Decrease In Immune Cells Research Articles

A Tumor-Immune System with Switching Threshold Depending on Tumor Cells and Its Change Rate

Tumor prevention and control, taking into account the load of tumor cells or immune cells, are often described by Filippov systems, usually with a smooth function on the right-hand side describing the tumor immunity. However, these systems only consider the load of tumor cells or immune cells as a threshold function, which suggest that patients will only be treated if the load of tumor cells or immune cells exceeds a certain threshold. As a result, there may be an excessive growth of tumor cells or a rapid decrease in immune cells, which can lead to undesirable results. Considering this problem, we propose a weighted switching system using the load of tumor cells and its change rate as the threshold. Theoretical analysis and numerical simulation of the system are performed by changing the threshold value. We find that in the proposed nonlinear weighted threshold control method for the system, on the one hand, the system can produce rich dynamical behaviors, including many possible cases of bistability and sliding segments of the system, etc., and on the other hand, it is also very important for the prevention and control of tumor.

A NEW APPROACH FOR TREATMENT OF ULCERATIVE COLITIS: A MELANOCORTIN RECEPTOR AGONIST PL8177

Abstract INTRODUCTION The melanocortin system plays an important role in resolving inflammatory processes. The melanocortin 1 receptor (MC1R)–specific agonist PL8177 has demonstrated MC1R binding affinity and functional activity that mirrors that of α-melanocyte–stimulating hormone. The effect of PL8177 on inflammation, cell population composition, and gene and protein expression was investigated in colons from a dextran sulfate sodium (DSS)–induced rat model of colitis. METHODS Colitis was induced by 5% DSS in drinking water. Rats received vehicle control (placebo) capsules, oral PL8177 capsules (20, 50, and 100 μg per animal), or mesalazine (positive control). Colons were harvested on day 8. Samples were analyzed for cytokines, and by single nuclei RNA-seq and data-independent acquisition tandem mass spectrometry phosphoproteome profiling. Colitis was assessed by diarrhea and rectal bleeding, colon length shortening, colon weight gain, and histopathology. Total colitis index assessed inflammatory damage. RESULTS PL8177 50 μg showed a significant (P<0.05) improvement in colon weight (53% reduction), stool consistency, and fecal occult blood score vs vehicle, and there was significant improvement in the total colitis index for the PL8177 100-μg group vs vehicle. All PL8177 cohorts showed greater improvement in the total colitis index than mesalazine. Mesalazine produced a marked reduction in colon length, but only moderate improvement (35%) in colon weight. Single nuclei RNA-seq showed that in the PL8177 100-μg group, relative cell populations and key gene expression levels were closer to those of healthy controls PL8177 100-μg treatment caused a relative decrease in immune cells and an increase in enterocytes and enteric glial cells compared to vehicle control. Subclustering analysis revealed significant differences between PL8177 100-μg and vehicle populations. Although both showed the presence of macrophages, vehicle-treated colons were primarily M1 macrophages involved in inflammation. In PL8177 100 μg–treated colons, macrophages were primarily pro-resolution M2. Proteomic analysis showed that PL8177-treated colons are more similar to sham colons than to vehicle colons. Also after treatment with PL8177, Smad 2 and 3, proteins known to promote intestinal homeostasis showed expression similar to that seen in the sham group, a result not seen in vehicle-treated colons. DISCUSSION Oral PL8177 treatment showed significant improvement in anatomical markers of colitis vs the vehicle and mesalazine control groups, supporting the aim of treating inflammatory bowel disease (IBD). Transcriptomics and proteomics data show that oral PL8177 treatment causes diseased colons to move toward the healthy state and to resolve inflammation. Resolving inflammation—rather than blocking it—provides the possibility of efficacy coupled with safety in treating IBD.

