Cytotoxic T-lymphocyte Immune Response Research Articles

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Global stability of a general HTLV-I infection model with Cytotoxic T-Lymphocyte immune response and mitotic transmission

Mathematical models have been considered as a robust tool to support biological and medical studies of human viral infections. The global stability of viral infection models remains an important and largely open research problem. Such results are necessary to evaluate treatment strategies for infections and to establish thresholds for treatment rates. Human T-lymphotropic virus class I (HTLV-I) is a retrovirus which infects the CD4+T cells and causes chronic and deadly diseases. In this article, we developed a general nonlinear system of ODEs which describes the within-host dynamics of HTLV-I under the effect Cytotoxic T-Lymphocytes (CTLs) immunity. The mitotic division of actively infected cells are modeled. We consider general nonlinear functions for the generation, proliferation and clearancerates for all types of cells. The incidence rate of infection is also modeled by a general nonlinear function. These general functions are assumed to satisfy a set of suitable conditions and include several forms presented in the literature. We determine a bounded domain for the system’s solutions. We prove the existence of the system’s equilibrium points and determine two threshold numbers, the basic reproductive number R0 and the CTL immunity stimulation number R1. We establish the global stability of all equilibrium points by constructing Lyapunov function and applying Lyapunov-LaSalle asymptotic stability theorem. Under certain conditions it is shown that ifR0≤1, then the infection-free equilibrium point is globally asymptotically stable (GAS) and the HTLV-I infection is cleared. If R1≤1<R0, then the infected equilibrium point without CTL immunity is GAS and the HTLV-I infection becomes chronic with no sustained CTL immune response. If R1>1, then the infected equilibrium point with CTL immunity is GAS and the infection becomes chronic with persistent CTL immune response. We present numerical simulations for the system by choosing special shapes of the general functions. The effect of Crowley-Martin functional response and mitotic division of actively infected cells on the HTLV-I progression are studied. Our results cover and improve several ones presented in the literature.

Modeling the Adaptive Immune Response in an HBV Infection Model with Virus to Cell Transmission in Both Liver with CTL Immune Response and the Extrahepatic Tissue

The objective of this paper is to investigate a mathematical model describing the infection of hepatitis B virus (HBV) in intrahepatic and extrahepatic tissues. Additionally, the model includes the effect of the cytotoxic T cell (CTL) immunity, which is described by a linear activation rate by infected cells. The positivity and boundedness of solutions for non-negative initial data are proven, which is consistent with the biological studies. The local stability of the equilibrium is established. In addition to this, the global stability of the disease-free equilibrium and the endemic equilibrium is fulfilled by using appropriate Lyapanov functions. Finally, numerical simulations are performed to support our theoretical findings. It has been revealed that the fractional-order derivatives have no influence on the stability but only on the speed of convergence toward the equilibria.

A delayed diffusive HBV model with nonlinear incidence and CTL immune response

In this paper, we develop a diffusive and delayed hepatitis B virus (HBV) infection model, which incorporates both virus‐to‐cell and cell‐to‐cell transmissions along with cytotoxic T lymphocyte (CTL) immune response. Two threshold parameters (basic reproduction number) and (immune response reproduction number) are defined, which determine the dynamic behavior of the model. Employing the approach of Lyapunov functionals, we show that the infection‐free steady state is globally asymptotically stable when ; the immune‐free infected steady state is globally asymptotically stable when ; and the immune‐present steady state is globally asymptotically stable when , and . We perform the sensitivity and uncertainly analysis on with respect to parameters and find that the most important parameter that drives the HBV infection is the mortality of HBV DNA capsids. Moreover, the theoretical results are supported with numerical simulations.

Ketone Bodies Improve Human CD8+ Cytotoxic T-Cell Immune Response During COVID-19 Infection.

