In the Acharya Lab at Case Western Reserve University’s Case School of Engineering, we’re interested in autoimmune diseases, cancer, and inflammatory and infectious diseases. Some of our research interests include drug delivery materials, biomaterial development, metabolite delivery, mitochondrial biology, murine animal models, and studying different immune cell types.
Immune Engineering
Immune engineering is a field that brings together the areas of engineering and immunology to harness the power of the immune system and resolve different diseases. We work on these areas to address cancer, inflammation, injury and autoimmune diseases.
Immunometabolism
Immunometabolism is a field that is at the interface of immunology and metabolism. Metabolic processes play a pivotal role in governing the immune cell responses in both healthy individuals in inflammation, infection, cancer, autoimmune disorders, and obesity. Notably, metabolites originating from the mammalian cells, microbiota and infectious agents influence the behavior of the immune cells and overall immune responses.
Based on these ideas, our lab is heralding innovative treatments for chronic inflammatory conditions, autoimmune diseases, and cancer by developing novel immunotherapies. Acharya Lab works on these areas to address a variety of diseases including melanoma, ovarian cancer, traumatic brain injury, rheumatoid arthritis, osteoarthritis, weight loss, and pain dynamics, among other areas.
Our long-term goals are to develop translational biomaterials that can engineer the metabolism of immune cells and develop immunotherapies. To achieve these goals, we develop biomaterials that can effectively modulate the function of immune cells by modulating different metabolic pathways and affect disease outcomes.
Our Projects
Immunometabolism Modulating Formulations for Cancer Immunotherapy (Inamdar et al., Suresh et. al)
Our lab focuses on modulating metabolism of innate immune cells (such as dendritic cells, macrophages, etc.) to generate metabolically fit immune cells for cancer vaccines. For example, we have generated succinate based polymers as adjuvants to generate robust immune responses. We have also developed subcutaneous vaccine mouse models and adoptive cell therapy of dendritic cells. This vaccine consists of the metabolite fructose 1,6 bisphosphate that accelerates glycolysis, poly(I:C) as an adjuvant and TRP2 as the melanoma tumor antigen. Moreover, we also develop metabolite based formulations to accelerate metabolism of adaptive T cells to affect ovarian cancer immunotherapy.
References
Nature Communications 14 (1), 5333, 2023 - https://doi.org/10.1038/s41467-023-41016-z
Biomaterials 301, 122292, 2023 - https://doi.org/10.1016/j.biomaterials.2023.122292
Journal of Controlled Release 358, 541-554, 2023 - https://doi.org/10.1016/j.jconrel.2023.05.014
Metabolically Activated CAR-Macrophages as a Therapy Against Lymphoma (Abhirami P. Suresh et al.)
Although chimeric antigen receptor (CAR) T cell (an immune cell type) therapy has revolutionized cancer treatment, response against solid tumors is not robust. Notably, macrophages are actively recruited by solid tumors, and therefore CAR-macrophage (CAR-macs) mediated therapies might be able to target solid tumors effectively. Unfortunately, once in the tumor, due to lack of nutrients and immunosuppressive environment, macrophages are converted to their immune-suppressive phenotype (M2).
These macrophages are highly immunosuppressive, and thus have pro-tumor response. Therefore, if CAR-macs are to succeed as a viable strategy to target and kill cancer cells they need to remain activated even in resource-poor environments. In this work, we have utilized drug delivery approaches to enhance the ability of CAR macrophages to kill lymphoma cells. Moreover, when the CAR-macrophages are pre-treated with F16BP microparticles (MPs) the glycolysis is increased, when external glucose is added (Red and blue lines). This demonstrates that F16BP MPs are able to allow for cells to survive and glycolysis to move forward.
Covalent Organic Frameworks to Understand the Effect of Crystallinity of Biomaterials on Immune Activation (Arezoo Esrafili et al.)
Crystalline biomaterials based on the level of crystallinity may be able to activate the dendritic cells differentially. Shown on the left are schematic of covalent organic frameworks (COFs) with varying crystal structures, and on the right are dendritic cells with a COF affecting downstream T cell responses.
Rheumatoid Arthritis Treatment (Abhirami Thumsi et al.; Mangal et al.)
Humans have recurrence of inflammation termed as flare-ups. This is typically caused by resident T-cells in the tissues. Recapitulating this in mice, we developed a mouse model where the disease can be re-induced by T-cells. We were able to show the efficacy of a metabolite-based modulator- paKG(PFK15+bc2) in prevention of these flare ups in mice.
Efficacy of Metabolism Modulating Inverse Vaccines in Restoring Metabolic and Immunological Homeostasis (Abhirami Thumsi et al.)
Inflammation leads to an imbalance in energy demand and immune cell profiles in diseases, thereby affecting the normal homeostasis of the body. We aim to evaluate the efficacy of our microparticle- paKG(PFK15+bc2) in restoring homeostasis in collagen induced arthritis in different stages of the disease. We also look at regulatory T cell infiltration in rheumatoid arthritis affected tissue by staining for Foxp3. Shown below is a confocal image of Foxp3+ cells in the paw tissue of a rheumatoid arthritis mouse.
References
Drug Delivery and Translational Research 13 (7), 1925-1935, 2023 - https://doi.org/10.1007/s13346-023-01333-8
Biomaterials Science 10 (23), 6688-6697, 2022 - DOI: 10.1039/D2BM00415A
Biomaterials 277, 121079, 2021 - https://doi.org/10.1016/j.biomaterials.2021.121079
Journal of Materials Chemistry B 8 (24), 5195-5203, 2020 - DOI
https://doi.org/10.1039/D0TB00790K
Improving Cutaneous Wound Healing Rates (Jaggarapu et al.)
This project focuses on polyesters of alpha-ketoglutarate (paKG), generated by reacting alpha-ketoglutarate with aliphatic diols. These paKG particles, developed through an emulsion-evaporation technique, show accelerated keratinocyte wound closures in a scratch assay and faster wound healing responses in mice models. The sustained release of alpha-ketoglutarate from these microparticles presents a promising approach for regenerative therapeutic interventions.
Reference
Journal of Biomedical Materials Research Part A, 2023 - https://doi.org/10.1002/jbm.a.37539
T Cell Modulation via Oral Delivery of Metabolites (Jaggarapu et al.)
Covalent organic framework (COF) crystalline biomaterials have great potential for drug delivery since they can load large amounts of small molecules (e.g. metabolites) and release them in a controlled manner, as compared to their amorphous counterparts. We screened different metabolites for their ability to modulate T cell responses in vitro and identified Kynurenine (KyH) as a key metabolite that not only decreases frequency of pro-inflammatory RORgt + T cells but also supports frequency of anti-inflammatory GATA3+ T cells in vitro.
Moreover, we developed a methodology to generate imine-based TAPB-PDA COF at room temperature and loaded these COFs with KyH. KyH loaded COFs (COF-KyH) were able to then release KyH in a controlled manner and when delivered orally in mice induced with collagen-induced rheumatoid arthritis (CIA) were able to increase frequency of anti-inflammatory GATA3+CD8+ T cells in the lymph nodes and decrease antibody titers in the serum as compared to the controls.
Reference
Biomaterials, 122204, 2023 - https://doi.org/10.1016/j.biomaterials.2023.122204
Current Research Sponsor
1 R01 AI155907-01
1 R01 AI155907-01
1R01GM144966-01
NSF CAREER AWARD # 2145877
NSF STTR AWARD # 2151586
TBIHRP – Idea Award