Displaying publications 1 - 20 of 27 in total

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  1. Application of Ti3 C2 MXene Quantum Dots for Immunomodulation and Regenerative Medicine
    Rafieerad A, Yan W, Sequiera GL, Sareen N, Abu-El-Rub E, Moudgil M, et al.
    Adv Healthc Mater, 2019 08;8(16):e1900569.
    PMID: 31265217 DOI: 10.1002/adhm.201900569
    Inflammation is tightly linked to tissue injury. In regenerative medicine, immune activation plays a key role in rejection of transplanted stem cells and reduces the efficacy of stem cell therapies. Next-generation smart biomaterials are reported to possess multiple biologic properties for tissue repair. Here, the first use of 0D titanium carbide (Ti3 C2 ) MXene quantum dots (MQDs) for immunomodulation is presented with the goal of enhancing material-based tissue repair after injury. MQDs possess intrinsic immunomodulatory properties and selectively reduce activation of human CD4+ IFN-γ+ T-lymphocytes (control 87.1 ± 2.0%, MQDs 68.3 ± 5.4%) while promoting expansion of immunosuppressive CD4+ CD25+ FoxP3+ regulatory T-cells (control 5.5 ± 0.7%, MQDs 8.5 ± 0.8%) in a stimulated lymphocyte population. Furthermore, MQDs are biocompatible with bone marrow-derived mesenchymal stem cells and induced pluripotent stem cell-derived fibroblasts. Finally, Ti3 C2 MQDs are incorporated into a chitosan-based hydrogel to create a 3D platform with enhanced physicochemical properties for stem cell delivery and tissue repair. This composite hydrogel demonstrates increased conductivity while maintaining injectability and thermosensitivity. These findings suggest that this new class of biomaterials may help bridge the translational gap in material and stem cell-based therapies for tissue repair and treatment of inflammatory and degenerative diseases.
    Matched MeSH terms: CD4-Positive T-Lymphocytes/metabolism
  2. Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes
    Barathan M, Gopal K, Mohamed R, Ellegård R, Saeidi A, Vadivelu J, et al.
    Apoptosis, 2015 Apr;20(4):466-80.
    PMID: 25577277 DOI: 10.1007/s10495-014-1084-y
    Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex(®) 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.
    Matched MeSH terms: T-Lymphocytes/metabolism
  3. Fulltext Reduced CD4+ terminally differentiated effector memory T cells in moderate-severe house dust mites sensitized allergic rhinitis patients
    Sani MM, Ashari NSM, Abdullah B, Wong KK, Musa KI, Mohamud R, et al.
    Asian Pac J Allergy Immunol, 2019 Sep;37(3):138-146.
    PMID: 29981564 DOI: 10.12932/AP-191217-0220
    BACKGROUND: Terminally differentiated effector memory (TEMRA) T cells exert potent effector function after activation. The proportions of CD4+ T cell subsets especially memory cells in allergic rhinitis (AR) patients sensitized to house dust mites (HDMs) have not been extensively studied.

    OBJECTIVE: This study aimed to compare the mean percentages and absolute counts of CD4+ memory T cell subsets between: (i) non-allergic controls and AR patients; (ii) mild AR patients and moderate-severe AR patients.

    METHODS: Sensitization to Dermatophagoides farinae and Dermatophagoides pteronyssinus were determined in 33 non -allergic controls, 28 mild AR and 29 moderate-severe AR patients. Flow cytometry was used to determine the percentage of CD4+ na?ve (TN; CD45RA+CCR7+), central memory (TCM; CD45RA-CCR7+), effector memory (TEM; CD45RA-CCR7-) and TEMRA (CD45RA+CCR7-) T cells from the peripheral blood. The absolute counts of CD4+ T cell subsets were obtained by dual platform method from flow cytometer and hematology analyzer.

    RESULTS: There were no significant differences in the mean percentages and absolute counts of CD4+ T cell subsets between non-allergic controls and AR patients sensitized to HDMs. However, there were significant reduction in the mean percentage (p=0.0307) and absolute count (p=0.0309) of CD4+ TEMRA cells in moderate-severe AR patients compared to mild AR patients sensitized to HDMs and 13/24 (54.2%) moderate-severe AR patients sensitized to HDMs had persistent symptoms.

    CONCLUSION: Reduction in the mean percentage and absolute count of CD4+CD45RA+CCR7- TEMRA cells were observed in moderate-severe AR patients compared to mild AR patients in our population of AR patients sensitized to HDMs.

