Donalyn Bily

Background: Systemic Lupus Erythematosus, or SLE, is a multifactorial autoimmune disease that involves many organs, including the heart, kidneys, skin, and central nervous system.¹ It is clinically diverse, with 20-150 individuals affected per 100,000 people.¹ SLE is more prevalent among African, Asian, and Hispanic ethnicities, and disproportionately affects women, especially of childbearing age.¹ While there are current treatments to manage the disease, including lifestyle changes and immunosuppressant therapies, patients with SLE have a higher risk of mortality than the average population.² This increased mortality risk is potentially from infections early in the disease, and from damage and cardiovascular failure due to chronic immunosuppressant use later in the disease.² Therefore, looking at treatment options that reduce the needed dose of immunosuppressants could benefit individuals diagnosed with SLE.

Objective: The purpose of this review was to determine potential alternative treatments for SLE compared to that of the current protocol. Therefore, pathways implicated in the Treg/Th17 cell ratio were researched to determine their impact on disease symptoms of SLE.

Search Methods: An online search in the PubMed database was conducted from 2019 to 2024 including the following keywords: “Systemic Lupus Erythematosus,” “Treg,” “Th17,” “Rapamycin,” “IL-2,” “mTOR,” “foxp3,” and “nanoparticle.”

Results: Many immune cells are involved in SLE, and the ratio of Treg/Th17 is significantly reduced in patients with the disease compared to healthy individuals.³ Treg cells express many molecules on their surface, including PD-1 and PD-L1.⁴ Low expression of PD-1 is thought to be associated with a higher number of Th17 cells. Low expression of PD-L1 may cause decreased Treg cell differentiation from naïve CD4⁺ T-cells, because it normally increases Foxp3 expression and inhibits the mTOR pathway.⁴ Likewise, PD-1 is implicated in the development of Treg cells through decreasing the mTOR pathway. ⁴ A study used nanoparticles that contained dexamethasone in mouse models targeting PD-1 in inflamed organs. Dexamethasone was abundant in inflamed organs, SLE symptoms were reduced, and the Treg/Th17 ratio was increased in model organisms.⁵ Rapamycin is implicated in the mTOR pathway, and IL-2 is a vital cytokine for Treg development.^3,6 A phase II clinical trial combining IL-2 injections and oral rapamycin to treat refractory SLE shows promising results, as the ratio of Treg/Th17 increased significantly.³ A study in mice demonstrated that nanoparticles containing rapamycin (ImmTOR) combined with a selective IL-2 variant for Treg increased Foxp3 expression, and greater demethylation was seen in Foxp3 genes. The ImmTOR and IL-2 molecules selected for Treg development worked synergistically to increase Treg proliferation and inhibit effector T-cells, increasing the Treg/Th17 cell ratio.⁷

Conclusion: While there are therapeutics currently in trials for the treatment of SLE, such as a combined therapy of IL-2 and rapamycin to correct the Treg/Th17 imbalance seen in the disease, there is convergence on the mTOR and Foxp3 pathways as molecular targets in management of the disease. Advances in biomaterials as potential therapeutics can be tested, and if proven successful, utilized to treat SLE in the future to improve patient quality of life.

Works Cited:

1. Tsokos GC. Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol. Jun 2020;21(6):605-614. doi:10.1038/s41590-020-0677-6
2. Durcan L, O’Dwyer T, Petri M. Management strategies and future directions for systemic lupus erythematosus in adults. Lancet. Jun 8 2019;393(10188):2332-2343. doi:10.1016/s0140-6736(19)30237-5
3. Zhao C, Chu Y, Liang Z, et al. Low dose of IL-2 combined with rapamycin restores and maintains the long-term balance of Th17/Treg cells in refractory SLE patients. BMC Immunol. 2019;20(1):32. Published 2019 Sep 4. doi:10.1186/s12865-019-0305-0
4. Zhao L, Zhou X, Zhou X, et al. Low expressions of PD-L1 and CTLA-4 by induced CD4⁺CD25⁺ Foxp3⁺ Tregs in patients with SLE and their correlation with the disease activity. Cytokine. 2020;133:155119. doi:10.1016/j.cyto.2020.155119
5. Guo Q, Chen C, Wu Z, et al. Engineered PD-1/TIGIT dual-activating cell-membrane nanoparticles with dexamethasone act synergistically to shape the effector T cell/Treg balance and alleviate systemic lupus erythematosus. Biomaterials. 2022;285:121517. doi:10.1016/j.biomaterials.2022.121517
6. Zhang J, Wang X, Wang R, et al. Rapamycin Treatment Alleviates Chronic GVHD-Induced Lupus Nephritis in Mice by Recovering IL-2 Production and Regulatory T Cells While Inhibiting Effector T Cells Activation. Biomedicines. 2023;11(3):949. Published 2023 Mar 20. doi:10.3390/biomedicines11030949
7. Kishimoto TK, Fournier M, Michaud A, et al. Rapamycin nanoparticles increase the therapeutic window of engineered interleukin-2 and drive expansion of antigen-specific regulatory T cells for protection against autoimmune disease. J Autoimmun. Published online October 14, 2023. doi:10.1016/j.jaut.2023.103125