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Dysregulation of the immune response plays an important role in the progression of SARS-CoV-2 infection. A "cytokine storm", which is a phenomenon associated with uncontrolled production of large amounts of cytokines, very often affects patients with COVID-19. Elevated activity of chemotactic cytokines, called chemokines, can lead to serious consequences. CXCL10 has an ability to activate its receptor CXCR3, predominantly expressed on macrophages, T lymphocytes, dendritic cells, natural killer cells, and B cells. So, it has been suggested that the chemokine CXCL10, through CXCR3, is associated with inflammatory diseases and may be involved in the development of COVID-19. Therefore, in this review paper, we focus on the role of CXCL10 overactivity in the pathogenesis of COVID-19. We performed an extensive literature search for our investigation using the MEDLINE/PubMed database. Increased concentrations of CXCL10 were observed in COVID-19. Elevated levels of CXCL10 were reported to be associated with a severe course and disease progression. Published studies revealed that CXCL10 may be a very good predictive biomarker of patient outcome in COVID-19, and that markedly elevated CXCL10 levels are connected with ARDS and neurological complications. It has been observed that an effective treatment for SARS-CoV-2 leads to inhibition of "cytokine storm", as well as reduction of CXCL10 concentrations. It seems that modulation of the CXCL10–CXCR3 axis may be an effective therapeutic target of COVID-19. This review describes the potential role of CXCL10 in the pathogenesis of COVID-19, as well as its potential immune–therapeutic significance. However, future studies should aim to confirm the prognostic, clinical, and therapeutic role of CXCL10 in SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

The functional partial differential equation (FPDE) for cell division, $$ \begin{align*} &\frac{\partial}{\partial t}n(x,t) +\frac{\partial}{\partial x}(g(x,t)n(x,t))\\ &\quad = -(b(x,t)+\mu(x,t))n(x,t)+b(\alpha x,t)\alpha n(\alpha x,t)+b(\beta x,t)\beta n(\beta x,t), \end{align*} $$ is not amenable to analytical solution techniques, despite being closely related to the first-order partial differential equation (PDE) $$ \begin{align*} \frac{\partial}{\partial t}n(x,t) +\frac{\partial}{\partial x}(g(x,t)n(x,t)) = -(b(x,t)+\mu(x,t))n(x,t)+F(x,t), \end{align*} $$ which, with known $F(x,t)$ , can be solved by the method of characteristics. The difficulty is due to the advanced functional terms $n(\alpha x,t)$ and $n(\beta x,t)$ , where $\beta \ge 2 \ge \alpha \ge 1$ , which arise because cells of size x are created when cells of size $\alpha x$ and $\beta x$ divide. The nonnegative function, $n(x,t)$ , denotes the density of cells at time t with respect to cell size x. The functions $g(x,t)$ , $b(x,t)$ and $\mu (x,t)$ are, respectively, the growth rate, splitting rate and death rate of cells of size x. The total number of cells, $\int _{0}^{\infty }n(x,t)\,dx$ , coincides with the $L^1$ norm of n. The goal of this paper is to find estimates in $L^1$ (and, with some restrictions, $L^p$ for $p>1$) for a sequence of approximate solutions to the FPDE that are generated by solving the first-order PDE. Our goal is to provide a framework for the analysis and computation of such FPDEs, and we give examples of such computations at the end of the paper. [ABSTRACT FROM AUTHOR]

Background: Clinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe3O4-siPD-L1@M-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM. Results: Fe3O4-siPD-L1@M-BV2 significantly increased the accumulation of siPD-L1 and Fe2+ in orthotopic drug-resistant GBM tissue in mice. Fe3O4-siPD-L1@M-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe3O4-siPD-L1@M-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe3O4-siPD-L1@M-BV2. Conclusion: The mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe3O4-siPD-L1@M-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice. [ABSTRACT FROM AUTHOR]

Ebola virus (EBOV) targets immune cells and tries to inactivate dendritic cells and interferon molecules to continue its replication process. Since EBOV detailed mechanism has not been identified so far, it would be useful to understand the growth and spread of EBOV dynamics based on mathematical methods and simulation approaches. Computational approaches such as Cellular Automata (CA) have the advantage of simplicity over solving complicated differential equations. The spread of Ebola virus in lymph nodes is studied using a simplified Cellular Automata model with only four parameters. In addition to considering healthy and infected cells, this paper also considers T lymphocytes as well as cell movement ability during the simulation in order to investigate different scenarios in the dynamics of an EBOV system. It is shown that the value of the probability of death of T cells affects the number of infected cells significantly in the steady-state. For a special case of parameters set, the system shows oscillating dynamics. The results were in good agreement with an ordinary differential equation-based model which indicated CA method in combination with experimental discoveries could help biologists find out more about the EBOV mechanism and hopefully to control the disease. [ABSTRACT FROM AUTHOR]

Interleukin-2 receptor (IL-2R), as the specific ligand of interleukin-2 (IL-2), binds to IL-2 and transmits signals and then can induce the proliferation of T lymphocytes in mammals. In this paper, the subunit of IL-2R in flounder (Paralichthys olivaceus), interleukin-2 receptor subunit gamma (IL-2Rγ) was cloned, and polyclonal antibodies (Abs) against its extracellular region were produced, then the expression of flounder IL-2Rγ (fIL-2Rγ) at transcriptional and cellular levels were characterized. Moreover, the interaction of flounder IL-2 (fIL-2) with fIL-2Rγ was investigated, and the variations on CD4+/IL-2Rγ+ cells in flounder after treatment with recombinant IL-2 (rIL-2), anti-IL-2Rγ Abs were detected, respectively. The results showed that fIL-2Rγ protein had a typical fibronectin type III (FN3) domain. The Abs could specifically recognize native fIL-2Rγ molecules at 39.9 kDa. FIL-2Rγ was localized on both T and B lymphocytes, and the percentages of CD4+/IL-2Rγ+ and IgM+/IL-2Rγ+ lymphocytes were high in spleen. In addition, pBiFC-VN173-IL-2Rγ plasmids could bind to pBiFC-VC155-IL-2 plasmids. The percentage of CD4+/IL-2Rγ+ lymphocytes was significantly decreased after blocking with anti-IL-2Rγ Abs both in vivo and in vitro. In the meantime, four T cell markers genes and six IL-2-IL-2R pathway genes were down-regulated in anti-IL-2Rγ Abs group. These results first demonstrated that fIL-2Rγ molecules were expressed on both T and B lymphocytes in flounder, and the bond between fIL-2Rγ and fIL-2 activated the CD4 T lymphocytes. This study gave a new sight into the exploration of IL-2R function on T lymphocytes proliferation in fish. • IL-2Rγ mRNA was highly expressed in peripheral blood leukocytes, spleen and head kidney in flounder. • IL-2Rγ molecules were localized on both T and B lymphocytes in flounder. • Flounder IL-2 could bind to flounder IL-2Rγ. • The addition of recombinant IL-2 significantly increased the percentage of CD4+/IL-2Rγ+ lymphocytes at 72 h. [ABSTRACT FROM AUTHOR]

Understanding the T-cell response to SARS-CoV-2 is key in patients who lack antibody production. We demonstrate the applicability of a functional assay to measure the T-cell response in a cohort of patients with immunodeficiency. T-cell responses to COVID are now linked to improved outcomes. This paper demonstrates a method to robustly test responses for routine diagnostic use in healthy controls and those unable to make a detectable antibody response due to underlying immune deficiency (primary or acquired). [ABSTRACT FROM AUTHOR]

