice had gene signatures suggestive of adaptations to hypoxia mediated by the transcription factor HIF1α. Chen and colleagues determined that this transcriptional profile was the direct result of low oxygen concentrations by injecting the mice with pimonidazole, a substance that only binds to proteins in hypoxic conditions. Double staining of kidneyinfiltrating T cells with pimonidazole and HIF1α confirmed that these cells had adapted to the hypoxic environment, and T cell depletion experiments partially reversed hypoxia in the renal cortex. “T cells are known to infiltrate the kidney, and many labs have shown that these cells have a proinflammatory phenotype and that manipulations (therapeutic or genetic) that lead to decreased kidney damage are linked to the decreased presence of T cells,” explains George Tsokos, an expert on T cells and SLE who was not involved in this study. “The conceptual brilliance of this paper is the consideration that the extended hypoxia (which can easily be assumed given that the filtration in the glomeruli is compromised) accounts for and/or contributes to T cellmediated kidney damage.” Using human singlecell RNA sequencing data from the Accelerating Medicines Partnership SLE project, the researchers found similar HIF1αregulated gene signatures to those they found in mouse models of lupus and confirmed the expression of HIF1αregulated proteins in T cellrich areas of nephritic human kidneys by immunohistochemistry. Chen and colleagues then tested whether HIF1α blockade (using the selective inhibitor PX-478) could ameliorate kidney damage in B6.Sle1.Yaa mice. “We found the drug slowed the infiltration of T cells into kidney tissue and reversed their ability to incite tissue damage,” says corresponding author Joe Craft. “These findings suggest this therapy might be beneficial for human lupus nephritis.” “Since this drug and others that block HIF1α function have been used in humans with cancer, they potentially could be available for the treatment of patients with SLE,” adds Chen. The researchers also studied lupusprone mice that lacked HIF1α in their T cells to examine the effects of T cellspecific depletion of HIF1α on kidney damage. The T cellspecific loss of HIF1α did not affect glomerular injury and the development of proteinuria in B6.Sle1.Yaa mice, but did reduce tubulointerstitial inflammation, implicating T cells in only the later stages of LN development. “Unlike the current trend for therapeutics in SLE that suppress systemic immunity, our study suggests that targeting tissueinfiltrating immune cells is feasible as a treatment for organ damage,” asserts Craft. “More detailed research on understanding how the local tissue environment modulates the effector function of tissueinfiltrating immune cells into the kidneys or other damaged organs in SLE could lead to more therapeutic options,” he concludes.