The cell surface glycoprotein CD47 is commonly understood as an immune-evasive “don’t eat me” signal. We report that CD47 also limits insulin secretion by human and mouse pancreatic beta cells. Reducing CD47 improved glucose homeostasis and insulin sensitivity in an in vivo model of streptozotocin-induced diabetes and delayed disease onset and reduced disease severity in a model of autoimmune diabetes. Blocking islet CD47 with an antibody before syngeneic transplantation also improved graft survival and function, illustrating potential therapeutic relevance for type 1 diabetes.

Ghimire K, Kale A, Li J, Julovi SM, O’Connell P, Grey ST, Hawthorne WJ, Gunton JE, Rogers NM. Sci Transl Med. 2023;15(717):eadd2387.

Ischemia reperfusion injury is a common precipitant of acute kidney injury that occurs following disrupted perfusion to the kidney. Acute kidney injury is associated with adverse long-term clinical outcomes and requires effective interventions that can modify the disease process. Immunomodulatory cell therapies such as tolerogenic dendritic cells remain a promising tool, and here we demonstrate that adoptively transferred tolerogenic dendritic cells can limit kidney injury. When infused systemically, these cells successfully abrogated kidney injury without modifying infiltrating inflammatory cell populations. They also provided protection against ischemia reperfusion injury in mice pre-treated with liposomal clodronate, suggesting the process was regulated by live, rather than reprocessed cells. Co-culture experiments and spatial transcriptomic analysis confirmed reduced kidney tubular epithelial cell injury. This technology may provide a clinical advantage for bench-to-bedside translation to affect patient outcomes.

Li JSY, Robertson H, Trinh K, Raghubar AM, Nguyen Q, Matigian N, Patrick E, Thomson AW, Mallett AJ, Rogers NM.

Kidney Int. 2023 Sep;104(3):492-507.

Objective: The prevalence of comorbid chronic kidney disease (CKD) and osteoarthritis (OA) is increasing globally. While sharing common risk factors, the mechanism and consequences of concurrent CKD-OA are unclear. We have developed a preclinical comorbid model, and to investigate the disease-modifying interactions.Our findings show significant bidirectional disease-modifying interaction between CKD and OA.

Julovi SM, Dao A, Trinh K, O’Donohue AK, Shu C, Smith S, Shingde M, Schindeler A, Rogers NM*, Little CB*.

*co-senior authors

RMD Open. 2023 Aug;9(3):e003109.

Nuclear factor κB (NF-κB) activation is a deleterious molecular mechanism that drives acute kidney injury (AKI). The TNFAIP3 gene encodes A20, a cytoplasmic ubiquitin ligase and a master negative regulator of the NF- κB signaling pathway. Here, we functionally identified a series of unique human TNFAIP3 coding variants linked to the autoimmune genome-wide association studies. We tested a mouse Tnfaip3 hypomorph in a model of ischemia reperfusion injury (IRI). The I325N variant influenced the outcome of IRI by changing the dynamic expression of multiple cytoprotective mechanisms, particularly by increasing NF- κB-dependent anti-apoptotic factors, altering the active redox state of the kidney, and enhancing cellular protective mechanisms including increased Foxp3⁺ T cells. Thus, TNFAIP3 gene variants represent a kidney and population-specific molecular factor that can dictate the course of IRI.
Rogers NM, Zammit N, Nguyen-Ngo D, Souilmi Y, Minhas N, Meijles DN, Self E, Walters SN, Warren J, Cultrone D, El-Rashid M, Li J, Chtanova T, O’Connell PJ, Grey ST.

Kidney Int. 2023 Jun;103(6):1105-1119.

Current pharmacological approaches can alter DC phenotype to induce tolerogenic DC (tolDC), a maturation-resistant DC subset capable of directing a regulatory immune response. TolDC may be better defined using gene signatures, but there is no consensus definition regarding genotypic markers. We address this shortcoming by analyzing available transcriptomic data to yield an independent set of differentially expressed genes that characterize human tolDC. Our gene signature will potentially provide greater understanding regarding transcriptional regulators of tolerance and allow researchers to standardize identification of tolDC used for cellular therapy in clinical trials.

Robertson H, Li J, Kim HJ, Rhodes JW, Harman AN, Patrick E, Rogers NM. Front Immunol. 2021 Oct 20:12:733231.