Vaccines against bovine babesiosis must, ideally, induce a humoral immune response characterized by neutralizing antibodies against conserved epitopes and a cellular Th1 immune response. In Babesia bovis , proteins such as AMA-1, MSA-2c, and RAP-1 have been characterized and antibodies against these proteins have shown a neutralizing effect, demonstrating the implication of B and T-cell epitopes in the immune response. There is evidence of the existence of B and T-cell epitopes in these proteins, however, it remains to be defined, the presence of conserved peptides in strains from around the world containing B and T-cell epitopes, and their role in the generation of a long-lasting immunity. The aim in this paper was to identify peptides of Babesia bovis AMA-1, MSA-2c, and RAP-1 that elicit a neutralizing and long-lasting Th1 immune response. Peptides containing B-cell epitopes of AMA-1, MSA-2c and RAP-1, were identified. The immune response generated by each peptide was characterized in cattle. All peptides tested induced antibodies that recognized intraerythrocytic parasites, however, only 5 peptides generated neutralizing antibodies in vitro : P2AMA-1 (6.28%), P3MSA-2c (10.27%), P4MSA-2c (10.42%), P1RAP-1 (32.45%), and P4RAP-1 (36.98%). When these neutralizing antibodies were evaluated as a pool, the inhibition percentage of invasion increased to 52.37%. When the T cellular response was evaluated, two peptides: P3MSA2c and P2AMA1 induced a higher percentage (>70%) of activated CD4 +/CD45RO+ T cells than unstimulated cells. Additionally, both peptides induced the production of gamma interferon (IFN−) in PBMCs from vaccinated cattle after one year proving the implication of a long-lasting Th1 immune response. In conclusion, we identified conserved peptides containing B and T-cell epitopes in antigens of B. bovis that elicit a Th1 immune response and showed evidence that peptides from the same protein elicit different immune responses, which has implication for vaccine development in bovine babesiosis. [ABSTRACT FROM AUTHOR]

[Objective] The present paper aimed to construct the eukaryotic expression vector of rotavirus（Rotavirus, RV）non-structural protein1（NSP1）and 3（NSP3）and express it in human embryonic kidney epithelial HEK239 T cells, and then to study the preliminary effect of rotavirus NSP3 on the activity of IFN-β/ISRE reporter gene in vitro. [Method] First, the NSP1 and NSP3 coding genes of ape rotavirus SA11 strain were synthesized and cloned into the cloning vector pUCm-T, the target fragments of NSP1 and NSP3 were amplified by PCR, and then the eukaryotic expression plasmids specifically expressing recombinant proteins pRK-Flag-NSP1/pRK-HA-NSP1 and pRK-Flag-NSP3/pRK-HA-NSP3 were constructed by using eukaryotic expression vectors pRK-Flag and pRK-HA as skeletons. The plasmids were transfected into HEK293 T cells after restriction endonuclease digestion and sequencing. The expression of NSP1/NSP3 protein was identified by Western blot. Then, the recombinant plasmid pRK-Flag-NSP1/pRK-Flag-NSP3 and IFN-β-Luc/ISRE-Luc plasmid were co-transfected into HEK239 T cells. After stimulated by RIG-IN（RIG-I activation domain）, the effect of NSP1/NSP3 protein on the activity of IFN-β/ISRE reporter gene was determined by double luciferase reporter gene system. [Result] The full-length genes of NSP1 and NSP3 were cloned successfully, and the eukaryotic expression plasmids pRK-Flag-NSP1/pRK-HA-NSP1 and pRK-Flag-NSP3/pRK-HA-NSP3, of NSP1 and NSP3 protein of ape rotavirus strain SA11 were constructed. The successful expression of NSP1 and NSP3 protein was confirmed by transfection and expression of Western blot in HEK293 T cells. Recombinant plasmids pRK-Flag-NSP1 and pRK-Flag-NSP3 could significantly reduce the activity of double luciferase induced by RIG-IN. [Conclusion] NSP1 and NSP3 proteins can inhibit the activities of IFN-β and ISRE promoters stimulated by RIG-IN, which proves that NSP3 protein has the same function as NSP1 protein in inhibiting IFN-β signal pathway, which lays a theoretical foundation for further study on the mechanism of NSP3 protein regulating type I interferon signal pathway. [ABSTRACT FROM AUTHOR]

Ethyl pyruvate (EP) has potent influence on redox processes, cellular metabolism, and inflammation. It has been intensively studied in numerous animal models of systemic and organ-specific disorders whose pathogenesis involves a strong immune component. Here, basic chemical and biological properties of EP are discussed, with an emphasis on its redox and metabolic activity. Further, its influence on myeloid and T cells is considered, as well as on intracellular signaling beyond its effect on immune cells. Also, the effects of EP on animal models of chronic inflammatory and autoimmune disorders are presented. Finally, a possibility to apply EP as a treatment for such diseases in humans is discussed. Scientific papers cited in this review were identified using the PubMed search engine that relies on the MEDLINE database. The reference list covers the most important findings in the field in the past twenty years. [ABSTRACT FROM AUTHOR]

A mathematical model for the quantitative analysis of the interaction between cancer cells and cell-mediated immune system with two discrete-time delays, considering the role of antibodies, is studied in this paper. The model is analyzed both analytically and numerically to understand the dynamics of interaction delay and proliferation enhancement effect delay in the eradication of cancer. Hopf bifurcation occurs when one-time delay crosses the critical value in the absence of the other. It is also observed that as we increase any of the delays, it will increase the cancer burden. The analysis shows that a cancer-free state cannot be obtained solely by the killing rate of cytotoxic T-lymphocytes, but humoral response in combination with cell-mediated immune responses plays an important role to eradicate cancer. [ABSTRACT FROM AUTHOR]

In this paper, using the methods of killing tumors and impulsive differential equations, two immunotherapy antitumor models for describing therapies of general tumors and advanced solid tumors are established. By using the theories of impulsive equations, small amplitude perturbation techniques, and the comparison technique, we obtain the conditions which guarantee the global asymptotical stability of the tumor‐eliminated periodic solution and system permanence, when immunotherapy alone is performed. The numerical results of the influences of the impulsive perturbation on the inherent oscillation show rich dynamics, such as period‐doubling bifurcation and chaos. Moreover, the effects of the combination of radiotherapy with immunotherapy on antitumor are obtained, including the threshold value of stability conditions of tumor‐eradication periodic solution when the mixed combination treatment of immunotherapy and radiotherapy is performed. Some numerical simulations for the effects of the timing of radiotherapy application and the timing of injection T cells on the threshold value are performed. Finally, we present some theoretical methods for suppressing the growth of tumors. [ABSTRACT FROM AUTHOR]

In this paper, we formulate a within‐host dynamics model for HIV/HTLV‐I co‐infection under the influence of cytotoxic T lymphocytes (CTLs). The model incorporates silent HIV‐infected CD4+T cells and silent HTLV‐infected CD4+T cells. The model includes two routes of HIV transmission, virus to cell (VTC) and cell to cell (CTC). It also incorporates two modes of HTLV‐I transmission, horizontal transmission via direct CTC contact and vertical transmission through mitotic division of Tax‐expressing HTLV‐infected cells. The model takes into account five types of distributed‐time delays. We analyze the model by proving the nonnegativity and boundedness of the solutions, calculating all possible equilibria, deriving a set of key threshold parameters, and proving the global stability of all equilibria. The global asymptotic stability of all equilibria is established by utilizing Lyapunov function and LaSalle's invariance principle. We present numerical simulations to justify the applicability and effectiveness of the theoretical results. In addition, we discuss the effect of HTLV‐I infection on the HIV dynamics and vice versa. [ABSTRACT FROM AUTHOR]