    Matched MeSH terms: CD4-Positive T-Lymphocytes/metabolism
  4. The immunomodulation potential of the synthetic derivatives of benzothiazoles: Implications in immune system disorders through in vitro and in silico studies
    Khan KM, Mesaik MA, Abdalla OM, Rahim F, Soomro S, Halim SA, et al.
    Bioorg Chem, 2016 Feb;64:21-8.
    PMID: 26637945 DOI: 10.1016/j.bioorg.2015.11.004
    Benzothiazole and its natural or synthetic derivatives have been used as precursors for several pharmacological agents for neuroprotective, anti-bacterial, and anti-allergic activities. The objective of the present study was to evaluate effects of benzothiazole analogs (compounds 1-26) for their immunomodulatory activities. Eight compounds (2, 4, 5, 8-10, 12, and 18) showed potent inhibitory activity on PHA-activated peripheral blood mononuclear cells (PBMCs) with IC50 ranging from 3.7 to 11.9 μM compared to that of the standard drug, prednisolone <1.5 μM. Some compounds (2, 4, 8, and 18) were also found to have potent inhibitory activities on the production of IL-2 on PHA/PMA-stimulated PBMCs with IC50 values ranging between <4.0 and 12.8 μM. The binding interaction of these compounds was performed through silico molecular docking. Compounds 2, 8, 9, and 10 significantly suppressed oxidative burst ROS production in phagocytes with IC50 values between <4.0 and 15.2 μM. The lipopolysaccharide (LPS)-induced nitrites in murine macrophages cell line J774 were found to be inhibited by compounds 4, 8, 9, and 18 at a concentration of 25 μg/mL by 56%, 91%, 58%, and 78%, respectively. Furthermore, compounds 5, 8, 12, and 18 showed significant (P<0.05) suppressive activity on Th-2 cytokine, interleukin 4 (IL-4) with an IC50 range of <4.0 to 40.3 μM. Interestingly compound 4 has shown a selective inhibitory activity on IL-2 and T cell proliferation (naïve T cell proliferation stage) rather than on IL-4 cytokine, while compound 12 displayed an interference with T-cell proliferation and IL-4 generation. Moreover compound 8 and 18 exert non-selective inhibition on both IL-2 and IL-4 cytokines, indicating a better interference with stage leading to humoral immune response and hence possible application in autoimmune diseases.
    Matched MeSH terms: T-Lymphocytes/metabolism
  5. Altered phenotype and function of NK cells infiltrating human papillomavirus (HPV)-associated genital warts during HIV infection
    Bere A, Tayib S, Kriek JM, Masson L, Jaumdally SZ, Barnabas SL, et al.
    Clin Immunol, 2014 Feb;150(2):210-9.
    PMID: 24440646 DOI: 10.1016/j.clim.2013.12.005
    HIV-infected individuals experience more persistent HPV infections and are less likely to resolve genital warts. This study compared phenotype and functions of NK and T cells from genital warts and blood from 67 women. We compared in vitro functional responses of NK and T cells by multiparametric flow cytometry. HIV+ women had significantly lower frequencies of CD4 T cells in warts (p = 0.001) and blood (p = 0.001). While the distribution of NK cell subsets was similar, HIV+ women tended to have lower frequencies of CD56(Dim) NK cells in both blood (p = 0.0001) and warts (p = 0.006) than HIV- women. Wart NK cells from HIV+ women expressed significantly lower CD107a and produced IFN-γ. HAART status was not associated with differences in NK cell functionality. We conclude that wart NK cells from HIV+ women have defects in their ability to degranulate and/or secrete IFN-γ, which may provide insights into why HIV+ women fail to spontaneously resolve genital warts.
    Matched MeSH terms: CD4-Positive T-Lymphocytes/metabolism
  6. Human mesenchymal stromal cells modulate T-cell immune response via transcriptomic regulation
    Vellasamy S, Tong CK, Azhar NA, Kodiappan R, Chan SC, Veerakumarasivam A, et al.
    Cytotherapy, 2016 10;18(10):1270-83.
    PMID: 27543068 DOI: 10.1016/j.jcyt.2016.06.017
    BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have been identified as pan-immunosuppressant in various in vitro and in vivo inflammatory models. Although the immunosuppressive activity of MSCs has been explored in various contexts, the precise molecular signaling pathways that govern inhibitory functions remain poorly elucidated.

    METHODS: By using a microarray-based global gene expression profiling system, this study aimed to decipher the underlying molecular pathways that may mediate the immunosuppressive activity of umbilical cord-derived MSCs (UC-MSCs) on activated T cells.

    RESULTS: In the presence of UC-MSCs, the proliferation of activated T cells was suppressed in a dose-depended manner by cell-to-cell contact mode via an active cell-cycle arrest at the G0/G1 phase of the cell cycle. The microarray analysis revealed that particularly, IFNG, CXCL9, IL2, IL2RA and CCND3 genes were down-regulated, whereas IL11, VSIG4, GFA1, TIMP3 and BBC3 genes were up-regulated by UC-MSCs. The dysregulated gene clusters associated with immune-response-related ontologies, namely, lymphocyte proliferation or activation, apoptosis and cell cycle, were further analyzed.

    CONCLUSIONS: Among the nine canonical pathways identified, three pathways (namely T-helper cell differentiation, cyclins and cell cycle regulation, and gap/tight junction signalling pathways) were highly enriched with these dysregulated genes. The pathways represent putative molecular pathways through which UC-MSCs elicit immunosuppressive activity toward activated T cells. This study provides a global snapshot of gene networks and pathways that contribute to the ability of UC-MSCs to suppress activated T cells.