Intestinal flora, intestinal metabolism, and intestinal immunity changes in complete Freud's adjuvant-rheumatoid arthritis C57BL/6 mice

Rheumatoid arthritis (RA) is an inflammatory-mediated autoimmune disease characterized by persistent joint enlargement, synovial cartilage damage, and inflammatory infiltrates. Although the pathogenesis and treatment of RA are still currently insufficient, the importance of the intestine flora, metabolism and immunity for RA has been gradually recognized, and many intestine regulatory strategies have been used to treat RA. However, the relationship between RA and intestine flora, metabolism and immunity has not been fully expounded. In this study, Complete Freund's Adjuvant (CFA) was used to establish RA model, CyTOF technology was used to study the changes of intestinal immune cell types, 16S rRNA technology was used to analyze the differences of intestinal flora, and LC-MS technology was used to explain the effects of metabolites produced by the changed intestinal flora on RA. Moreover, we systematically explored how the imbalance of intestinal flora changed the intestinal immune status through its metabolites in RA mice. Our results showed that the intestinal flora of RA mice changed significantly, and the bacteria producing short-chain fatty acids (SCFAs), indole classes and secondary bile acids were significantly reduced. The abundance of SCFAs, indole classes and secondary bile acids in the intestine were significantly decreased. The balance of immune cells in the intestine of RA mice was significantly disrupted, with an overall decrease in immune cells. This work reveals the possible relationship between intestinal flora, metabolism and immunity and RA in mice, which will provide new therapeutic strategies for RA.

High expression of IL6 and decrease in immune cells in COVID-19 patients combined with myocardial injury.

Myocardial injury, as a serious complication of coronavirus disease-2019 (COVID-19), increases the occurrence of adverse outcomes. Identification of key regulatory molecules of myocardial injury may help formulate corresponding treatment strategies and improve the prognosis of COVID-19 patients. Gene Set Enrichment Analysis (GSEA) was conducted to identify co-regulatory pathways. Differentially expressed genes (DEGs) in GSE150392 and GSE169241 were screened and an intersection analysis with key genes of the co-regulatory pathway was conducted. A protein-protein interaction (PPI) network was constructed to screen for key regulatory genes. Preliminarily screened genes were verified using other datasets to identify genes with consistent expression. Based on the hierarchical cluster, we divided the patients from GSE177477 into high- and low-risk groups and compared the proportion of immune cells. A total of 267 COVID-19 patients from the Zhejiang Provincial Hospital of Chinese Medicine from December 26, 2022, to January 11, 2023, were enrolled to verify the bioinformatics results. Univariate and multivariate analyses were performed to analyze the risk factors for myocardial injury. According to high-sensitivity troponin (hsTnI) levels, patients with COVID-19 were divided into high- and low-sensitivity groups, and interleukin 6 (IL6) expression and lymphocyte subsets were compared. Patients were also divided into high and low groups according to the IL6 expression, and hsTnI levels were compared. Interleukin signaling pathway and GPCR ligand binding were shown to be co-regulatory pathways in myocardial injury associated with COVID-19. According to the hierarchical cluster analysis of seven genes (IL6, NFKBIA, CSF1, CXCL1, IL1R1, SOCS3, and CASP1), patients with myocardial injury could be distinguished from those without myocardial injury. Age, IL6 levels, and hospital stay may be factors influencing myocardial injury caused by COVID-19. Compared with COVID-19 patients without myocardial injury, the levels of IL6 in patients with myocardial injury increased, while the number of CD4+ T cells, CD8+ T cells, B cells, and NK cells decreased (P<0.05). The hsTnI levels in COVID-19 patients with high IL6 levels were higher than those in patients with low IL6 (P<0.05). The COVID-19 patients with myocardial injury had elevated IL6 expression and decreased lymphocyte counts. IL6 may participate in myocardial injury through the interleukin signaling pathway.

Imaging immunomodulatory treatment responses in a multiple sclerosis mouse model using hyperpolarized 13C metabolic MRI