Stable fault self-healing ensures the smooth operation of intelligent industrial manufacturing processes. However, current research, while capable of inferring fault propagation paths or individually controlling manufacturing processes, still faces some challenges and limitations in addressing issues within manufacturing processes. In particular, it is easy to overlook the impact of fault variables on normal causal relationships in the manufacturing process and how to achieve adaptive fault repair from the source of faults. The biological immune system possesses sensitive nodes and a neuro-endocrine-immune network with interconnected functionalities, bearing remarkable resemblance to the sensor arrays, information networks, and intelligent controller systems in modern self-healing control systems. These problem domains have significant practical implications in industrial manufacturing processes and urgently require new methods and technologies to address them. To address the issue of root cause fault self-healing in intelligent industrial manufacturing processes, this paper proposes an innovative method that utilizes root cause inference and bio-inspired heuristic reinforcement learning models to achieve fault self-healing in industrial processes. First, innovatively introduce the Variational Autoencoder (VAE) into the Time Convolutional Network (TCN) to construct the TCN-VAE network. By performing feature reconstruction, the network's feature extraction capability is enhanced, further exploring the relationships between latent variables, and consequently building a causal graph of faults. A multi-head attention mechanism is introduced into the network, and the inference process is quantitatively evaluated, thereby improving the generalization and accuracy of root cause inference. Root cause determination rules are established to identify the fundamental reasons for fault occurrence, ensuring self-healing from the source of faults. Next, we developed for the first time a fault self-healing model based on reinforcement learning, utilizing the immune repair process of effector T cells to characterize the fault self-healing process. It effectively adapts to eliminate various levels of faults based on the state transition process of antigens in T helper cells. Additionally, stability control analysis is performed on the proposed model. The average reward function curve and Sobol sensitivity index demonstrates the model's strong robustness in practical applications. The validation results from case studies on the Tennessee Eastman (TE) and Continuous Stirred Tank Reactor (CSTR) show that the average improvement in fault repair F1 score was 0.0941 and 0.105 respectively, and the fastest improvement in fault repair response time was 0.266s and 0.258s respectively. It was confirmed that the root cause inference and fault repair results align with the actual mechanisms of the manufacturing processes. The proposed method has been verified to achieve stable and accurate root cause fault repair in real-world intelligent industrial manufacturing systems, making a significant contribution to achieving stable and accurate root cause fault repair in intelligent industrial manufacturing systems. • TCN-VAE enables feature reconstruction and latent variable exploration for root cause reasoning. • Multi-head attention enhances generality and accuracy in root cause reasoning. • Effector T-cell immune-inspired RL adapts to eliminate faults effectively. • The fault self-healing model exhibits strong reliability and robustness. • Method validated on Tennessee Eastman and continuous stirred-tank reactor datasets. [ABSTRACT FROM AUTHOR]

Plastic waste degrades slowly in aquatic environments, transforming into microplastics (MPs) and nanoplastics (NPs), which are subsequently ingested by fish and other aquatic organisms, causing both physical blockages and chemical toxicity. The fish immune system serves as a crucial defense against viruses and pollutants present in water. It is imperative to comprehend the detrimental effects of MPs on the fish immune system and conduct further research on immunological assessments. In this paper, the immune response and immunotoxicity of MPs and its combination with environmental pollutants on fish were reviewed. MPs not only inflict physical harm on the natural defense barriers like fish gills and vital immune organs such as the liver and intestinal tract but also penetrate cells, disrupting intracellular signaling pathways, altering the levels of immune cytokines and gene expression, perturbing immune homeostasis, and ultimately compromising specific immunity. Initially, fish exposed to MPs recruit a significant number of macrophages and T cells while activating lysosomes. Over time, this exposure leads to apoptosis of immune cells, a decline in lysosomal degradation capacity, lysosomal activity, and complement levels. MPs possess a small specific surface area and can efficiently bind with heavy metals, organic pollutants, and viruses, enhancing immune responses. Hence, there is a need for comprehensive studies on the shape, size, additives released from MPs, along with their immunotoxic effects and mechanisms in conjunction with other pollutants and viruses. These studies aim to solidify existing knowledge and delineate future research directions concerning the immunotoxicity of MPs on fish, which has implications for human health. [Display omitted] [ABSTRACT FROM AUTHOR]

Adoptive T cell therapy has undergone remarkable advancements in recent decades; nevertheless, the rapid and effective ex vivo expansion of tumor-reactive T cells remains a formidable challenge, limiting their clinical application. Artificial antigen-presenting substrates represent a promising avenue for enhancing the efficiency of adoptive immunotherapy and fostering T cell expansion. These substrates offer significant potential by providing flexibility and modularity in the design of tailored stimulatory environments. Polydimethylsiloxane (PDMS) silicone elastomer stands as a widely utilized biomaterial for exploring the varying sensitivity of T cell activation to substrate properties. This paper explores the optimization of PDMS surface modification and formulation to create customized stimulatory surfaces with the goal of enhancing T cell expansion. By employing soft PDMS elastomer functionalized through silanization and activating agent, coupled with site-directed protein immobilization techniques, a novel T cell stimulatory platform is introduced, facilitating T cell activation and proliferation. Notably, our findings underscore that softer modified elastomers (Young' modulus E∼300 kPa) exhibit superior efficacy in stimulating and activating mouse CD4+ T cells compared to their stiffer counterparts (E∼3 MPa). Furthermore, softened modified PDMS substrates demonstrate enhanced capabilities in T cell expansion and Th1 differentiation, offering promising insights for the advancement of T cell-based immunotherapy. [Display omitted] • Chemically modified layers and Protein A enhance antibody density and stability. • Softer elastomers better stimulate CD4+ T cells compared to stiffer ones. • Softened PDMS substrates enhance T cell expansion and Th1 differentiation. • Study shows surface chemistry and mechanical cues influence T cell behavior. [ABSTRACT FROM AUTHOR]

CAR T therapy has revolutionized the treatment of hematologic cancers. In their recent Nature Medicine paper, Mackensen et al. report the use of CAR T cells to treat systemic lupus erythematosus in five patients. This provides enthusiasm to further explore CAR T therapy beyond oncology. [ABSTRACT FROM AUTHOR]

Despite recent breakthroughs of immune-checkpoint inhibitors in the management of bladder cancer (BC), only 20% of patients with non-muscle invasive BC (NMIBC) completely respond, leaving room for improvement. Due to challenges in developing a preclinical model which reflects the heterogeneity and biology of bladder tumors, patient-derived xenograft (PDX) models were created. PDX models involve implanting tumor extracted from patients into immunocompromised mice, which therefore keep the morphology and genomic fidelity of their parental patient cancers. The state of immunodeficiency, however, precludes study of immunotherapy and consequently humanized mice models engrafted with a human immune system were developed, though this led to spontaneous xenogenic graft vs host disease (GVHD). As a potential solution to GVHD in humanized mouse models, this paper describes successful creation of a double-humanized mouse (DHM) by simultaneously engrafting human immune cells and human tumors from the same donor. BC tissue was processed +/- digested into single-cell suspensions (SCS, F0 tissue) and injected orthotopically or subcutaneously into flanks of NSG™ mice. Subsequent tumor growth (PDX-F1) was measured, and PDX-F1 tumors reaching >200mm3 were processed into SCS and reimplanted subcutaneously into a new NSG™ (PDX-F2). Continuous passages (PDX-Fn) were repeated.; Extra SCS-F1 and Fn was analyzed for human epithelial cell adhesion molecule (EpCAM) expression. From an individual F1, a stable cell line (PDX257S) was cultured, and also analyzed for EpCAM expression by flow cytometry. For the DHM model, autologous γδ T-cells expanded in vitro from PDX257S donors were injected with PDX257S cells (effector: target = 2:1) into the NSG™ flanks and were observed for body condition/hematuria for 45 days. Total RNA-sequencing was performed on F0, PDX-Fn and PDX257S cell line. Tumor growth curves were analyzed with 2-way analysis of variance (ANOVA). F0 tissue was obtained from 60 patients. Tumor acceptance in orthotopic injection was not observed in the first 11 suitable tumors, and this method was ceased. Subcutaneous tumor acceptance rate improved with digestion and processing of F0 rather than processing alone (11% vs 5%). EpCAM expression was 98% vs 70% in PDX257S vs its F1 tissue, and < 30% in F1 tissue from other donors that did not yield further passages. In the DHM, while tumor growth was significantly reduced compared to control group after 45 days (mean vol 200 mm3 vs 580 mm3, p=0.02) post injection, it was not completely suppressed. RNA sequencing revealed increased expression of genes including BCL2L1, KRAS, MYC, E2F1, and E2F4 in both PDX257 subcutaneous tumor and cell line compared with donor tumor tissue, and very low/no expression of CDKN2A and FHIT genes in both PDX257 cell line and donor tumor tissue. Creation of a double-humanized mouse model is feasible, and tumor growth is not completely suppressed with the addition of autologous γδ T-cells. PDX257S tumor and cell line is associated with increased EpCAM expression and on RNA sequencing, increased expression of BCL2L1, KRAS, MYC, E2F1, and E2F4. [ABSTRACT FROM AUTHOR]