Severe COVID-19 is characterized by profound CD8+ T-cell dysfunction, which cannot be specifically treated to date. We here investigate whether metabolic CD8+ T-cell reprogramming by ketone bodies could be a promising strategy to overcome the immunoparalysis in COVID-19 patients. This approach was triggered by our recent pioneering study, which has provided evidence that CD8+ T-cell capacity in healthy subjects could be significantly empowered by a Ketogenic Diet. These improvements were achieved by immunometabolic rewiring toward oxidative phosphorylation. We here report similar strengthening of CD8+ T cells obtained from severely diseased COVID-19 patients: Flow cytometry and ELISA revealed elevated cytokine expression and secretion (up to + 24%) upon ketone treatment and enhanced cell lysis capacity (+ 21%). Metabolic analyses using Seahorse technology revealed upregulated mitochondrial respiratory chain activity (+ 25%), enabling both superior energy supply (+ 44%) and higher mitochondrial reactive oxygen species signaling. These beneficial effects of ketones might represent evolutionary conserved mechanisms to strengthen human immunity. Our findings pave the road for metabolic treatment studies in COVID-19.

Dynamics of a reaction-diffusion fractional-order model for M1 oncolytic virotherapy with CTL immune response

Despite many years of research, cancer continues to be a major worldwide concern. Several researchers proposed their mathematical models to understand and describe the dynamics of tumor cells under some cancer treatments. In this paper, we present a fractional partial differential equation system to describe the dynamics in space and time of the concentration of normal cells, tumor cells, nutrient, M1 virus, and cytotoxic T lymphocytes (CTL) cells, as well as the interaction between them. We study and analyze the equilibrium points of the presented system. The global stability of these equilibrium points is proved by constructing adequate Lyapunov functional for each equilibrium point. Furthermore, we give some numerical simulations to illustrate our results.

Threshold dynamics of an HIV-1 model with both virus-to-cell and cell-to-cell transmissions, immune responses, and three delays

Abstract In this paper, the dynamical behaviors of a multiple delayed HIV-1 infection model which describes the interactions of humoral, cytotoxic T lymphocyte (CTL) immune responses, and two modes of transmission that are the classical virus-to-cell infection and the direct cell-to-cell transmission are investigated. The model incorporates three delays, including the delays of cell infection, virus production and activation of immune response. We first prove the well-posedness of the model, and calculate the biological existence of equilibria and the reproduction numbers, which contain virus infection, humoral immune response, CTL immune response, CTL immune competition, and humoral immune competition. Further, the threshold conditions for the local and global stability of the equilibria for infection-free, immune-free, antibody response, CTL response, and interior are established by utilizing linearization method and the Lyapunov functionals. The existence of Hopf bifurcation with immune delay as a bifurcation parameter is investigated by using the bifurcation theory. Numerical simulations are carried out to illustrate the theoretical results and reveal the effects of some key parameters on viral dynamics.

Periodic oscillation for a class of in-host MERS-CoV infection model with CTL immune response.

The purpose of this paper is to give some sufficient conditions for the existence of periodic oscillation of a class of in-host MERS-Cov infection model with cytotoxic T lymphocyte (CTL) immune response. A new technique is developed to obtain a lower bound of the state variable characterizing CTL immune response in the model. Our results expand on some previous works.

Stochastic HIV Infection Model with CTLs Immune Response Driven by L&amp;#233;vy Jumps

This paper mainly investigates the effect of the lévy jumps on the stochastic HIV infection model with cytotoxic T lymphocytes (CTLs) immune response. First, we prove that there is a unique global positive solution in any population dynamics, then we find sufficient conditions for the extinction of the disease. For proofing the persistence in mean, a special Lyapunov function be established, we obtain that if the infected CD4+ T-cells and virus particles will persistence in mean. Finally, numerical simulations are carried out to illustrate the theoretical results.

Stability analysis of general delayed HTLV-I dynamics model with mitosis and CTL immunity.

