Lupus glomerulonephritis (GN) is an autoimmune disease with immune complex deposits, complement activation and cellular infiltrates in the affected kidney, leading to renal failure. Reduced IL-2 in patients and mouse models of lupus has been documented to contribute to Treg deficiency. Our previous studies show IL-2 promotes TH2 response, which is protective against inflammation in Treg-deficient mice. We found that Tregs express IL1RL1 (ST2; the IL-33 receptor) and that IL-33 promotes Treg homeostasis synergistically with IL-2. We hypothesized that a combination therapy with IL-2 and IL-33 will boost homeostasis of Tregs to inhibit pro- inflammatory responses and be effective in treating lupus GN. Since Tregs express high-affinity IL-2 receptor, we generated a novel immunomodulatory cytokine (IL233), which has IL-2 and IL-33 activities linked together for better targeting of Tregs. We have used both the adeno-IFN? accelerated lupus GN and spontaneous GN mouse models of NZM2328 and MRL/lpr to determine that IL233 is effective in preventing and treating lupus GN in these models without any apparent atopy or deleterious side effects. IL233 prevents the onset and also reversed the development of severe proteinuria resulting in prolonged survival. IL233 is also effective in preventing the progression of GN with mild proteinuria to chronic GN with severe proteinuria and early death in untreated NZM2328 and MRL/lpr mice. Data have also been obtained showing that IL233 is more effective than IL-2 and IL-33 alone in markedly improving the metabolic fitness, proliferation, activation and recruitment of Tregs. This increase in Treg accounts for its effectiveness in treating murine lupus GN and that this novel hybrid cytokine may be useful in translational medicine. These preliminary data support our thesis that IL233 is effective in promoting Treg and can be used as a new therapeutic tool for lupus GN and other autoimmune disorders. Three mechanistic specific aims are proposed.
Aim 1 : Demonstrate that IL233 improves the metabolic function, suppressive potential and recruitment of organ-specific Tregs to inhibit autoimmunity.
Aim 2 : Demonstrate that IL233 induces persistent immune tolerance through altered maturation of kidney resident macrophages that are refractory to inflammation.
Aim 3 : Demonstrate that IL-33/ST2 pathway constitutes an important mechanism for recruitment of Tregs and resolution of inflammation. We will determine whether damaged kidneys in lupus GN express IL-33 and whether ST2-bearing Tregs are more efficient in suppressing lupus GN. The results of this investigation will provide us better understanding of the IL-2/IL-33 axis in SLE. Data will support the development of IL233 as a therapeutic agent and provide a novel method to expand Treg in vitro for therapy. Thus the application has significant translational implications.

Public Health Relevance

Lupus glomerulonephritis (GN) is a complex disease predominantly affecting females of reproductive age. It occurs when the immune system attacks its own organs including the kidneys. Current treatments for lupus nephritis include prednisone and immunosuppressive agents, both of which increase the risk of infections. We have adopted a new approach by devising a novel therapeutic agent. We are hopeful the proposed therapy will have lesser side effects and will be well tolerated. The proposed studies fulfill the goals of the National Institutes of Health.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Abbott, Kevin C
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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Sharma, Rahul; Kinsey, Gilbert R (2018) Regulatory T cells in acute and chronic kidney diseases. Am J Physiol Renal Physiol 314:F679-F698
Stremska, Marta E; Jose, Sheethal; Sabapathy, Vikram et al. (2017) IL233, A Novel IL-2 and IL-33 Hybrid Cytokine, Ameliorates Renal Injury. J Am Soc Nephrol 28:2681-2693
Chien, Ming-Hsien; Chang, Wei-Min; Lee, Wei-Jiunn et al. (2017) A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio. Mol Cancer Ther 16:1102-1113
Sung, Sun-Sang J; Ge, Yan; Dai, Chao et al. (2017) Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice. J Immunol 198:2589-2601