Highly expressed azo-reductase (AZOR) selectively reduces Azo-DON to DON in hypoxic tumor environments, impair glutamine metabolism in cancer cells, and promote tumor cell death without affecting T cell metabolism and proliferation, thereby generating strong antitumor immune responses. CB-PLG nanoparticles (CBP) mentioned in the paper can enhance the degree of hypoxia in normoxic tumors, which is conducive to efficient reduction of Azo-DON at tumor sites. [Display omitted] • Azo-DON is a novel hypoxia-active prodrug of glutamine antagonist. • Azo-DON selectively blocks tumor glutamine metabolism after reducing to DON. • T cells continue to proliferate and remain active when Azo-DON is reduced to DON. • CBP nanoparticles increase tumor hypoxia and facilitate the reduction of Azo-DON. Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON), have demonstrated remarkable anti-tumor effects by blocking tumor glutamine metabolism, but their use is frequently causing toxicity. Despite the existence of multiple glutamine antagonist prodrug designs, a tumor-selective prodrug has yet to be developed. Herein, a novel prodrug of DON, Azo-DON, has been developed, which remains stable and inactive in normal tissues with sufficient oxygen levels, while can be selectively reduced to DON by highly expressed azo-reductase in hypoxic tumor environments. This leads to blockade of glutamine metabolism in cancer cells and promotes cell death without affecting T cell proliferation. In a high-hypoxic H22 hepatoma cancer model, Azo-DON showed a 1.8-fold enhancement in glutamine blockade compared to the control group, resulting in a tumor suppression rate (TSR) of 84.2% in vivo with no significant weight loss. In a low-hypoxic CT26 colon cancer model, when combined with vascular disrupting agent nanoparticles (CBP) to induce a hypoxic environment, Azo-DON exhibited a 4.6-fold enhancement in glutamine blockade over the control group, resulted in a remarkable TSR of 96.6% in vivo. This innovative approach represents a promising strategy for the application of broad-spectrum metabolic inhibitors in the field of precision cancer treatment. [ABSTRACT FROM AUTHOR]

With the success of immunosuppressive checkpoint in tumor therapy, the corresponding adverse response and drug resistance defects have been exposed. T cells and NK cells are the body's immune system of the two substantial main forces. in recent years, study of T cell checkpoints appeared a certain block, such as PD-1 the effect not benign, on the distribution of NK cell surface excitatory and inhibitory receptors under normal conditions to maintain steady, could be targeted in the tumor treatment blockade have therapeutic effect. This paper reviews the function of NK cells and the effects of corresponding receptors in various types of tumors, providing a direction for the selection of appropriate gate control sites for future treatment. [ABSTRACT FROM AUTHOR]

HIV-1 establishes a persistent proviral reservoir by integrating into the genome of infected host cells. Current antiretroviral treatments do not target this persistent population of proviruses which include latently infected cells that upon treatment interruption can be reactivated to contribute to HIV-1 rebound. Deep sequencing of persistent HIV proviruses has revealed that greater than 90% of integrated HIV genomes are defective and unable to produce infectious virions. We hypothesized that intragenic elements in the HIV genome support transcription of aberrant HIV-1 RNAs from defective proviruses that lack long terminal repeats (LTRs). Using an intact provirus detection assay, we observed that resting CD4+ T cells and monocyte-derived macrophages (MDMs) are biased towards generating defective HIV-1 proviruses. Multiplex reverse transcription droplet digital PCR identified env and nef transcripts which lacked 5' untranslated regions (UTR) in acutely infected CD4+ T cells and MDMs indicating transcripts are generated that do not utilize the promoter within the LTR. 5'UTR-deficient env transcripts were also identified in a cohort of people living with HIV (PLWH) on ART, suggesting that these aberrant RNAs are produced in vivo. Using 5' rapid amplification of cDNA ends (RACE), we mapped the start site of these transcripts within the Env gene. This region bound several cellular transcription factors and functioned as a transcriptional regulatory element that could support transcription and translation of downstream HIV-1 RNAs. These studies provide mechanistic insights into how defective HIV-1 proviruses are persistently expressed to potentially drive inflammation in PLWH. Author summary: People living with HIV establish a persistent reservoir which includes latently infected cells that fuel viral rebound upon treatment interruption. However, the majority of HIV-1 genomes in these persistently infected cells are defective. Whether these defective HIV genomes are expressed and whether they contribute to HIV associated diseases including accelerated aging, neurodegenerative symptoms, and cardiovascular diseases are still outstanding questions. In this paper, we demonstrate that acute infection of macrophages and resting T cells is biased towards generating defective viruses which are expressed by DNA regulatory elements in the HIV genome. These studies describe an alternative mechanism for chronic expression of HIV genomes. [ABSTRACT FROM AUTHOR]

In this paper, a deterministic model characterizing the within-host infection of Hepatitis C virus (HCV) in intrahepatic and extrahepatic tissues is presented. In addition, the model also includes the effect of the cytotoxic T lymphocyte (CTL) immunity described by a linear activation rate by infected cells. Firstly, the non-negativity and boundedness of solutions of the model are established. Secondly, the basic reproduction number R 01 and immune reproduction number R 02 are calculated, respectively. Three equilibria, namely, infection-free, CTL immune response-free and infected equilibrium with CTL immune response are discussed in terms of these two thresholds. Thirdly, the stability of these three equilibria is investigated theoretically as well as numerically. The results show that when R 01 < 1 , the virus will be cleared out eventually and the CTL immune response will also disappear; when R 02 < 1 < R 01 , the virus persists within the host, but the CTL immune response disappears eventually; when R 02 > 1 , both of the virus and the CTL immune response persist within the host. Finally, a brief discussion will be given. [ABSTRACT FROM AUTHOR]

The cellular adaptive immune response to influenza has been analyzed through several recent mathematical models. In particular, Zarnitsyna et al. (Front Immunol 7:1–9, 2016) show how central memory CD8+ T cells reach a plateau after repeated infections, and analyze their role in the immune response to further challenges. In this paper, we further investigate the theoretical features of that model by extracting from the infection dynamics a discrete map that describes the build-up of memory cells. Furthermore, we show how the model by Zarnitsyna et al. (Front Immunol 7:1–9, 2016) can be viewed as a fast-scale approximation of a model allowing for recruitment of target epithelial cells. Finally, we analyze which components of the model are essential to understand the progressive build-up of immune memory. This is performed through the analysis of simplified versions of the model that include some components only of immune response. The analysis performed may also provide a theoretical framework for understanding the conditions under which two-dose vaccination strategies can be helpful. [ABSTRACT FROM AUTHOR]

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 R0∗ between extinction and persistence of the virus is obtained. Finally, numerical simulations are carried out to illustrate the theoretical results. [ABSTRACT FROM AUTHOR]

