Progress,implications,and challenges in using humanized immune system mice in CAR-T therapy-Application evaluation and improvement

In recent years,humanized immune system(HIS)mice have been gradually used as models for preclinical research in pharmacotherapies and cell therapies with major breakthroughs in tumor and other fields,better mimicking the human immune system and the tumor immune microenvironment,compared to traditional immunodeficient mice.To better promote the application of HIS mice in preclinical research,we se-lectively summarize the current prevalent and breakthrough research and evaluation of chimeric antigen receptor(CAR)-T cells in various antiviral and antitumor treat-ments.By exploring its application in preclinical research,we find that it can better reflect the actual clinical patient condition,with the advantages of providing high-efficiency detection indicators,even for progressive research and development.We believe that it has better clinical patient simulation and promotion for the updated design of CAR-T cell therapy than directly transplanted immunodeficient mice.The characteristics of the main models are proposed to improve the use defects of the existing models by reducing the limitation of antihost reaction,combining multiple models,and unifying sources and organoid substitution.Strategy study of relapse and toxicity after CAR-T treatment also provides more possibilities for application and development.

B cell development and antibody responses in human immune system mice:current status and future perspective

Humanized immune system(HIS)mice have been developed and used as a small surrogate model to study human immune function under normal or disease conditions.Although variations are found between models,most HIS mice show robust human T cell responses.However,there has been unsuccessful in constructing HIS mice that produce high-affinity human antibodies,primarily due to defects in terminal B cell differentiation,antibody affinity maturation,and development of primary follicles and germinal centers.In this review,we elaborate on the current knowledge about and previous attempts to improve human B cell development in HIS mice,and propose a potential strategy for constructing HIS mice with improved humoral immunity by transplantation of human follicular dendritic cells(FDCs)to facilitate the development of secondary follicles.

Human T-cell immunity against the emerging and re-emerging viruses

Over the past decade, we have seen an alarming number of high-profile outbreaks of newly emerging and re-emerging viruses.Recent outbreaks of avian influenza viruses, Middle East respiratory syndrome coronaviruses, Zika virus and Ebola virus present great threats to global health. Considering the pivotal role of host T-cell immunity in the alleviation of symptoms and the clearance of viruses in patients, there are three issues to be primarily concerned about T-cell immunity when a new virus emerges: first, does the population possess pre-existing T-cells against the new virus through previous infections of genetically relevant viruses; second, does a proper immune response arise in the patients to provide protection through an immunopathogenic effect; lastly, how long can the virus-specific immune memory persist. Herein, we summarize the current updates on the characteristics of human T-cell immunological responses against recently emerged or re-emerged viruses, and emphasize the necessity for timely investigation on the T-cell features of these viral diseases, which may provide beneficial recommendations for clinical diagnosis and vaccine development.

Against all odds:The road to success in the development of human immune reconstitution mice

The mouse genome has a high degree of homology with the human genome,and its physiological,biochemical,and developmental regulation mechanisms are similar to those of humans;therefore,mice are widely used as experimental animals.However,it is undeniable that interspecies differences between humans and mice can lead to experimental errors.The differences in the immune system have become an impor-tant factor limiting current immunological research.The application of immunodefi-cient mice provides a possible solution to these problems.By transplanting human immune cells or tissues,such as peripheral blood mononuclear cells or hematopoietic stem cells,into immunodeficient mice,a human immune system can be reconstituted in the mouse body,and the engrafted immune cells can elicit human-specific immune responses.Researchers have been actively exploring the development and differen-tiation conditions of host recipient animals and grafts in order to achieve better im-mune reconstitution.Through genetic engineering methods,immunodeficient mice can be further modified to provide a favorable developmental and differentiation microenvironment for the grafts.From initially only being able to reconstruct single T lymphocyte lineages,it is now possible to reconstruct lymphoid and myeloid cells,providing important research tools for immunology-related studies.In this review,we compare the differences in immune systems of humans and mice,describe the devel-opment history of human immune reconstitution from the perspectives of immuno-deficient mice and grafts,and discuss the latest advances in enhancing the efficiency of human immune cell reconstitution,aiming to provide important references for im-munological related researches.

An Intrusion Detection System Model Based on Immune Principle and Performance Analysis

The study of security in computer networks is a key issue, which is a rapidlygrowing area of interest because of its importance. Main network security problems are analyzed inthis paper above all, which currently are confronted with network systems and existing works inintrusion detection. And then an intrusion detection system model based on Immune Principle (IPIDS)is presented. Meanwhile, it expatiates detailed implementation of the methods how to reduce the highfalse positive and negative alarms of the traditional Intrusion Detection System (IDS). At last asimple simulation is performed on this model just using string match algorithm as binding mechanism.The simulation results indicate that the model can detect malicious activity effectively, andconsequently the security and steadiness of the whole network system are improved also.

A close look at the biology of SARS-CoV-2,and the potential influence of weather conditions and seasons on COVID-19 case spread

Background:There is sufficient epidemiological and biological evidence of increased human susceptibility to viral pathogens such as Middle East respiratory syndrome coronavirus,respiratory syncytial virus,human metapneumovirus and influenza virus,in cold weather.The pattern of outbreak of the coronavirus disease 2019(COVID-19)in China during the flu season is further proof that meteorological conditions may potentially influence the susceptibility of human populations to coronaviruses,a situation that may become increasingly evident as the current global pandemic of COVID-19 unfolds.Main body:A very rapid spread and high mortality rates have characterized the COVID-19 pandemic in countries north of the equator where air temperatures have been seasonally low.It is unclear if the currently high rates of COVID-19 infections in countries of the northern hemisphere will wane during the summer months,or if fewer people overall will become infected with COVID-19 in countries south of the equator where warmer weather conditions prevail through most of the year.However,apart from the influence of seasons,evidence based on the structural biology and biochemical properties of many enveloped viruses similar to the novel severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2(aetiology of COVID-19),support the higher likelihood of the latter of the two outcomes.Other factors that may potentially impact the rate of virus spread include the effectiveness of infection control practices,individual and herd immunity,and emergency preparedness levels of countries.Conclusion:This report highlights the potential influence of weather conditions,seasons and non-climatological factors on the geographical spread of cases of COVID-19 across the globe.