BackgroundIn recent years, the ability of conventional magnetic resonance imaging (MRI), including T1 contrast-enhanced (CE) MRI, to monitor high-efficacy therapies and predict long-term disability in multiple sclerosis (MS) has been challenged. Therefore, non-invasive methods to improve MS lesions detection and monitor therapy response are needed.MethodsWe studied the combined cuprizone and experimental autoimmune encephalomyelitis (CPZ-EAE) mouse model of MS, which presents inflammatory-mediated demyelinated lesions in the central nervous system as commonly seen in MS patients. Using hyperpolarized 13C MR spectroscopy (MRS) metabolic imaging, we measured cerebral metabolic fluxes in control, CPZ-EAE and CPZ-EAE mice treated with two clinically-relevant therapies, namely fingolimod and dimethyl fumarate. We also acquired conventional T1 CE MRI to detect active lesions, and performed ex vivo measurements of enzyme activities and immunofluorescence analyses of brain tissue. Last, we evaluated associations between imaging and ex vivo parameters.ResultsWe show that hyperpolarized [1-13C]pyruvate conversion to lactate is increased in the brain of untreated CPZ-EAE mice when compared to the control, reflecting immune cell activation. We further demonstrate that this metabolic conversion is significantly decreased in response to the two treatments. This reduction can be explained by increased pyruvate dehydrogenase activity and a decrease in immune cells. Importantly, we show that hyperpolarized 13C MRS detects dimethyl fumarate therapy, whereas conventional T1 CE MRI cannot.ConclusionsIn conclusion, hyperpolarized MRS metabolic imaging of [1-13C]pyruvate detects immunological responses to disease-modifying therapies in MS. This technique is complementary to conventional MRI and provides unique information on neuroinflammation and its modulation.

Outcomes of Children with Fetal and Lactation Immunosuppression Exposure Born to Female Transplant Recipients.

Solid organ transplantation (SOT) is a lifesaving procedure for those with end-stage kidney, liver, heart, lung, and intestinal diseases, including females of childbearing age who wish to proceed with pregnancy following transplantation. While there is clear risk associated with use of mycophenolate during pregnancy, the risks associated with use of other immunosuppressant agents are less well understood, and the timing of use in pregnancy may be pertinent when considering the risk versus benefit for individual patients. In addition to overall fetal outcomes, including gestational age, birth weight, and mortality, this review summarizes published literature on additional complications that have been examined in association with maternal use during pregnancy and postpartum while breastfeeding. Compared with non-transplant pregnancies, pregnancies in transplant recipients are associated with lower birth weight and earlier gestational age. Effects associated with particular immunosuppressant agents in the infant include renal dysfunction from calcineurin inhibitors, myelosuppression from azathioprine, and decreased circulating immune cells with several agents. However, these effects are noted to primarily be transient, though the decrease in immune cells may predispose the infant to increased infectious complications in the first year of life. Utilizing relative infant dose estimations, nearly all commonly utilized immunosuppressants are likely safe during breastfeeding given the limited exposure to the infant.

NK Cells Accumulate in Infected Tissues and Contribute to Pathogenicity of Ebola Virus in Mice

Understanding the immune parameters responsible for survival following Ebola virus (EBOV) infection is paramount for developing countermeasures. In lethal EBOV infections, levels of both NK and T cells decline drastically in the circulation and lymphoid tissues before death. However, the fate of these lymphocytes in viral replication sites remains unknown. In this study, reverse transcription-PCR (RT-PCR) and fluorescence-activated cell sorting (FACS) analysis were used to investigate lymphocyte frequencies in various infected mouse tissues after challenge with mouse-adapted EBOV (MA-EBOV). A decrease in NK cell numbers from systemic circulation was observed concomitant to an increase of these cells in tissues that are supporting active replication of EBOV. Unexpectedly, NK accumulation in virus replication sites correlated with enhanced EBOV disease progression in specific conditions; at a high challenge dose, NK-depleted mice displayed lower viremia and liver damage and higher hepatic T cell levels. Upregulation of UL16 binding protein 1 (ULBP-1) was detected in hepatic T cells, suggesting that NK cells participate in their elimination. Overall, this study supports the concept that NK cells accumulate in EBOV-infected tissues and can contribute to viral pathogenicity.IMPORTANCE Ebola virus (EBOV) outbreaks can claim numerous lives and also devastate the local health infrastructure, as well as the economy, of affected countries. Lethal EBOV infection has been documented to decrease the levels of several immune cells in the blood that are necessary to defend the host. This decrease in immune cells is, however, not observed in individuals who survive EBOV infection. Having a better grasp of how these immune cells are lost is therefore of high importance to develop and improve new and existing therapeutics. The significance of our research is in identifying the mechanism responsible for the apparent loss of immune cells in lethal EBOV infection. This will allow therapeutic options aimed at preventing the loss of these immune cells, therefore allowing infected individuals to better fight the infection.