A two‐dimensional tumor‐immune model with the time delay of the adaptive immune response is considered in this paper. The model is designed to account for the interaction between cytotoxic T lymphocytes (CTLs) and cancer cells on the surface of a solid tumor. The model considers the surface growth as a major growth pattern of solid tumors in order to describe the existence of necrotic kernels. The qualitative analysis shows that the immune‐free equilibrium is unstable, and the behavior of positive equilibrium is closely related to the ratio of the immune killing rate to tumor volume growth rate. The positive equilibrium is locally asymptotically stable when the ratio is smaller than a critical value. Otherwise, the occurrence of the delay‐driven Hopf bifurcation at the positive equilibrium is proved. Applying the center manifold reduction and normal form method, we obtain explicit formulas to determine the properties of the Hopf bifurcation. The global continuation of a local Hopf bifurcation is investigated based on the coincidence degree theory. The results reveal that the time of the adaptive immune system taken to response to tumors can lead to oscillation dynamics. We also carry out detailed numerical analysis for parameters and numerical simulations to illustrate our qualitative analysis. Numerically, we find that shorter immune response time can lead to longer patient survival time, and the period and amplitude of a stable periodic solution increase with the increasing immune response time. When CTLs recruitment rate and death rate vary, we show how the ratio of the immune killing rate to tumor volume growth rate and the first bifurcation value change numerically, which yields further insights to the tumor‐immune dynamics. [ABSTRACT FROM AUTHOR]

Tim-3 is a transmembrane protein that is highly expressed on subsets of chronically stimulated CD4+ helper and CD8+ cytotoxic T cells, with more transient expression during acute activation and infection. Tim-3 is also constitutively expressed by multiple types of myeloid cells. Like other TIM family members, Tim-3 can bind to phosphatidylserine displayed by apoptotic cells, and this interaction has been shown to mediate uptake of such cells by dendritic cells and cross-presentation of antigens to CD8+ T cells. In contrast, how the recognition of PS by Tim-3 might regulate the function of Tim- 3+ T cells is not known. In their recent paper, Lemmon and colleagues demonstrate for the first time that recognition of PS by Tim-3 leads to enhanced T cell activation. [ABSTRACT FROM AUTHOR]

Leukocyte extravasation into inflamed tissue is a complex process that is difficult to capture as a whole in vitro. We employed a bloodvessel- on-a-chip model in which human endothelial cells were cultured in a tube-like lumen in a collagen-1 matrix. The vessels are leak tight, creating a barrier for molecules and leukocytes. Addition of inflammatory cytokine TNF-α (also known as TNF) caused vasoconstriction, actin remodelling and upregulation of ICAM-1. Introducing leukocytes into the vessels allowed real-time visualization of all different steps of the leukocyte transmigration cascade, including migration into the extracellular matrix. Individual cell tracking over time distinguished striking differences in migratory behaviour between T-cells and neutrophils. Neutrophils cross the endothelial layer more efficiently than T-cells, but, upon entering the matrix, neutrophils display high speed but low persistence, whereas T-cells migrate with low speed and rather linear migration. In conclusion, 3D imaging in real time of leukocyte extravasation in a vessel-on-a-chip enables detailed qualitative and quantitative analysis of different stages of the full leukocyte extravasation process in a single assay. This article has an associated First Person interview with the first authors of the paper. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. We aimed to use a mouse model to elucidate the molecular mechanisms of immune-related hepatitis, one of the common irAEs associated with ICIs. Immune phenotyping and molecular profiling were performed on Pdcd1 -/- mice treated with anti-CTLA4 and/or the IDO1 inhibitor epacadostat or a 4-1BB agonistic antibody. ICI combination-induced hepatitis and 4-1BB agonist-mediated hepatitis share similar features yet maintain distinct immune signatures. Both were characterized by an expansion of periportal infiltrates and pan-zonal inflammation albeit with different morphologic characteristics. In both cases, infiltrates were predominantly CD4+ and CD8+ T cells with upregulated T-cell activation markers, ICOS and CD44. Depletion of CD8+ T cells abolished ICI-mediated hepatitis. Single-cell transcriptomics revealed that the hepatitis induced by combination ICIs is associated with a robust immune activation signature in all subtypes of T cells and T helper 1 skewing. Expression profiling revealed a central role for IFNγ and liver monocyte-derived macrophages in promoting a pro-inflammatory T-cell response to ICI combination and 4-1BB agonism. We developed a novel mouse model which offers significant value in yielding deeper mechanistic insight into immune-mediated liver toxicity associated with various immunotherapies. Hepatitis is one of the common immune-related adverse events in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. The mechanisms of ICI-induced hepatitis are not well understood. In this paper, we identify key molecular mechanisms mediating immune intracellular crosstalk between liver T cells and macrophages in response to ICI in a mouse model. [Display omitted] • P dcd 1 -/- mouse can be utilized as a model for immune checkpoint inhibitor-mediated liver injury. • Single-cell immune transcriptional profiling revealed a landscape of molecular pathways responding to inhibition of PD1, CTLA4 and IDO1. • We identified a subset-specific T cell activation signature and common IFNγ signature. • Monocyte-derived macrophages coordinate the T cell response to immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

The Astragalus membranaceus polysaccharide (APS4) with direct cytotoxicity on various cancer cells has been prepared in our previous study, while the underlying therapeutic role of APS4 on solid tumors in vivo hasn't been investigated yet. Therefore, in this paper, the lymphocytes-mediated antitumor and immunoregulatory activities of APS4 were researched by establishing S180 tumor-bearing mice model. Flow cytometry analysis revealed that APS4 could effectively regulate the percentages of CD3+, CD4+, CD8+ T cells and CD19+ B cells in thymus, peripheral blood and spleen of S180 tumor-bearing mice, dose-dependently. H&E staining and cell cycle determination of solid tumors manifested that APS4 treatment could significantly inhibit the growth of solid tumors by inducing cells apoptosis. Furthermore, two-dimensional electrophoresis and western blot analysis further demonstrated that APS4 could activate antitumor-related immune cells and promote anaerobic metabolism of tumor microenvironment, thereby causing the apoptosis of S180 tumor cells. These data implicated that APS4 could be used as a potential dietary supplement for immune enhancement. [ABSTRACT FROM AUTHOR]

Treatment failure or relapse due to tumor escape caused by reduction in target antigen expression has become a challenge in the field of CART therapy. Target antigen density is closely related to the effectiveness of CART therapy, and reduced or lost target antigen expression limits the efficacy of CART therapy and hinders the durability of CAR T cells. Epigenetic drugs can regulate histones for molecular modifications to regulate the transcriptional, translational and post-translational modification processes of target agents, and we demonstrated for the first time the role in regulating CD22 expression and its effect on the efficacy of CD22 CART. In this paper, we found that Chidamide promoted the expression of CD22 on the surface of B-cell tumor cells in vitro and in vivo, and enhanced the function of CD22 CART. As for mechanisms, we demonstrated that Chidamide did not affect CD22 mRNA transcription, but significantly increased the expression of total CD22 protein, indicating that Chidamide may upregulate cell surface CD22 expression by affecting the distribution of CD22 protein. In summary, our results suggest that Chidamide may enhance the efficacy of CD22 CART by inhibiting histone deacetylases to regulate post-transcriptional modifications that affect protein distribution to increase the expression of CD22 on the cell surface. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) is the most common subtype of primary cutaneous T cell lymphoma (CTCL). The erythrodermic form (T4) especially impairs health-related quality of life (HR-QoL), making patients often incapable of self-care. Mycosis fungoides and Sézary syndrome (SS) are immunogenic neoplasms and can be recognized by the patient's immune system. The disease is chronic and immunotherapy allows for long-term control of CTCL. The paper presents a description of 2 cases of nivolumab use in the salvage treatment of erythroderma in the course of refractory mycosis fungoides. Nivolumab was used as emergency treatment, and previously patients exhausted the available treatment options. The discussed cases confirm the effectiveness of immunotherapy in the treatment of primary cutaneous T cell lymphomas. The applied treatment achieved the effect of more than one year of response (15 months), as well as a significant benefit in terms of subjective and objective quality of life. The effect was mainly related to the condition of the skin. The use of the PD-1 checkpoint inhibitor allowed for over 12 months of control in advanced, refractory and heavily pretreated cutaneous lymphoma, and was very well tolerated. More research is needed on the use of such inhibitors in the treatment of cutaneous lymphomas. [ABSTRACT FROM AUTHOR]