This paper formulates and analyzes a general delayed mathematical model which describe the within-host dynamics of Human T-cell lymphotropic virus class I (HTLV-I) under the effect Cytotoxic T Lymphocyte (CTL) immunity. The models consist of four components: uninfected CD$ 4^{+} $T cells, latently infected cells, actively infected cells and CTLs. The mitotic division of actively infected cells are modeled. We consider general nonlinear functions for the generation, proliferation and clearance rates for all types of cells. The incidence rate of infection is also modeled by a general nonlinear function. These general functions are assumed to be satisfy some suitable conditions. To account for series of events in the infection process and activation of latently infected cells, we introduce two intracellular distributed-time delays into the models: (ⅰ) delay in the formation of latently infected cells, (ⅱ) delay in the activation of latently infected cells. We determine a bounded domain for the system's solutions. We calculate two threshold numbers, the basic reproductive number $ R_{0} $ and the CTL immunity stimulation number $ R_{1} $. We determine the conditions for the existence and global stability of the equilibrium points. We study the global stability of all equilibrium points using Lyapunov method. We prove the following: (a) if $ R_{0}\leq 1 $, then the infection-free equilibrium point is globally asymptotically stable (GAS), (b) if $ R_{1}\leq 1 < R_{0} $, then the infected equilibrium point without CTL immunity is GAS, (c) if $ R_{1} > 1 $, then the infected equilibrium point with CTL immunity is GAS. We present numerical simulations for the system by choosing special shapes of the general functions. The effects of proliferation of CTLs and time delay on the HTLV-I progression is investigated. We noted that the CTL immunity does not play the role in clearing the HTLV-I from the body, but it has an important role in controlling and suppressing the viral infection. On the other hand, we observed that, increasing the time delay intervals can have similar influences as drug therapies in removing viruses from the body. This gives some impression to develop two types of treatments, the first type aims to extend the intracellular delay periods, while the second type aims to activate and stimulate the CTL immune response.

Global stability of HIV/HTLV co-infection model with CTL-mediated immunity

&lt;p style='text-indent:20px;'&gt;Mathematical modeling of human immunodeficiency virus (HIV) and human T-lymphotropic virus type Ⅰ (HTLV-I) mono-infections has received considerable attention during the last decades. These two viruses share the same way of transmission between individuals; through direct contact with certain contaminated body fluids. Therefore, a person can be co-infected with both viruses. In the present paper, we construct and analyze a new HIV/HTLV-I co-infection model under the effect of Cytotoxic T lymphocytes (CTLs) immune response. The model describes the interaction between susceptible CD&lt;inline-formula&gt;&lt;tex-math id="M1"&gt;\begin{document}$ 4^{+} $\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt;T cells, silent HIV-infected cells, active HIV-infected cells, silent HTLV-infected cells, Tax-expressing (active) HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. The HIV can spread by two routes of transmission, virus-to-cell (VTC) and cell-to-cell (CTC). Both active and silent HIV-infected cells can infect the susceptible CD&lt;inline-formula&gt;&lt;tex-math id="M2"&gt;\begin{document}$ 4^{+} $\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt;T cells by CTC mechanism. On the other side, HTLV-I has only one mode of transmission via direct cell-to-cell contact. The well-posedness of the model is established by showing that the solutions of the model are nonnegative and bounded. We calculate all possible equilibria and define the key threshold parameters which govern the existence and stability of all equilibria of the model. We explore the global asymptotic stability of all equilibria by utilizing Lyapunov function and LaSalle's invariance principle. We have discussed the influence of CTL immune response on the co-infection dynamics. We have presented numerical simulations to justify the applicability and effectiveness of the theoretical results. In addition, we evaluate the effect of HTLV-I infection on the HIV dynamics and vice versa.&lt;/p&gt;

Modeling the Effect of Reactive Oxygen Species and CTL Immune Response on HIV Dynamics

Individuals infected by human immunodeficiency virus (HIV) are under oxidative stress due to the imbalance between reactive oxygen species (ROS) production and elimination. This paper presents a mathematical model with the cytotoxic T lymphocytes (CTL) immune response to examine the role of ROS in the dynamics of HIV infection. We classify the equilibria of the model and study the stability of these equilibria. Numerical simulations show that incorporating ROS and CTL immune response into the model leads to very rich dynamics, including bistable phenomena and periodic solutions. Although the current antiretroviral therapy can suppress viral load to the undetectable level, it cannot eradicate the virus. A high level of ROS may be a factor for HIV persistence in patients despite suppressive therapy. These results suggest that oxidative damage and anti-oxidant therapy should be considered in the study of HIV infection and treatment.

