Biology subjects

Kumbhari, A.

Publications and source records attributed to Kumbhari, A..

3 recordsLinked to original sources

bioRxiv2020

A minimal model of T cell avidity may identify subtherapeutic vaccine schedules

T cells protect the body from cancer by recognising tumour-associated antigens. Recognising these antigens depends on multiple factors, one of which is T cell avidity, i.e., the total interaction strength between a T cell and a cancer cell. While both high- and low-avidity T cells can kill cancer cells, durable anti-cancer immune responses require the selection of high-avidity T cells. Previous experimentation with anti-cancer vaccines, however, has shown that most vaccines elicit low-avidity T cells. Optimising vaccine schedules may remedy this by preferentially selecting high-avidity T cells. Here, we use mathematical modelling to develop a simple, phenomenological model of avidity selection that may identify vaccine schedules that disproportionately favour low-avidity T cells. We calibrate our model to our prior, more complex model, and then validate it against several experimental data sets. We find that the sensitivity of the models parameters change with vaccine dosage, which allows us to use a patients data and clinical history to screen for suitable vaccine strategies.

immunology↗

bioRxiv2020

An in-silico study to determine whether changes to mitochondria organization through engineered mitochondrial dynamics can enhance bioenergetics in cardiomyocytes

Mitochondria are the powerhouse of the cell and owing to their unique energetic demands, heart muscles contain a high density of mitochondria. In conditions such as heart failure and diabetes-induced heart disease, changes in the organization of cardiac mitochondria are common. While recent studies have also shown that cardiac mitochondria split and fuse throughout the cell, a mechanistic understanding of how mitochondrial dynamics may affect energy output is lacking. Using a mathematical model that has been fitted to experimental data, we test if briefly altering fission or fusion rates improves ATP production and supply in cardiomyocytes. Unexpectedly, we found that cardiac bioenergetics, e.g., the ADP/ATP ratio, were robust to changes in fusion and fission rates and consequently mitochondria organization. Our study highlights complex nonlinear feedback loops that are at play in the cross-talk between mitochondrial dynamics and bioenergetics. The study motivate further in-silico and experimental investigations to determine the mechanistic basis for new therapies that target mitochondrial dynamics.

systems biology↗

bioRxiv2020

Immature dendritic cells promote high avidity tuning of vaccine T cell response

Therapeutic vaccines can elicit tumor-specific cytotoxic T lymphocytes (CTLs), but durable reductions in tumor burden require vaccines that stimulate high-avidity CTLs. Recent advances in immunotherapy responses have led to renewed interest in vaccine approaches, including dendritic cell vaccine strategies. However, dendritic cell requirements for vaccines that generate potent anti-tumor T-cell responses are unclear. Here we use mathematical modeling to show that counterintuitively, increasing levels of immature dendritic cells may lead to selective expansion of high-avidity CTLs. This finding contrasts with traditional dendritic cell vaccine approaches that have sought to harness ex vivo generated mature dendritic cells. We show that the injection of vaccine antigens in the context of increased numbers of immature dendritic cells results in a decreased overall peptide:MHC complex load that favors high-avidity CTL activation and expansion. Overall, our results provide a firm basis for further development of this approach, both alone and in combination with other immunotherapies such as checkpoint blockade.

immunology↗