Motivation Identifying rare subpopulations of cells is a critical step in order to extract knowledge from single-cell expression data, especially when the available data is limited and rare subpopulations only contain a few cells. In this paper, we present a data mining method to identify small subpopulations of cells that present highly specific expression profiles. This objective is formalized as a constrained optimization problem that jointly identifies a small group of cells and a corresponding subset of specific genes. The proposed method extends the max-sum submatrix problem to yield genes that are, for instance, highly expressed inside a small number of cells, but have a low expression in the remaining ones. Results We show through controlled experiments on scRNA-seq data that the MicroCellClust method achieves a high F 1 score to identify rare subpopulations of artificially planted human T cells. The effectiveness of MicroCellClust is confirmed as it reveals a subpopulation of CD4 T cells with a specific phenotype from breast cancer samples, and a subpopulation linked to a specific stage in the cell cycle from breast cancer samples as well. Finally, three rare subpopulations in mouse embryonic stem cells are also identified with MicroCellClust. These results illustrate the proposed method outperforms typical alternatives at identifying small subsets of cells with highly specific expression profiles. Availabilityand implementation The R and Scala implementation of MicroCellClust is freely available on GitHub, at https://github.com/agerniers/MicroCellClust/ The data underlying this article are available on Zenodo, at https://dx.doi.org/10.5281/zenodo.4580332. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Clinicians are facing questions from some patients about speculative cell banking. Researchers recently published a paper intended to be a resource to prepare clinicians in all fields to discuss the limitations of gene cell therapy with their patients. They also hope they have created a resource for the general public. [ABSTRACT FROM AUTHOR]

Objective: To investigate clinical efficacy of pediatric massage combined with Xiaoer Xiaoji Zhike oral liquid and azithromycin in the treatment of children of mycoplasma pneumoniae pneumonia (MPP) and its effect on immune function and inflammatory factors. Methods: 80 cases of children with MPP who were treated in our hospital from March 2018 to June 2019 were selected. According to the different treatment methods, they were divided into the control group (azithromycin and Xiaoer Xiaoji Zhike oral liquid treatment, n=40) and the study group (pediatric massage, Xiaoer Xiaoji Zhike oral liquid, azithromycin treatment, n=40). The clinical efficacy of the two groups and the improvement of children's symptoms during the treatment were observed, peripheral blood T lymphocyte subsets, adverse reactions and serum inflammatory factors between the two groups were compared. Results: Compared with the control group, the clinical total effective rate of the study group was higher (P<0.05). Compared with the control group, the study group had a shorter of lung rales, cough and X-ray film of lung lesions to disappear time and antipyretic time (P<0.05). Compared with the control group, CD3+, CD4+ and CD4+/CD8+ in the study group was higher at 14 d after treatment, CD8+ was lower (P<0.05). Compared with the control group, interleukin-1β (IL-1β), C-reactive protein (CRP) and interleukin-6 (IL-6) in the study group were lower (P<0.05). There was no significant difference in incidence of adverse reactions in two groups (P>0.05). Conclusion: Pediatric massage combined with Xiaoer Xiaoji Zhike oral liquid and azithromycin in the treatment of children with MPP can promote the improvement of symptoms, optimize the clinical treatment effect, and effectively regulate the immune function and inflammatory factor levels of children. [ABSTRACT FROM AUTHOR]

In this essay, we show that 3 distinct approaches to immunological exhaustion coexist and that they only partially overlap, generating potential misunderstandings. Exploring cases ranging from viral infections to cancer, we propose that it is crucial, for experimental and therapeutic purposes, to clarify these approaches and their interconnections so as to make the concept of exhaustion genuinely operational. Author summary: In this essay, we have written a critical review on immunological exhaustion. We believe that this widely used concept often remains in fact imprecise because there exist 3 different approaches to exhaustion, namely, in terms of dysfunction, cause, and marker, and those are not sufficiently well distinguished and articulated in most scientific papers. We also propose to talk about "exhaustion" for and only for the phenomena in which all 3 approaches are aligned. This can be called the "convergence strategy": T cells would be described as "exhausted" if and only if they are simultaneously dysfunctional, express given markers such as programmed cell death protein 1 (PD-1), and induced by a specific cause such as chronicity. This strategy could be perfectly reasonable, and we see much value in adopting it, because it would force everyone to be more specific and rigorous when talking about exhaustion. Clarifying the characteristics of cells defined as "exhausted," and using a convergent strategy to define T-cell exhaustion could have major experimental and clinical consequences, including for viral infections such as the Coronavirus Disease 2019 (COVID-19). [ABSTRACT FROM AUTHOR]

Despite many recent advances on cancer novel therapies, researchers have yet a long way to cure cancer. They have to deal with tough challenges before they can reach success. Nonetheless, it seems that recently developed immunotherapy-based therapy approaches such as adoptive cell transfer (ACT) have emerged as a promising therapeutic strategy against various kinds of tumors even the cancers in the blood (liquid cancers). The hematological (liquid) cancers are hard to be targeted by usual cancer therapies, for they do not form localized solid tumors. Until recently, two types of ACTs have been developed and introduced; tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR)-T cells which the latter is the subject of our discussion. It is interesting about engineered CAR-T cells that they are genetically endowed with unique cancer-specific characteristics, so they can use the potency of the host immune system to fight against either solid or liquid cancers. Multiple myeloma (MM) or simply referred to as myeloma is a type of hematological malignancy that affects the plasma cells. The cancerous plasma cells produce immunoglobulins (antibodies) uncontrollably which consequently damage the tissues and organs and break the immune system function. Although the last few years have seen significant progressions in the treatment of MM, still a complete remission remains unconvincing. MM is a medically challenging and stubborn disease with a disappointingly low rate of survival rate. When comparing the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma), myeloma has the lowest 5-year survival rate (around 40%). A low survival rate indicates a high mortality rate with difficulty in treatment. Therefore, novel CAR-T cell-based therapies or combination therapies along with CAT-T cells may bring new hope for multiple myeloma patients. CAR-T cell therapy has a high potential to improve the remission success rate in patients with MM. To date, many preclinical and clinical trial studies have been conducted to investigate the ability and capacity of CAR T cells in targeting the antigens on myeloma cells. Despite the problems and obstacles, CAR-T cell experiments in MM patients revealed a robust therapeutic potential. However, several factors might be considered during CAR-T cell therapy for better response and reduced side effects. Also, incorporating the CAT-T cell method into a combinational treatment schedule may be a promising approach. In this paper, with a greater emphasis on CAR-T cell application in the treatment of MM, we will discuss and introduce CAR-T cell's history and functions, their limitations, and the solutions to defeat the limitations and different types of modifications on CAR-T cells. [ABSTRACT FROM AUTHOR]

Immunological memory can be regarded as the key aspect of adaptive immunity, i.e. a specific response to first contact with an antigen, which in mammals is determined by the properties of T, B and NK cells. Re-exposure to the same antigen results in a more rapid response of the activated specific cells, which have a unique property that is the immunological memory acquired upon first contact with the antigen. Such a state of immune activity is also to be understood as related to "altered behavior of the immune system" due to genetic alterations, presumably maintained independently of the antigen. It also indicates a possible alternative mechanism of maintaining the immune state at a low level of the immune response, "directed" by an antigen or dependent on an antigen, associated with repeated exposure to the same antigen from time to time, as well as the concept of innate immune memory, associated with epigenetic reprogramming of myeloid cells, i.e. macrophages and NK cells. Studies on Teleostei have provided evidence for the presence of immunological memory determined by T and B cells and a secondary response stronger than the primary response. Research has also demonstrated that in these animals macrophages and NK-like cells (similar to mammalian NK cells) are able to respond when re-exposed to the same antigen. Regardless of previous reports on immunological memory in teleost fish, many reactions and mechanisms related to this ability require further investigation. The very nature of immunological memory and the activity of cells involved in this process, in particular macrophages and NK-like cells, need to be explained. This paper presents problems associated with adaptive and innate immune memory in teleost fish and characteristics of cells associated with this ability. • The presence of adaptive and innate immune memory has been confirmed in fish. • Adaptive immune memory in fish develops with the participation of T and B lymphocytes. • Innate immune memory is related to the properties of macrophages and NK-like cells. • There is a need to further verify the biological basis of this property. [ABSTRACT FROM AUTHOR]