Dynamics of stochastic HTLV‐I infection model with nonlinear CTL immune response

In this paper, the dynamics of stochastic human T‐cell leukemia virus type I (HTLV‐I) infection model with cytotoxic T lymphocyte (CTL) immune response is investigated. First, we show that the stochastic model exists as a unique positive global solution originating from the positive initial value. Second, we demonstrate that the stochastic model is stochastically permanent and stochastically ultimately bounded for any positive initial value. Third, we establish sufficient conditions for the existence of ergodic stationary distribution of the stochastic model. Fourth, the threshold between extinction and persistence of the virus is obtained. Finally, numerical simulations are carried out to illustrate the theoretical results.

Developing Acid-Responsive Glyco-Nanoplatform Based Vaccines for Enhanced Cytotoxic T-lymphocyte Responses Against Cancer and SARS-CoV-2.

Cytotoxic T‐lymphocytes (CTLs) are central for eliciting protective immunity against malignancies and infectious diseases. Here, for the first time, partially oxidized acetalated dextran nanoparticles (Ox‐AcDEX NPs) with an average diameter of 100 nm are fabricated as a general platform for vaccine delivery. To develop effective anticancer vaccines, Ox‐AcDEX NPs are conjugated with a representative CTL peptide epitope (CTLp) from human mucin‐1 (MUC1) with the sequence of TSAPDTRPAP (referred to as Mp1) and an immune‐enhancing adjuvant R837 (referred to as R) via imine bond formation affording AcDEX‐(imine)‐Mp1‐R NPs. Administration of AcDEX‐(imine)‐Mp1‐R NPs results in robust and long‐lasting anti‐MUC1 CTL immune responses, which provides mice with superior protection from the tumor. To verify its universality, this nanoplatform is also exploited to deliver epitopes from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) to prevent coronavirus disease 2019 (COVID‐19). By conjugating Ox‐AcDEX NPs with the potential CTL epitope of SARS‐CoV‐2 (referred to as Sp) and R837, AcDEX‐(imine)‐Sp‐R NPs are fabricated for anti‐SARS‐CoV‐2 vaccine candidates. Several epitopes potentially contributing to the induction of potent and protective anti‐SARS‐CoV‐2 CTL responses are examined and discussed. Collectively, these findings shed light on the universal use of Ox‐AcDEX NPs to deliver both tumor‐associated and virus‐associated epitopes.

Pembrolizumab (anti-PD-1) Treatment Increases Anti-Tumor Activities of XBP1/CD138/CS1-Specific Cytotoxic T Lymphocytes Against Multiple Myeloma

