Immunomodulatory effects of 7 hydroxy frullanolide a plant based sesquiterpene lactone in inhibiting immune cell responses and roles of disease and vaccination outcomes on Covid19 mortality

Abstract

Immunomodulation is a process by which the immune response of the host is either enhanced or suppressed due to various factors which either protects or makes the host more susceptible to particular diseases. Immunomodulators are a broad class of drugs that are used either to suppress (immunosuppressants) or enhance (immunostimulants) immune responses. These have been used to combat against the dysregulated immune system, observed during tissue/organ transplantation and disorders such as rheumatoid arthritis, ulcerative colitis and cancer. Plant-based immunomodulators such as capsaicin, curcumin and resveratrol are extensively used as immunomodulators and anti-inflammatory drugs. Sesquiterpene lactones are a major class of plant-based immunomodulators that are derivatives of sesquiterpenoids and are obtained from Asteraceae. These molecules are known for its anti-inflammatory and anti-tumor effects. The objective of my first study was to understand the roles of 7-hydroxy frullanolide (7HF) on different immune cells and to decipher the underlying mechanisms of action. Primary CD4+ T cells were isolated from lymph nodes of C57BL/6 mice, followed by treatment with different doses of 7HF and in-vitro activation with plate bound (pb) and#945;CD3 and soluble and#945;CD28. 7HF in a dose dependent manner caused a reduction in IL2 production and inhibition of upregulation of CD69, an early activation marker in CD4+ T cells. Subsequently, it was also observed that 7HF abrogated the increase in cell size and cellular proliferation with T cell activation. Ca2+ -dependent signaling pathways are an indispensable part of CD4+ T cell activation and overall T cell responses; hence it was important to understand whether 7HF had any effects on Ca2+ levels. Surprisingly, 7HF increased intracellular Ca2+ levels, more than optimal levels, during CD4+ T cell activation at early timepoints. We functionally confirmed this observation using a specific intracellular Ca2+ chelator, BAPTA-AM which rescued cellular proliferation with 7HF treatment during...