Summary: Ageing dramatically affects number and function of both innate and adaptive arms of immune system, particularly T cell subsets, contributing to reduced vaccination efficacy, decreased resistance to infections and increased prevalence of cancer in older people. In the present paper, we analysed the age‐related changes in the absolute number of lymphocytes in 214 Sicilian subjects, and in the percentages of T and natural killer (NK) cells in a subcohort of donors. We compared these results with the immunophenotype of the oldest living Italian supercentenarian (aged 111 years). The results were also sorted by gender. The correlation between number/percentage of cells and age in all individuals. and separately in males and females, was examined using a simple linear regression analysis. We did not record the increase in the rate of inversion of the CD4/CD8 ratio, frequently reported as being associated with ageing in literature. Our observation was the direct consequence of a flat average trend of CD4+ and CD8+ T cell percentages in ageing donors, even when gender differences were included. Our results also suggest that CD4+ and CD8+ subsets are not affected equally by age comparing females with males, and we speculated that gender may affect the response to cytomegalovirus (CMV) infection. The supercentenarian showed a unique immunophenotypic signature regarding the relative percentages of her T cell subsets, with CD4+ and CD8+ T cell percentages and CD4+ naive T cell values in line with those recorded for the octogenarian subjects. This suggests that the supercentenarian has a naive 'younger' T cell profile comparable to that of a >80‐year‐old female. [ABSTRACT FROM AUTHOR]

Despite many recent advances on cancer novel therapies, researchers have yet a long way to cure cancer. They have to deal with tough challenges before they can reach success. Nonetheless, it seems that recently developed immunotherapy-based therapy approaches such as adoptive cell transfer (ACT) have emerged as a promising therapeutic strategy against various kinds of tumors even the cancers in the blood (liquid cancers). The hematological (liquid) cancers are hard to be targeted by usual cancer therapies, for they do not form localized solid tumors. Until recently, two types of ACTs have been developed and introduced; tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR)-T cells which the latter is the subject of our discussion. It is interesting about engineered CAR-T cells that they are genetically endowed with unique cancer-specific characteristics, so they can use the potency of the host immune system to fight against either solid or liquid cancers. Multiple myeloma (MM) or simply referred to as myeloma is a type of hematological malignancy that affects the plasma cells. The cancerous plasma cells produce immunoglobulins (antibodies) uncontrollably which consequently damage the tissues and organs and break the immune system function. Although the last few years have seen significant progressions in the treatment of MM, still a complete remission remains unconvincing. MM is a medically challenging and stubborn disease with a disappointingly low rate of survival rate. When comparing the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma), myeloma has the lowest 5-year survival rate (around 40%). A low survival rate indicates a high mortality rate with difficulty in treatment. Therefore, novel CAR-T cell-based therapies or combination therapies along with CAT-T cells may bring new hope for multiple myeloma patients. CAR-T cell therapy has a high potential to improve the remission success rate in patients with MM. To date, many preclinical and clinical trial studies have been conducted to investigate the ability and capacity of CAR T cells in targeting the antigens on myeloma cells. Despite the problems and obstacles, CAR-T cell experiments in MM patients revealed a robust therapeutic potential. However, several factors might be considered during CAR-T cell therapy for better response and reduced side effects. Also, incorporating the CAT-T cell method into a combinational treatment schedule may be a promising approach. In this paper, with a greater emphasis on CAR-T cell application in the treatment of MM, we will discuss and introduce CAR-T cell's history and functions, their limitations, and the solutions to defeat the limitations and different types of modifications on CAR-T cells. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) and human T-lymphotropic virus type I (HTLV-I) are two retroviruses that infect the susceptible CD 4 + T cells. It is known that HIV and HTLV-I have in common a way of transmission through direct contact with certain body fluids related to infected individuals. Therefore, it is not surprising that a mono-infected person with one of these viruses can be co-infected with the other virus. In the literature, a great number of mathematical models has been presented to describe the within-host dynamics of HIV or HTLV-I mono-infection. However, the within-host dynamics of HIV/HTLV-I co-infection has not been modeled. In this paper, we develop a new within-host HIV/HTLV-I co-infection model. The model includes the impact of Cytotoxic T lymphocytes (CTLs) immune response, which is important to control the progression of viral co-infection. The model describes the interaction between susceptible CD 4 + T cells, silent HIV-infected cells, active HIV-infected cells, silent HTLV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. We first show the nonnegativity and boundedness of the model's solutions and then we calculate all possible equilibria. 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 LaSalle's invariance principle. We have presented numerical simulations to illustrate the effectiveness of our main results. In addition, we discuss the effect of HTLV-I infection on the HIV-infected patients and vice versa. [ABSTRACT FROM AUTHOR]

Interleukin-2 (IL-2) is a cytokine involved in the development and maturation of the subsets of T cells, critically associated with the progression of several immune-related diseases (e.g. liver disease, bowel disease). Interestingly, a recent study suggests that coffee may contain several compounds to inhibit IL-2 expression in activated T-lymphocytic cells. However, there is little information about the potential effects of several coffee compounds (e.g. kahweol, cafestol, trigonelline, niacin and chlorogenic acids) on IL-2 expression in activated T-lymphocytic cells. Therefore, in this paper, their effects on IL-2 expression were evaluated in PHA/PMA-activated lymphocytic Jurkat cells. Among the tested compounds, only kahweol and cafestol were able to reduce IL-2 production significantly in the cells (p < 0.05). However, the inhibition of kahweol was a bit stronger than cafestol. Therefore, the molecular mechanism underlying the IL-2 inhibition was investigated using kahweol. Kahweol (≤ 20 µM) was able to inhibit the phosphorylations of ERK and c-Fos (p < 0.05) with little effects on p38 and JNK phosphorylations in the Jurkat cells. Subsequently, the inhibition of ERK/c-Fos led to the reduction of IL-2 mRNA expression in the Jurkat cells. In summary, the data suggest that kahweol may be a potential coffee compound to reduce IL-2 production via inhibiting the phosphorylations of ERK/c-Fos in PHA/PMA-activated lymphocytic Jurkat cells. [ABSTRACT FROM AUTHOR]

We do not mention or discuss glucose intolerance in our study and regard Diabetes as a real disease and not glucose intolerance. The cohort described in the paper (cohort 1) is a part of Swedish population-based SCAPIS cohort containing more than 30 000 individuals. [Extracted from the article]

Summary: Prolonged cytopenia after CAR‐T cell therapy is an acknowledged problem. At present, the causes and implications of prolonged cytopenia are unclear. The paper by Kitamura et al identified that prolonged cytopenia is associated with alterations in the bone marrow niche identified before CAR‐T therapy, indicating a potential predictor of this serious side‐effect of treatment. Commentary on: Kitamura et al. Bone marrow microenvironment disruption and sustained inflammation with prolonged haematologic toxicity after CAR T‐cell therapy? Br J Haematol 2023;202:294‐307. [ABSTRACT FROM AUTHOR]

A list of forthcoming papers related to immunology is presented. These include "Variable influences of iodine on the T-cell recognition of a single thyroglobulin epitope," by Hong Jiang, "Triacylated lipoproteins derived from Mycoplasma pneumoniae activate NF-jB through TLR1 and TLR2," by Takashi Shimizu, and "Disruption of Rxra gene in thymocytes and T lymphocytes modestly alters lymphocyte frequencies, proliferation, survival and Th1/Th2 balance," by Alexander Borowsky and Kevin Kent Lloyd.

