IL233, A Novel IL-2 and IL-33 Hybrid Cytokine, Ameliorates Renal Injury

Abstract

CD4Foxp3 regulatory T cells (Tregs) protect the kidney during AKI. We previously found that IL-2, which is critical for Treg homeostasis, upregulates the IL-33 receptor (ST2) on CD4 T cells, thus we hypothesized that IL-2 and IL-33 cooperate to enhance Treg function. We found that a major subset of Tregs in mice express ST2, and coinjection of IL-2 and IL-33 increased the number of Tregs in lymphoid organs and protected mice from ischemia-reperfusion injury (IRI) more efficiently than either cytokine alone. Accordingly, we generated a novel hybrid cytokine (IL233) bearing the activities of IL-2 and IL-33 for efficient targeting to Tregs. IL233 treatment increased the number of Tregs in blood and spleen and prevented IRI more efficiently than a mixture of IL-2 and IL-33. Injection of IL233 also increased the numbers of Tregs in renal compartments. Moreover, IL233-treated mice had fewer splenic Tregs and more Tregs in kidneys after IRI. , splenic Tregs from IL233-treated mice suppressed CD4 T cell proliferation better than Tregs from saline-treated controls. IL233 treatment also improved the ability of isolated Tregs to inhibit IRI in adoptive transfer experiments and protected mice from cisplatin- and doxorubicin-induced nephrotoxic injury. Finally, treatment with IL233 increased the proportion of ST2-bearing innate lymphoid cells (ILC2) in blood and kidneys, and adoptive transfer of ILC2 also protected mice from IRI. Thus, the novel IL233 hybrid cytokine, which utilizes the cooperation of IL-2 and IL-33 to enhance Treg- and ILC2-mediated protection from AKI, bears strong therapeutic potential.

Renal regeneration after acute kidney injury

“…Administration of anti‐CD28 superagonist antibody was shown to increase Tregs and protect from AKI in a mice model, but phase I studies in healthy volunteers showed unexpected life‐threatening adverse effects with this drug . Very recently, treatment of mice with a hybrid cytokine (IL‐233, that bears the activities of IL‐2 and IL‐33) increased Treg mediated protection from AKI . Clinical studies are awaited.…”

“…90,91 Very recently, treatment of mice with a hybrid cytokine (IL-233, that bears the activities of IL-2 and IL-33) increased Treg mediated protection from AKI. 92 Clinical studies are awaited.…”

Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

“…Intriguingly, a beneficial function of IL-33 has also recently been reported in a study that developed a hybrid IL-2-IL-33 fusion; researchers observed a protective role for the fusion protein in kidney IRI models, mediated via the expansion of renal ILC2s [54]. Short-term treatment with IL-33 also leads to the sustained expansion of renal ILC2s and protects against adriamycin-induced glomerulosclerosis [55].…”

Regulatory T cells in renal disease

“…80 As IL-2 and IL-33 promote the expansion of murine Tregs in vivo, Stremska et al generated an IL-2 and IL-33 fusion cytokine that they termed IL-233, and which they found increased the recruitment of Tregs into the kidney and protected mice from IRI more efficiently than either cytokine alone. 81 Thus, these studies collectively suggest that strategies aimed at enhancing numbers, recruitment and function of endogenous Tregs demonstrates therapeutic potential in AKI, especially as therapies prior to injury in situations where AKI is likely or probable.…”

“…The renoprotective effects of human‐umbilical cord blood‐derived MSCs administered early after cisplatin administration are potentially via Tregs . As in IRI, the hybrid cytokine IL‐233 protected mice from cisplatin‐induced AKI, but whether this was mediated through increased recruitment of Tregs to the kidney (as in IRI) was not determined . Given that patients with solid organ tumours are given cisplatin in a known timeframe, IL‐233 as well as PLA2 and MSCs, assuming they do not limit the anticancer effects of cisplatin may have therapeutic potential.…”