Lipid-based regulators of immunity.

Lipids constitute a diverse class of molecular regulators with ubiquitous physiological roles in sustaining life. These carbon-rich compounds are primarily sourced from exogenous sources and may be used directly as structural cellular building blocks or as a substrate for generating signaling mediators to regulate cell behavior. In both of these roles, lipids play a key role in both immune activation and suppression, leading to inflammation and resolution, respectively. The simple yet elegant structural properties of lipids encompassing size, hydrophobicity, and molecular weight enable unique biodistribution profiles that facilitate preferential accumulation in target tissues to modulate relevant immune cell subsets. Thus, the structural and functional properties of lipids can be leveraged to generate new materials as pharmacological agents for potently modulating the immune system. Here, we discuss the properties of three classes of lipids: polyunsaturated fatty acids, short-chain fatty acids, and lipid adjuvants. We describe their immunoregulatory functions in modulating disease pathogenesis in preclinical models and in human clinical trials. We conclude with an outlook on harnessing the diverse and potent immune modulating properties of lipids for immunoregulation.

Triggers, Timescales, and Treatments for Cytokine-Mediated Tissue Damage.

Inflammation is an essential cytokine-mediated process for generating a neutralizing immune response against pathogens and is generally protective. However, aberrant or excessive production of pro-inflammatory cytokines is associated with uncontrolled local and systemic inflammation, resulting in cell death and often irreversible tissue damage. Uncontrolled inflammation can manifest over timescales spanning hours to years and is primarily dependent on the triggering event. Rapid and potentially lethal increase in cytokine production, or a 'cytokine storm,' develops in hours to days and is associated with cancer cell-based immunotherapies, such as CAR-T cell therapy. On the other hand, some bacterial and viral infections with high microbial replication or highly potent antigens elicit immune responses that result in supraphysiological systemic cytokine concentrations which manifest over days to weeks. Immune dysregulation in autoimmune diseases can lead to chronic cytokine-mediated tissue damage spanning months to years, which often occurs episodically. While the initiating events and cellular participants may differ in these disease processes, many of the cytokines that drive disease progression are shared. For example, upregulation of IL-1, IL-6, IFN-γ, TNF, and GM-CSF frequently coincides with cytokine storm, sepsis, and autoimmune disease. Targeted inhibition of these pro-inflammatory molecules via antagonist monoclonal antibodies has improved clinical outcomes, but the complexity of the underlying immune dysregulation results in high variability. Rather than a "one size fits all" treatment approach, an identification of disease endotypes may permit the development of effective therapeutic strategies that address the contributors of disease progression. Here, we present a literature review of the cytokine-associated etiology of acute and chronic cytokine-mediated tissue damage, describe successes and challenges in developing clinical treatments, and highlight advancements in preclinical therapeutic strategies for mitigating pathological cytokine production.

Characterization of regulatory T cell expansion for manufacturing cellular immunotherapies.

Regulatory T cells (Tregs) are critical mediators of peripheral immune tolerance. Tregs suppress immune activation against self-antigens and are the focus of cell-based therapies for autoimmune diseases. However, Tregs circulate at a very low frequency in blood, limiting the number of cells that can be isolated by leukapheresis. To effectively expand Tregsex vivo for cell therapy, we report the metabolic modulation of T cells using mono-(6-amino-6-deoxy)-ß-cyclodextrin (ßCD-NH2) encapsulated rapamycin (Rapa). Encapsulating Rapa in ß-cyclodextrin increased its aqueous solubility ∼154-fold and maintained bioactivity for at least 30 days. ßCD-NH2-Rapa complexes (CRCs) enriched the fraction of CD4+CD25+FoxP3+ mouse T (mT) cells and human T (hT) cells up to 6-fold and up to 2-fold respectively and suppressed the overall expansion of effector T cells by 5-fold in both species. Combining CRCs and transforming growth factor beta-1 (TGF-ß1) synergistically promoted the expansion of CD4+CD25+FoxP3+ T cells. CRCs significantly reduced the fraction of pro-inflammatory interferon-gamma (IFN-γ) expressing CD4+ T cells, suppressing this Th1-associated cytokine while enhancing the fraction of IFN-γ- tumor necrosis factor-alpha (TNF-α) expressing CD4+ T cells. We developed a model using kinetic rate equations to describe the influence of the initial fraction of naïve T cells on the enrichment of Tregsin vitro. The model related the differences in the expansion kinetics of mT and hT cells to their susceptibility for immunophenotypic modulation. CRCs may be an effective and potent means for phenotypic modulation of T cells and the enrichment of Tregsin vitro. Our findings contribute to the development of experimental and analytical techniques for manufacturing Treg based immunotherapies.