The immune cell infiltrate in the microenvironment of vulvar Paget disease

BackgroundNon-invasive vulvar Paget disease (VPD) is a rare skin disorder mainly affecting elderly women. Recently, the immune modulator imiquimod was reported as an effective treatment option. Knowledge about the immune microenvironment of VPD is lacking. MethodsThis study investigates the basic characteristics of the immune infiltrate in VPD (n = 10); moreover the influence of imiquimod was studied (n = 6). Immunohistochemistry for CD4, CD8, CD14, CD20, CD56 and FoxP3 was performed. The infiltrates of VPD were compared to vulvar high-grade squamous cell intraepithelial lesions (HSIL) (n = 43), a HPV induced vulvar premalignancy with known response to imiquimod cream, and healthy controls (n = 30). Immune cell counts in samples taken before and after treatment were compared. ResultsThe microenvironment in VPD differs from the healthy vulvar skin and vulvar HSIL. VPD is characterized by a decrease in immune cells in the epithelium and an abundant number of immune cells in the stroma, consisting predominantly of T cells. The intraepithelial CD8+/Foxp3+ ratio and number of CD56+ increased after imiquimod therapy, whereas the numbers of CD14+ cells decreased which may point to a treatment-induced type 1 immune response. ConclusionsThe epithelium in VPD contains less immune cells, but a dense stromal immune infiltrate. Changes in immune cell counts after immune modulation in relation to clinical responses should be further investigated.

Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer.

Interleukin 12 (IL-12) is a powerful immunostimulatory cytokine with a strong antitumoural activity. In this work, the immunological, anti-angiogenic and clinical effects of three consecutive intratumoural IL-12 electrogene therapy (EGT) treatments were evaluated in nine dogs with spontaneous cancer. In all the dogs, tumour biopsies and blood samples were taken prior, during and after the intratumoural IL-12 EGT (on days 1, 8, 35 and 1, 3, 8, 15, 35, respectively). An initial decrease in immune cells was followed by an increase above baseline 1-3 weeks after treatment initiation. Interestingly, the decrease in peripheral leukocytes 2 days after the first intratumoural IL-12 EGT coincided with erythema and tumour swelling. Transient increases of IL-12 and interferon γ were measured in the serum and the tumour tissue, whereas IL-10 transiently increased only in the serum. The effect of intratumoural IL-12 EGT on the levels of IL-24 and vascular endothelial growth factor in the sera and tumour biopsies differed per dog. Via contrast-enhanced ultrasound (US) (on days 1, 8 and 35), we demonstrated that intratumoural IL-12 EGT resulted in a significant decrease of the relative blood volume and blood flow speed in the tumour compared with baseline. Metastases were present in two dogs. In one of these dogs, IL-12 EGT of the primary tumour caused a transient partial regression of the metastases, but not of the primary tumour. The second dog with metastases did not survive long enough to complete the entire treatment cycle. Despite encouraging immunostimulatory and anti-angiogenic effects after intratumoural IL-12 EGT, no clinically relevant outcomes were observed in this study, as persistent tumour regression could not be obtained. On the other hand, the laboratory and US results hold great promise for combinatorial strategies of intratumoural IL-12 EGT with conventional antitumour (immuno)therapies.

Alemtuzumab, a monoclonal antibody against CD52: hopes and fears

CD52, an antigen expressed on immune cells including mature T lymphocytes, is thought to be involved in immunomodulatory mechanisms. Alemtuzumab is a humanized monoclonal antibody against CD52, which causes a marked and long-term decrease in immune cells, especially CD4-positive T lymphocytes. A few randomized clinical trials have revealed the efficacy of alemtuzumab to be much greater than that of interferon-β in patients with relapsing-remitting multiple sclerosis. However, the development of other autoimmune disorders, including autoimmune thyroid disorders and thrombocytic purpura, because of alemtuzumab application has been considered an obstacle in its widespread use.