In these studies, we investigated the role of Pembrolizumab (anti-PD-1)to enhance the function of myeloma-specific CD8+ cytotoxic T lymphocytes (CTL) and maintain their antigens-specific CTL activities against multiple myeloma cells. Bone marrow or peripheral blood mononuclear cells (BMMC, PBMC) from healthy donors or MGUS, smoldering multiple myeloma (SMM), newly diagnosed multiple myeloma (MM), relapsed MM, relapsed/refractory MM patients (N=5, respectively) were evaluated for expression of immune checkpoints that regulate antigen-specific CTL development and function. Active MM patients had higher levels of CD138+ tumor cells as compared to MGUS and SMM patients. PD-L1 and PD-L2 expression levels on myeloma cells were also higher in active MM patients than healthy donors. CD4 Treg (CD3+CD4+CD25+FoxP3+), but not CD8 Treg (CD3+CD8+CD25+FoxP3+), frequencies were highest in both BMMC and PBMC from MM patients. PD-L1, but not PD-L2 nor PD-1, was expressed on the CD4 Treg in BMMC and PBMC from MM patients. G-type MDSC (CD11b+CD33+HLA-DRlowCD15+), but not M-type MDSC (CD11b+CD33+HLA-DRlowCD14+), was increased in MM as compared to MGUS, SMM or healthy donors. The MDSC from active MM patients also had high levels of PD-L1 and PD-L2 expression. BMMC and PBMC from newly diagnosed MM patients (N=3) treated in vitro with Pembrolizumab enhanced the CD3+ T cell proliferation as compared to the untreated group. Interestingly, Pembrolizumab treatment induced proliferation of T cells expressing immune agonists (OX40, GITR) beneficial for cell function and immune checkpoint (LAG3) involved in down-regulating T cell activities. XBP1/CD138/CS1 antigens-specific CTL (XBP1/CD138/CS1-CTL) generated in vitro with a cocktail of immunogenic peptides [heteroclitic XBP1 US184-192 (YISPWILAV), heteroclitic XBP1 SP367-375 (YLFPQLISV), native CD138260-268 (GLVGLIFAV), and native CS1239-247 (SLFVLGLFL)] displayed increased proliferation of CD8+ CTL expressing the CD28 co-stimulatory and CD38 activation markers upon treatment with Pembrolizumab. Importantly, the XBP1/CD138/CS1-specific central memory and effector memory CTL subsets increased the cell proliferation, following treatment with the PD-1-specific antibody. In addition, XBP1/CD138/CS1-CTL treated with Pembrolizumab demonstrated increased cytotoxic activity and Th1-specific cytokines production against U266 myeloma cells. Thus, these studies suggest the potential benefit of Pembrolizumab (a-PD-1) therapy in MM patients to enhance XBP1/CD138/CS1 antigens-specific memory CTL proliferation and boost their anti-tumor activities through blockage of the PD-1 specific immune checkpoint specifically expressed on antigens-specific CD8+ CTL. These data provide the framework for an immunotherapeutic strategy encompassing a combination of multipeptide-based cancer vaccine with PD1-specific antibody to enhance the antigens-specific T cells efficacy and promote stronger and long-lasting CD8+ CTL immune responses in myeloma patients. DisclosuresBae:OncoPep: Other: Scientific Founder. Hideshima:C4 Therapeutics: Equity Ownership; Acetylon: Consultancy. Anderson:C4 Therapeutics: Other: scientific founder; Oncopep: Other: scientific founder; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; MedImmune: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees.

The Double-Edged Sword of Beta2-Microglobulin in Antibacterial Properties and Amyloid Fibril-Mediated Cytotoxicity.

Beta2-microglobulin (B2M) a key component of major histocompatibility complex class I molecules, which aid cytotoxic T-lymphocyte (CTL) immune response. However, the majority of studies of B2M have focused only on amyloid fibrils in pathogenesis to the neglect of its role of antimicrobial activity. Indeed, B2M also plays an important role in innate defense and does not only function as an adjuvant for CTL response. A previous study discovered that human aggregated B2M binds the surface protein structure in Streptococci, and a similar study revealed that sB2M-9, derived from native B2M, functions as an antibacterial chemokine that binds Staphylococcus aureus. An investigation of sB2M-9 exhibiting an early lymphocyte recruitment in the human respiratory epithelium with bacterial challenge may uncover previously unrecognized aspects of B2M in the body’s innate defense against Mycobactrium tuberculosis. B2M possesses antimicrobial activity that operates primarily under pH-dependent acidic conditions at which B2M and fragmented B2M may become a nucleus seed that triggers self-aggregation into distinct states, such as oligomers and amyloid fibrils. Modified B2M can act as an antimicrobial peptide (AMP) against a wide range of microbes. Specifically, these AMPs disrupt microbe membranes, a feature similar to that of amyloid fibril mediated cytotoxicity toward eukaryotes. This study investigated two similar but nonidentical effects of B2M: the physiological role of B2M, in which it potentially acts against microbes in innate defense and the role of B2M in amyloid fibrils, in which it disrupts the membrane of pathological cells. Moreover, we explored the pH-governing antibacterial activity of B2M and acidic pH mediated B2M amyloid fibrils underlying such cytotoxicity.