Generation of mouse anti-human urate anion exchanger antibody by genetic immunization and its identification

Background Human urate anion exchanger (hURAT1) as a major urate transporter expressed on renal tubular epithelial cells regulates blood urate level by reabsorbing uric acid. Antibody is an important tool to study hURAT1. This study aimed, by genetic immunization, to produce mouse anti-hURAT1 polyclonal antibody with high throughput and high specificity and to detect the location of hURAT1 in human kidney.Methods Human renal total RNA was isolated and the entire cDNA of hURAT1 was amplified by RT-PCR. The sequence of intracellular high antigenicity fragment (A280 to R349) was chosen by prediction software of protein antigenicity, and its cDNA was amplified from cDNA of hURAT1, and then cloned into pBQAP-TT vector to construct recombinant plasmid pBQAP-TT-hURAT1-210 for genetic immunization. Mice were inoculated with this recombinant plasmid and two other adjuvant plasmids, pCMVi-GMCSF and pCMVi-Flt3L, which helped to enhance the antibody’s generation. After four weeks, the mice were sacrificed to obtain the anti-hURAT1 antibody from serum. The antibody was identified by western blot analysis and immunohistochemistry. At the same time, rabbit anti-hURAT1 antibody was produced by protein immunization. The specificity and efficiency between the rabbit and mouse anti-hURAT1 antibody were compared by western blot analysis and immunohistochemistry. Results The entire cDNA of hURAT1 and cDNA of its intracellular high immunogenic fragment were amplified successfully. Recombinant plasmid pBQAP-TT-hURAT1-210 for genetic immunization was confirmed by restriction digestion and sequencing. Both!the mouse anti-hURAT1 antibody and rabbit anti-hURAT1 antibody recognized 58kD hURAT1 and 64kD glycosylated hURAT1 protein bands in western blot. Immunohistochemically, hURAT1 was located at the brush border membrane of renal proximal tubular cells. In addition, the throughput and specificity of the mouse anti-hURAT1 antibody were higher than those of the rabbit anti-hURAT1 antibody.Conclusion Genetic immunization can generate anti-hURAT1 polyclonal antibody of high throughput and specificity.

Chinese Herbal Medicine for the Treatment of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome-Associated Diarrhea: A Protocol for the Systematic Review and Meta-Analysis of Randomized Clinical Trials

Diarrhea can occur at an early or advanced stage of acquired immunodeficiency syndrome(AIDS)as a usual symptom in people with human immunodeficiency virus(HIV)infection.While it is usually not fatal,it can influence patients’quality of life seriously.It has shown to be efficacious and improves people’s immune status to a certain extent to treat HIV/AIDS-related diarrhea on the basis of syndrome differentiation and treatment or Chinese herbs plus conventional treatment.Therefore,it may have a good application potential.Here,we outline a protocol for the systematic review of this health-care intervention,with the aim to evaluate the beneficial effects and safety of Traditional Chinese Medicine(TCM)for patients who suffer from HIV/AIDS-associated diarrhea.Randomized controlled trials that compare Chinese herbs with placebo or other effective treatments will be searched and included,in spite of publication status or language.The primary outcomes include diarrhea frequency and fecal character.The databases we will search as follows:China Science and Technology Journal Database(VIP),Chinese Biomedical Literature Database(Sino Med),Wanfang Data,China National Knowledge Infrastructure,Pub Med and the CENTRAL in Cochrane Library.Two authors will respectively conduct the screening of trials,data extraction,and use the Cochrane risk of bias tool to assess the methodological quality.We will analyze the data and perform a meta-analysis if possible.We intend to identify potential therapeutic modalities that may be of benefit to inform clinical practice by supplying existing evidence of the helpful effects and safety of TCM to treat patients suffering from HIV/AIDS-associated diarrhea.

Genetic variation in the chemokine receptor 5 gene and course of HIV infection;review on genetics and immunological aspect

Chemokines are small protein molecules associated with various physiological events precisely in immune modulation via dhemokine receptors.The chemokine receptors are G-protein coupled receptors express mainly on the cell surface of immune cells.Retrovi-ruses,including HIV in the early stage of infection,primarily target chemokines receptors and get intemalized easily into immune cells;T cell and escape from immune surveillance.HIV glycoprotein selectively develops an affinity for the extracellular domain of chemokines recep-tors and allows the pathogen to intemalize via CCR-5.Now,CCR-5 remains a crucial signaling pathway that can be translated into the therapeutic target by changing the receptor protein environment.Many populations have a mutation in coding and promoter regions of CCR-5,tun-ing a resistance for HIV infection.Natively,there are several mechanisms where the human genome remains in the dynamic state by changing its composition and acquiring variations.Sin-gle nucleotide polymorphism is spontaneous phenomenon responsible for precise and point mutation at the genome.Several studies have demonstrated that European and African Amer-ican populations are enriched in significant CCR5 promoter SNP(CCR5432)in the coding and promoter region as well.Now,such SNP can be an early-stage biomarker in studying HIV and other similar infections.Here,in this study,we have elucidated the role of SNP(both the pro-moter and coding region)and the fate of HIV infections.We also empathized with the genetics of such SNPs,mostly frequency and its immunological impact.