Changes in peripheral blood leukocyte subpopulations in piglets co-infected experimentally with porcine reproductive and respiratory syndrome virus and porcine circovirus type 2

Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) are pathogens, which can significantly affect the swine industry worldwide. Field surveys suggest that simultaneous PRRSV and PCV2 infection is common in pigs. The objective of this study was to measure the changes in peripheral blood leukocyte subpopulations in piglets co-infected experimentally with PRRSV and PCV2, in order to analyze the synergistic influence of co-infection on the immune system. Changes in peripheral blood leukocyte subpopulations were systematically measured by flow cytometry (FCM). The levels of antibodies to PRRSV and PCV2 were detected by indirect Enzyme-Linked ImmunoSorbent Assay (ELISA) and the indirect fluorescent antibody test (IFA), respectively. Serum viral loads were measured using real-time PCR. The results showed that piglets co-infected with PRRSV and PCV2 exhibited slower generation and lower levels of antibodies to PRRSV and PCV2, and increased amounts and a prolonged presence of both PRRSV and PCV2 in serum, in comparison to the piglets infected with either virus alone. The major finding in our study was that the total and differential leukocyte counts, including white blood cells (WBCs), monocytes, granulocytes and lymphocytes (T, B and NK cells, as well as T-cell subpopulations), dramatically decreased early during co-infection with PRRSV and PCV2 for about two weeks, in contrast with animals singly infected with either PRRSV or PCV2. These results suggest that PRRSV and PCV2 co-infection results in a synergistic decrease in immune cells in the peripheral blood of piglets. These data contribute to the understanding of the immunosuppressive effects resulting from PRRSV and PCV2 co-infection in pigs.

녹용 에탄올 추출물이 2,3,7,8 Tetrachlorodibenzo-p-dioxin에 노출된 랫드의 일반 혈액 화학 지수 및 조직 병변에 미치는 효과

본 연구에서는 TCDD에 노출된 랫드에 있어 녹용의 에탄올 추출물(EAV)이 혈액상(complete blood count) 및 임상 화학지수(common serum chemistry panels) 및 장기별 조직 병변에 미치는 효과를 구명하기 위하여 수행되었다. 본 연구 결과 TCDD에 노출된 랫드의 혈액상 및 혈액화학적 지수 중 혈소판 수 감소(p＜0.01), AST(p＜0.01) 및 ALT(p＜0.05) 활성 증가, CPK (p＜0.01) 및 LDH(p＜0.05) 활성 감소, BUN 활성 증가(p＜0.05), glucose 함량 감소(p＜0.05), lipase 활성 증가(p＜0.05), TG(p＜0.01) 및 LDH-cholesterol(p＜0.05) 함량 증가가 대조군에 비하여 유의하게 변화한 것으로 관찰되었다. 특히 혈소판 수 감소, serum lipase 활성 증가, abdominal lipoprotein lipase(LPL) 활성 저하 및 male에서 serum estrogen 함량 증가는 동물 종과 관계없이 매우 재현성이 있게 나타나는 독성 반응으로 본 실험에서도 대조군 대비 현저한 차이를 보였다. 본 실험에서 TCDD-노출 랫드의 체중 감소는 복부 지방 조직내 LPL 활성 저화와 serum에 존재하는 HSL의 활성 증가와 관련이 있을 것으로 사료된다. 또한 장기별 무게에 있어서도 TCDD는 고환의 무게를 현저하게 감소시켰다(p＜0.01). 한편, 녹용의 에탄올 추출물(EAV)은 TCDD에 노출된 랫드에 있어 LDH의 활성 감소(p＜0.05), glucose 함량 감소(p＜0.05), lipase 활성 증가(p＜0.05), 고환 무게 감소(p＜0.01)에 대하여 유의하게 억제하는 것으로 관찰되었다. TA군의 흉선은 거의 퇴화되어 CO 흉선 무게의 3.8%에 불과하였다. TCDD에 노출된 랫드에 EAV를 전처리하면 TA군과 비교하여 비록 무게 감소는 유의하게 억제되나 CO군과 비교하면 현저하게 작은 값을 나타냈다(p＜0.01). 이상의 결과로 보아 녹용은 랫드에 있어 다이옥신에 의하여 야기되는 일반 혈액화학지수 및 조직 병변에 미치는 효과를 개선시킬 수 있다고 판단한다.