Virus dynamic behavior of a stochastic HIV/AIDS infection model including two kinds of target cell infections and CTL immune responses

This study investigated the impact of white noise on the HIV/AIDS model with a cytotoxic T lymphocyte (CTL) immune response. The model introduced the interactions between the virus and two kinds of target cells, CD4+ T cells and macrophages. It was theoretically proved that the solution of the stochastic model is positive and global, as well as the existence of an ergodic stationary distribution. The sufficient conditions were established for viral eradication. By comparing these new results to those of a deterministic model, it is determined that white noise can promote the extinction of the virus. Theoretical results have been verified by numerical simulation of several examples.

Spatiotemporal dynamics of a fractional model for hepatitis B virus infection with cellular immunity

In this paper, we propose and investigate a fractional diffusive model for hepatitis B virus (HBV) infection with capsids and immune response presented by cytotoxic T lymphocyte (CTL) cells. We derive the conditions for global asymptotic stability of the steady states of the model in terms of the basic reproduction numberR0and the immune response reproduction numberR1. By constructing appropriate Lyapunov functionals, it is shown that the infection-free equilibrium is globally asymptotically stable whenR0≤ 1, the immune-free infection equilibrium is globally asymptotically stable whenR1≤ 1 &lt;R0and the infection equilibrium with CTL immune response is globally asymptotically stable whenR1&gt; 1. Numerical simulations are performed to illustrate the analytical results.

Mathematical analysis of an HTLV-I infection model with the mitosis of CD4+ T cells and delayed CTL immune response

In this paper, we consider an improved Human T-lymphotropic virus type I (HTLV-I) infection model with the mitosis of CD4+ T cells and delayed cytotoxic T-lymphocyte (CTL) immune response by analyzing the distributions of roots of the corresponding characteristic equations, the local stability of the infection-free equilibrium, the immunity-inactivated equilibrium, and the immunity-activated equilibrium when the CTL immune delay is zero is established. And we discuss the existence of Hopf bifurcation at the immunity-activated equilibrium. We define the immune-inactivated reproduction ratio R0 and the immune-activated reproduction ratio R1. By using Lyapunov functionals and LaSalle’s invariance principle, it is shown that if R0 &lt; 1, the infection-free equilibrium is globally asymptotically stable; if R1 &lt; 1 &lt; R0, the immunity-inactivated equilibrium is globally asymptotically stable; if R1 &gt; 1, the immunity-activated equilibrium is globally asymptotically stable when the CTL immune delay is zero. Besides, uniform persistence is obtained when R1 &gt; 1. Numerical simulations are carried out to illustrate the theoretical results.

Mathematical modeling of HIV/HTLV co-infection with CTL-mediated immunity

In the literature, a great number of HIV and HTLV-I mono-infection models has been formulated and analyzed. However, the within-host dynamics of HIV/HTLV-I co-infection has not been modeled. In the present paper we formulate and analyze a new HIV/HTLV-I co-infection model with latency and Cytotoxic T lymphocytes (CTLs) immune response. The model describes the interaction between susceptible CD$4^{+}$T cells, latently HIV-infected cells, actively HIV-infected cells, latently HTLV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. The HIV can spread by virus-to-cell and cell-to-cell transmissions, while the HTLV-I can only spread via cell-to-cell transmission. The well-posedness of the model is established by showing that the solutions of the model are nonnegative and bounded. We derive the threshold parameters which govern the existence and stability of all equilibria of the model. We prove the global asymptotic stability of all equilibria by utilizing Lyapunov function and Lyapunov-LaSalle asymptotic stability theorem. We have presented numerical simulations to illustrate the effectiveness of our main results. In addition, we have discussed the effect of HTLV-I infection on the HIV-infected patients and vice versa. We have pointed out the influence of CTL immune response on the co-infection dynamics.