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Awareness of RNA-based therapies has increased after the widespread adoption of mRNA vaccines against SARS-CoV-2 during the COVID-19 pandemic. These mRNA vaccines had a significant impact on reducing lung disease and mortality. They highlighted the potential for rapid development of RNA-based therapies and advances in nanoparticle delivery systems. Along with the rapid advancement in RNA biology, including the description of noncoding RNAs as major products of the genome, this success presents an opportunity to highlight the potential of RNA as a therapeutic modality. Here, we review the expanding compendium of RNAbased therapies, their mechanisms of action and examples of application in the lung. The airways provide a convenient conduit for drug delivery to the lungs with decreased systemic exposure. This review will also describe other delivery methods, including local delivery to the pleura and delivery vehicles that can target the lung after systemic administration, each providing access options that are advantageous for a specific application. We present clinical trials of RNA-based therapy in lung disease and potential areas for future directions. This review aims to provide an overview that will bring together researchers and clinicians to advance this burgeoning field. [ABSTRACT FROM AUTHOR]

Regulatory T cell (Treg) therapy is a potential curative approach for a variety of immune-mediated conditions, including autoimmunity and transplantation, in which there is pathological tissue damage. In mice, IL-33R (ST2)--expressing Tregs mediate tissue repair by producing the growth factor amphiregulin, but whether similar tissue-reparative Tregs exist in humans remains unclear. We show that human Tregs in blood and multiple tissue types produced amphiregulin, but this was neither a unique feature of Tregs nor selectively upregulated in tissues. Human Tregs in blood, tonsil, synovial fluid, colon, and lung tissues did not express ST2, so ST2+ Tregs were engineered via lentiviral-mediated overexpression, and their therapeutic potential for cell therapy was examined. Engineered ST2+ Tregs exhibited TCR-independent, IL-33--stimulated amphiregulin expression and a heightened ability to induce M2-like macrophages. The finding that amphiregulin-producing Tregs have a noneffector phenotype and are progressively lost upon TCR-induced proliferation and differentiation suggests that the tissue repair capacity of human Tregs may be an innate function that operates independently from their classical suppressive function. [ABSTRACT FROM AUTHOR]

Background: Survival after lung transplantation (LTx) is hampered by uncontrolled inflammation and alloimmunity. Regulatory T-cells (Tregs) are being studied as a cellular therapy in solid organ transplantation. Whether these systemically administered Tregs can function at the appropriate location and time is an important concern. We hypothesised that in vitro -expanded recipient-derived Tregs can be delivered to donor lungs prior to LTx via ex vivo lung perfusion (EVLP), maintaining their immunomodulatory ability., Methods: In a rat model, Wistar Kyoto (WKy) CD4 + CD25 high Tregs were expanded in vitro prior to EVLP. Expanded Tregs were administered to Fisher 344 (F344) donor lungs during EVLP; left lungs were transplanted into WKy recipients. Treg localisation and function post-transplant were assessed. In a proof-of-concept experiment, cryopreserved expanded human CD4 + CD25 + CD127 low Tregs were thawed and injected into discarded human lungs during EVLP., Results: Rat Tregs entered the lung parenchyma and retained suppressive function. Expanded Tregs had no adverse effect on donor lung physiology during EVLP; lung water as measured by wet-to-dry weight ratio was reduced by Treg therapy. The administered cells remained in the graft at 3 days post-transplant where they reduced activation of intra-graft effector CD4 + T-cells; these effects were diminished by day 7. Human Tregs entered the lung parenchyma during EVLP where they expressed key immunoregulatory molecules (CTLA4 + , 4-1BB + , CD39 + and CD15s + )., Conclusions: Pre-transplant Treg administration can inhibit alloimmunity within the lung allograft at early time points post-transplant. Our organ-directed approach has potential for clinical translation., Competing Interests: Conflict of interest: E. Miyamoto reports fellowships from The Kyoto University Foundation, Japan; the Cell Science Research Foundation, Japan; and the International Society for Heart and Lung Transplantation, during the conduct of the study. Conflict of interest: A. Takahagi has nothing to disclose. Conflict of interest: A. Ohsumi has nothing to disclose. Conflict of interest: T. Martinu has nothing to disclose. Conflict of interest: D. Hwang has nothing to disclose. Conflict of interest: K.M. Boonstra has nothing to disclose. Conflict of interest: B. Joe has nothing to disclose. Conflict of interest: J.M. Umana has nothing to disclose. Conflict of interest: K.F. Bei has nothing to disclose. Conflict of interest: D. Vosoughi has nothing to disclose. Conflict of interest: M. Liu has nothing to disclose. Conflict of interest: M. Cypel reports being co-founder of Perfusix Canada and Traferox Technologies Inc. Toronto, and reports consultancy for Lung Bioengineering and United Therapeutics, during the conduct of the study. Conflict of interest: S. Keshavjee reports being co-founder of Perfusix Canada and Traferox Technologies Inc. Toronto, and reports consultancy for Lung Bioengineering and United Therapeutics, during the conduct of the study. Conflict of interest: S.C. Juvet reports grants from Ontario Institute for Regenerative Medicine and Cystic Fibrosis Canada, during the conduct of the study., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Peripheral αβTCR(+)CD3(+)CD4(-)CD8(-) NK1.1/CD56(-) double-negative (DN) Treg cells are a relatively rare subset of regulatory cells found in both humans and mice, typically comprising less than 5% of the total peripheral T-cell pool. Numerous studies have shown that DN Tregs can inhibit CD4(+) and CD8(+) T-cell responses in vitro and in vivo using a variety of model systems [Zhang et al., Nature Medicine 6:782, 2000; Young et al., Blood 100:3408, 2002; Ford et al., Experimental Medicine 196:261, 2002; Young et al., Journal of Immunology 171:134, 2003; Ford et al., European Journal of Immunology 37:2234, 2007; Zhang et al., Blood 109:4071, 2007; Fischer et al., Blood 105:2828, 2005]. This chapter describes published methods for the phenotypic identification of DN Tregs, their isolation from secondary lymphoid organs of mice or human peripheral blood, activation and expansion, and assays for their ability to suppress T-cell proliferation, induce apoptosis, and promote tolerance to allografts in vivo.