Shivani Vyas
BME PhD Proposal Presentation

Date: 2024-05-16
Time: 12:00 PM
Location / Meeting Link: Krone Engineered Biosystems Building (EBB) Room 4029 / https://gatech.zoom.us/j/96399763971?pwd=cG5XSXBRSGRDNWtCelBZc08zeDBLQT09&from=addon

Committee Members:
Krishnendu Roy, PhD (Advisor); Jyothi Rengarajan, PhD; Shuichi Takayama, PhD; Leslie Chan, PhD; Jason Cook, PhD


Title: Targeting Immune Dysregulation in the Pulmonary Microenvironment

Abstract:
Lung inflammation plays a significant role during the onset of respiratory diseases, initiated by various inflammatory stimuli such as bacteria, viruses, mechanical injury, pollution, or chemicals. Acute pulmonary diseases arise from short-term immune imbalances initiated by specific stimuli. Once these initiating stimuli are eliminated or controlled, the inflammatory response subsides, allowing lung tissue to undergo remodeling and restoring immune homeostasis. Acute respiratory distress syndrome (ARDS) is a severe condition characterized by acute lung inflammation and respiratory failure, and results in a hospital mortality rate of approximately 40%. When inflammatory stimuli persist or the host’s immune response fails to resolve adequately, acute inflammation can transition into chronic inflammation, which can in turn contribute to prolonged tissue damage and disease progression. Tuberculosis (TB) is a chronic bacterial lung infection accompanied by granuloma formation. Immunosuppressive myeloid cells, termed myeloid-derived suppressor cells (MDSCs), play a vital role in shaping immune balance in both acute and chronic respiratory diseases. MDSCs, a heterogeneous population of immature myeloid cells, are involved in the pathogenesis of ARDS and TB due to their contribution to the amplification of pulmonary inflammation and tissue damage. Current therapies utilized to deplete MDSCs, ranging from chemotherapeutic agents to small molecule inhibitors and monoclonal antibodies (mAbs), encounter challenges in specifically targeting MDSCs, resulting in broad off-target effects and limited efficacy. The development of novel immunomodulatory therapies targeting MDSCs can potentially mitigate disease severity in these conditions. We have developed synthetic nanoparticle antibodies (SNAbs) to target and deplete MDSCs through antibody-like killing mechanisms in mouse triple-negative breast cancer and rat musculoskeletal trauma. SNAbs are multivalent, bifunctional Janus gold nanoparticles (AuNPs) featuring MDSC-targeting ligands on one face and antibody-fragment crystallizable (Fc)-mimicking ligands on the other. By bridging MDSCs with immune effector cells such as natural killer (NK) cells or macrophages, SNAbs have demonstrated the capability to induce the depletion of MDSCs. We aim to attenuate the effectiveness of SNAbs in mitigating immune dysregulation, reducing pulmonary inflammation, and improving disease outcomes in ARDS and TB. This thesis will serve as a foundation for developing personalized immunotherapeutic approaches for these debilitating pulmonary conditions. The central hypothesis of this proposal is that MDSC-targeting SNAbs will address immune imbalance in the lungs, and restore beneficial host immune responses in models of ARDS and TB. We aim to optimize the SNAbs and their formulation to specifically target MDSCs within the context of acute and chronic lung inflammation and evaluate their efficacy in depleting MDSCs in vitro. Further, we will evaluate the efficacy of SNAbs in models of ARDS and TB, assessing their potential to deplete MDSCs and improve host immunity. SNAbs have the potential to restore immune homeostasis and alleviate inflammation in both acute and chronic lung diseases, representing a potent immunotherapeutic strategy against respiratory illnesses.