Biology subjects

Khailaie, S.

Publications and source records attributed to Khailaie, S..

4 recordsLinked to original sources

bioRxiv2020

An adaptive control scheme for Interleukin-2 therapy

Regulatory T cells (Treg) are suppressor cells that control self-reactive and excessive effector conventional helper T cell (Tconv) responses. Breakdown of the balance between Tregs and Tconvs is a hallmark of autoimmune and inflammatory diseases. Due to the positive dependency of both populations on Interleukin-2 (IL-2), it is subtle leverage to restore the healthy immune balance. By employing a mechanistic mathematical model, we studied the IL-2 therapy in order to increase and stabilize Treg population and restrict inflammatory Tconv response. We introduced an adaptive control strategy to design the minimal IL-2 dosage. This adaptive strategy allows for an individualized therapy based on the feedback of immune kinetics of the patient. Our in silico results suggest that a minimal Treg population is required to restrict the transient side-effect of IL-2 injections on the effector Tconv response. The combination of IL-2 and adoptive Treg transfer therapies is able to limit this side effect in our simulations. Implications of our in silico results are discussed in the context of autoimmunity and transplantation.

immunology↗

bioRxiv2020

Murine Staphylococcus aureus chronic infection is cured by theory-driven therapy

Staphylococcus aureus is considered a dangerous pathogen due to its ability to evade the immune system and resist multiple antibiotics. These evasive strategies lead to difficult-to-treat chronic infections and abscesses in internal organs including kidneys, which are associated with the expansion of myeloid-derived suppressor cells (MDSCs) and their suppressive effect on T cells. Here, we developed a mathematical model of chronic S. aureus infection that incorporates the T-cell suppression by MDSCs and suggests therapeutic strategies to eradicate S. aureus. We quantified in silico a therapeutic protocol with heat-killed S. aureus (HKSA), which we tested in vivo. Contrary to conventional administration of heat-killed bacteria as vaccination prior to infection, we administered HKSA as treatment, when the hosts were already chronically infected. Our treatment cured all chronically S. aureus-infected mice, reduced MDSCs, and reversed T-cell dysfunction by inducing acute inflammation during ongoing, chronic infection without any use of standard treatments that involve antibiotics, MDSC-targeting drugs (chemotherapy), or procedures such as abscess drainage. This study is a proof-of-principle for a treatment protocol against chronic S. aureus infection and renal abscesses by repurposing heat-killed treatments, guided and quantified by mathematical modelling. Our mathematical model further explains why previous treatment with inactivated S. aureus administered to long-term infected human patients has not led to cure. Overall, our results can have direct relevance to the design of human therapeutics against chronic S. aureus infections. In briefA theory-driven treatment protocol with heat-killed S. aureus eradicates S. aureus, reduces MDSCs, and reverses T-cell dysfunction in vivo. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=157 HEIGHT=200 SRC="FIGDIR/small/910786v3_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1e2d0c9org.highwire.dtl.DTLVardef@1f97374org.highwire.dtl.DTLVardef@b0235org.highwire.dtl.DTLVardef@bdf2ee_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2019

Mathematical model shows how sleep may affect amyloid β fibrillization

Deposition of amyloid {beta} (A{beta}) fibers in extra-cellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimers disease (AD). While many of the biological aspects that contribute to the formation of A{beta} plaques are well addressed at the intra- and inter-cellular level in short timescales, an understanding of how A{beta} fibrillization usually starts to dominate at a longer timescale in spite of the presence of mechanisms dedicated to A{beta} clearance, is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in sleep-wake cycle. In this study, we develop a minimal model of A{beta} fibrillization to investigate the onset of AD over a long time-scale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble A{beta} (sA{beta}) to fibrillar A{beta} (fA{beta}) domination upon surpassing a threshold in the production rate of soluble A{beta}. By incorporating the circadian rhythm into our model, we reveal that fA{beta} accumulation is crucially dependent on the regulation of sleep-wake cycle, thereby indicating the importance of a good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fA{beta} accumulation in the brain by modification of the critical sA{beta} production rate.

systems biology↗

bioRxiv2017

Quantitative characterization of CTLA4 trafficking and turnover using a combined in vitro and in silico approach

CTLA4 is an essential negative regulator of T cell immune responses and is a key checkpoint regulating autoimmunity and anti-tumour immunity. Genetic mutations resulting in a quantitative defect in CTLA4 are associated with the development of an immune dysregulation syndrome. Endocytosis of CTLA4 is rapid and continuous with subsequent degradation or recycling. CTLA4 has two natural ligands, the surface transmembrane proteins CD80 and CD86 that are shared with the T cell co-stimulatory receptor CD28. Upon ligation with CD80/CD86, CTLA4 can remove these ligands from the opposing cells by transendocytosis. The efficiency of ligand removal is thought to be highly dependent on the processes involved in CTLA4 trafficking. With a combined in vitro-in silico study, we quantify the rates of CTLA4 internalization, recycling and degradation. We incorporate experimental data from cell lines and primary human T cells. Our model provides a framework for exploring the impact of altered affinity of natural ligands or therapeutic anti-CTLA4 antibodies and for predicting the effect of clinically relevant CTLA4 pathway mutations. The presented methodology for extracting trafficking rates can be transferred to the study of other transmembrane proteins.

immunology↗