Presents several abstracts on dermatology published in the July 1998 issue of the 'British Journal of Dermatology.' 'CD8 Positive Juvenile Cutaneous T-cell Lymphoma,' by L.R. Whittam, G. Orchard, E. Calonje, E. Fraser-Andrews, A. Woolford and R. Russell-Jones; 'Sex Lies and Dermatopathology,' by R.M. MacSween, L.G. Millard, A.S. Stevens and E.L. Speightl; 'A Histopathological Evaluation of Scarring Alopecia,' by J. Holder, R. Bull, A. Quinn and R. Cerio.

In a recent paper, Schriek et al. show that, in a complement-dependent reaction, marginal zone B cells (MZBs) steal MHC class II (MHCII) from dendritic cells (DCs). Activation of T cells by stolen MHCII complexes potentially allows MZBs to augment or regulate T cell activation in ways that are distinct from DCs. [ABSTRACT FROM AUTHOR]

The APOBEC3 (A3) genes encode cytidine deaminase proteins with potent antiviral and anti-retroelement activity. This locus is characterized by duplication, recombination, and deletion events that gave rise to the seven A3s found in primates. These include three single deaminase domain A3s (A3A, A3C, and A3H) and four double deaminase domain A3s (A3B, A3D, A3F, and A3G). The most potent of the A3 proteins against HIV-1 is A3G. However, it is not clear if double deaminase domain A3s have a generalized functional advantage to restrict HIV-1. In order to test whether superior restriction factors could be created by genetically linking single A3 domains into synthetic double domains, we linked A3C and A3H single domains in novel combinations. We found that A3C/A3H double domains acquired enhanced antiviral activity that is at least as potent, if not better than, A3G. Although these synthetic double domain A3s package into budding virions more efficiently than their respective single domains, this does not fully explain their gain of antiviral potency. The antiviral activity is conferred both by cytidine-deaminase dependent and independent mechanisms, with the latter correlating to an increase in RNA binding affinity. T cell lines expressing this A3C-A3H super restriction factor are able to control replicating HIV-1ΔVif infection to similar levels as A3G. Together, these data show that novel combinations of A3 domains are capable of gaining potent antiviral activity to levels similar to the most potent genome-encoded A3s, via a primarily non-catalytic mechanism. Author summary: Antiviral genes are encoded by all organisms to help protect them from viral infections, including proteins encoded by primates to protect them from viruses similar to HIV-1. These antiviral proteins are also called "restriction factors". Some restriction factors are broadly acting, while others are very specific. During the course of evolution, some of these genes have expanded into multiple copies and rearranged in different versions to give them new activities. In this paper, we validated the hypothesis that one particular antiviral gene family, called the APOBEC3 family, has the capability of making novel combinations of antiviral human genes with as great, or greater, potency against HIV-1 as the most potent natural member of this family. By combining parts of the APOBEC3 proteins into novel combinations, we created potent antiviral versions that act through a mechanism distinct from existing APOBEC3 proteins. [ABSTRACT FROM AUTHOR]

Biologic agents (BA) are able to induce an adaptive immune response in a proportion of exposed patients with the onset of anti-drug antibodies (ADA), which are usually responsible for hypersensitivity reactions (HR). Drug desensitization (DD) for BA allows transient clinical tolerance to the drug in reactive patients. The paper aimed to analyse the modification of drug-specific immune responses along DD in two patients with previous ADA-mediated HR (anaphylaxis) to rituximab and tocilizumab. The in vivo and in vitro assays of humoral and cellular response to drugs were carried out in a longitudinal manner throughout the DD cycles. We observed a progressive decrease of the pre-procedure ADA titer with negativization during the DD cycles in both patients. The monitoring of the drug-specific effector cell response showed the decrease in the BA-induced proliferation, while T cell response to unrelated antigens resulted unmodified along the DD cycles. Lastly, the increase of circulating drug-specific Treg cells mainly producing IL-35 were shown during the DD treatment. This study provides evidence that DD treatment to two BA inhibits humoral and cellular anti-drug response by increasing regulatory T cells and cytokines in an antigen-restricted manner. These modifications could contribute to the safety of the procedure. [ABSTRACT FROM AUTHOR]

Summary: The factors responsible for the spectrum of coronavirus 19 (COVID‐19) disease severity and the genesis and nature of protective immunity against COVID‐19 remain elusive. Multiple studies have investigated the immune responses to COVID‐19 in various populations, including those without evidence of COVID‐19 infection. Information regarding innate and adaptive immune responses to the novel severe respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has evolved rapidly. Data are accumulating defining disease phenotypes that aid in rational and informed development of new therapeutic approaches for the treatment of patients infected with SARS‐CoV‐2 and the development of novel vaccines. In this paper, data on important innate immune responses are summarized, including cytokines, specifically interleukin (IL)‐6 and complement, and potential treatments are explored. Adaptive immune responses and derivative therapeutics such as monoclonal antibodies directed at spike proteins are also examined. Finally, data on real‐time assessments of adaptive immune responses are explored, which include CD4+/CD8+ T cells, natural killer (NK) T cells, memory B cells and T follicular cells with specificities for COVID‐19 peptides in infected and normal individuals. Data of two novel vaccines have been released, both showing > 95% efficacy in preventing SARS‐CoV‐2 infection. Analysis of humoral and cellular responses to the vaccines will determine the robustness and durability of protection. In addition, long‐term assessment of SARS‐CoV‐2 memory B and T cell‐mediated immune responses in patients recovering from an infection or those with cross‐reactive immunological memory will help to define risk for future SARS‐CoV infections. Finally, patients recovering from SARS‐CoV‐2 infection may experience prolonged immune activation probably due to T cell exhaustion. This will be an important new frontier for study. This review summarizes published data on the relevant innate and adaptive immune responses to SARS‐CoV‐2. Data characterizing innate and adaptive immune responses have rapidly led to informed therapeutic interventions, including vaccine development and recognition of dysfunctional immune responses that are likely responsible for post‐COVID‐19 autoimmunity. [ABSTRACT FROM AUTHOR]

An interesting inference drawn by some COVID-19 epidemiological models is that there exists a proportion of the population who are not susceptible to infection—even at the start of the current pandemic. This paper introduces a model of the immune response to a virus. This is based upon the same sort of mean-field dynamics as used in epidemiology. However, in place of the location, clinical status, and other attributes of people in an epidemiological model, we consider the state of a virus, B and T-lymphocytes, and the antibodies they generate. Our aim is to formalise some key hypotheses as to the mechanism of resistance. We present a series of simple simulations illustrating changes to the dynamics of the immune response under these hypotheses. These include attenuated viral cell entry, pre-existing cross-reactive humoral (antibody-mediated) immunity, and enhanced T-cell dependent immunity. Finally, we illustrate the potential application of this sort of model by illustrating variational inversion (using simulated data) of this model to illustrate its use in testing hypotheses. In principle, this furnishes a fast and efficient immunological assay—based on sequential serology—that provides a (1) quantitative measure of latent immunological responses and (2) a Bayes optimal classification of the different kinds of immunological response (c.f., glucose tolerance tests used to test for insulin resistance). This may be especially useful in assessing SARS-CoV-2 vaccines. [ABSTRACT FROM AUTHOR]

Reducing the pool of HIV-1 reservoirs in patients is a must to achieve functional cure. The most prominent HIV-1 cell reservoirs are resting CD4 + T cells and brain derived microglial cells. Infected microglial cells are believed to be the source of peripheral tissues reseedings and the emergence of drug resistance. Clearing infected cells from the brain is therefore crucial. However, many characteristics of microglial cells and the central nervous system make extremely difficult their eradication from brain reservoirs. Current methods, such as the "shock and kill", the "block and lock" and gene editing strategies cannot override these difficulties. Therefore, new strategies have to be designed when considering the elimination of brain reservoirs. We set up an original gene suicide strategy using latently infected microglial cells as model cells. In this paper we provide proof of concept of this strategy. [ABSTRACT FROM AUTHOR]