Wiess School of Natural Sciences

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Browsing Wiess School of Natural Sciences by Author "Abhimanyu"

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    Persistent tailoring of MSC activation through genetic priming
    (Elsevier, 2024) Beauregard, Michael A.; Bedford, Guy C.; Brenner, Daniel A.; Sanchez Solis, Leonardo D.; Nishiguchi, Tomoki; Abhimanyu; Longlax, Santiago Carrero; Mahata, Barun; Veiseh, Omid; Wenzel, Pamela L.; DiNardo, Andrew R.; Hilton, Isaac B.; Diehl, Michael R.
    Mesenchymal stem/stromal cells (MSCs) are an attractive platform for cell therapy due to their safety profile and unique ability to secrete broad arrays of immunomodulatory and regenerative molecules. Yet, MSCs are well known to require preconditioning or priming to boost their therapeutic efficacy. Current priming methods offer limited control over MSC activation, yield transient effects, and often induce the expression of pro-inflammatory effectors that can potentiate immunogenicity. Here, we describe a genetic priming method that can both selectively and sustainably boost MSC potency via the controlled expression of the inflammatory-stimulus-responsive transcription factor interferon response factor 1 (IRF1). MSCs engineered to hyper-express IRF1 recapitulate many core responses that are accessed by biochemical priming using the proinflammatory cytokine interferon-γ (IFN-γ). This includes the upregulation of anti-inflammatory effector molecules and the potentiation of MSC capacities to suppress T cell activation. However, we show that IRF1-mediated genetic priming is much more persistent than biochemical priming and can circumvent IFN-γ-dependent expression of immunogenic MHC class II molecules. Together, the ability to sustainably activate and selectively tailor MSC priming responses creates the possibility of programming MSC activation more comprehensively for therapeutic applications.
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    Reversing Post-Infectious Epigenetic-Mediated Immune Suppression
    (Frontiers Media S.A., 2021) Abhimanyu; Ontiveros, Carlos O.; Guerra-Resendez, Rosa S.; Nishiguchi, Tomoki; Ladki, Malik; Hilton, Isaac B.; Schlesinger, Larry S.; DiNardo, Andrew R.; Systems, Synthetic, and Physical Biology Program
    Epigenetic changes limit the immune response from inducing exuberant collateral damage to host tissue after severe and chronic infections. However, following treatment for these infections, including sepsis, pneumonia, hepatitis B, hepatitis C, HIV, tuberculosis (TB) or schistosomiasis, detrimental epigenetic scars persist, and result in long-lasting immune suppression. This is believed to be one of the contributing factors for why survivors of infection have increased all-cause mortality and increased rates of unrelated secondary infections. Several mechanisms that induce epigenetic-mediated immune suppression have been demonstrated in-vitro and in animal models. Modulation of the AMPK-mTOR, NFAT or NR4A pathways is able to block or reverse the development of detrimental epigenetic scars. Similarly, drugs that directly modify epigenetic enzymes, such as those that inhibit histone deacetylase (HDAC) inhibitors, DNA hypomethylating agents or modifiers of the Nucleosome Remodeling and DNA methylation (NuRD) complex or Polycomb Repressive Complex (PRC) have demonstrated capacity to restore host immunity in the setting of cancer-, LCMV- or murine sepsis-induced epigenetic-mediated immune suppression. A third clinically feasible strategy for reversing detrimental epigenetic scars are bioengineering approaches to either directly reverse the detrimental epigenetic marks or to modify the epigenetic enzymes or transcription factors that induce detrimental epigenetic scars. Each of these approaches, alone or in combination, have ablated or reversed detrimental epigenetic marks in in-vitro or in animal models; translational studies are now required to evaluate clinical applicability.