    Matched MeSH terms: T-Lymphocytes/metabolism*
  7. Fulltext Immunosuppressive effects of the standardized extract of Phyllanthus amarus on cellular immune responses in Wistar-Kyoto rats
    Ilangkovan M, Jantan I, Mesaik MA, Bukhari SN
    Drug Des Devel Ther, 2015;9:4917-30.
    PMID: 26347462 DOI: 10.2147/DDDT.S88189
    Phyllanthus amarus (family: Euphorbiaceae) is of immense interest due to its wide spectrum of biological activities. In the present study, the standardized 80% ethanol extract of P. amarus was investigated for its modulatory activity on various cellular immune parameters, including chemotaxis of neutrophils, engulfment of Escherichia coli by neutrophils, and Mac-1 expression, in leukocytes isolated from treated/nontreated Wistar-Kyoto rats. The detailed cell-mediated activity of P. amarus was also investigated, including analysis of the effects on T- and B-cell proliferation and CD4(+) and CD8(+) T-cell subsets in splenic mononuclear cells, and estimation of serum cytokine production by activated T-cells. The main components of the extract, phyllanthin, hypophyllanthin, corilagin, geraniin, ellagic acid, and gallic acid were identified and quantitatively analyzed in the extracts, using validated reversed-phase high-performance liquid chromatography (HPLC) methods. N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophils isolated from rats administered with the extract of P. amarus, at doses ranging from 100 to 400 mg/kg for 14 days, revealed a significant dose-dependent reduction in neutrophil migration (P<0.05). Similar patterns of inhibition were also observed in phagocytic activity and in fMLP-induced changes in expression of β2 integrin polymorphonuclear neutrophils. The results in P. amarus-treated rats also demonstrated a dose-dependent inhibition of both lipopolysaccharide-stimulated B-cell proliferation and concanavalin A-stimulated T-cell proliferation as compared with sensitized control. At a dose of 400 mg/kg (P<0.01), there was a significant decrease in the (%) expression of CD4(+) and CD8(+) in splenocytes and in serum cytokines of T helper (Th1) (IL-2 and IFN-γ) and Th2 (IL-4). In conclusion, P. amarus showed effective immunosuppressive activities in cellular immune response, by various immune regulatory mechanisms, and may be useful for improvement of immune-related disorders.
    Matched MeSH terms: T-Lymphocytes/metabolism
  8. Fulltext Thalidomide as a Potential HIV Latency Reversal Agent: Is It the Right Time to Forget the Ancestral Sins?
    Vignesh R, Shankar EM
    EBioMedicine, 2017 Oct;24:20-21.
    PMID: 28865747 DOI: 10.1016/j.ebiom.2017.08.025
    Matched MeSH terms: CD4-Positive T-Lymphocytes/metabolism
  9. Fulltext T-cell receptor signaling induces proximal Runx1 transactivation via a calcineurin-NFAT pathway
    Wong WF, Looi CY, Kon S, Movahed E, Funaki T, Chang LY, et al.
    Eur J Immunol, 2014 Mar;44(3):894-904.
    PMID: 24310293 DOI: 10.1002/eji.201343496
    Runx1 transcription factor is a key player in the development and function of T cells. Runx1 transcripts consist of two closely related isoforms (proximal and distal Runx1) whose expressions are regulated by different promoters. Which Runx1 isoform is expressed appears to be tightly regulated. The regulatory mechanism for differential transcription is, however, not fully understood. In this study, we investigated the regulation of the proximal Runx1 promoter in T cells. We showed that proximal Runx1 was expressed at a low level in naïve T cells from C57BL/6 mice, but its expression was remarkably induced upon T-cell activation. In the promoter of proximal Runx1, a highly conserved region was identified which spans from -412 to the transcription start site and harbors a NFAT binding site. In a luciferase reporter assay, this region was found to be responsive to T-cell activation through Lck and calcineurin pathways. Mutagenesis studies and chromatin immunoprecipitation assay indicated that the NFAT site was essential for NFAT binding and transactivation of the proximal Runx1 promoter. Furthermore, TCR signaling-induced expression of proximal Runx1 was blocked by treatment of cells with cyclosporin A. Together, these results demonstrate that the calcineurin-NFAT pathway regulates proximal Runx1 transcription upon TCR stimulation.
    Matched MeSH terms: T-Lymphocytes/metabolism
  10. Repetitive cryotherapy attenuates the in vitro and in vivo mononuclear cell activation response
    Lindsay A, Othman MI, Prebble H, Davies S, Gieseg SP
    Exp Physiol, 2016 07 01;101(7):851-65.
    PMID: 27094349 DOI: 10.1113/EP085795
    What is the central question of this study? Acute and repetitive cryotherapy are routinely used to accelerate postexercise recovery, although the effect on resident immune cells and repetitive exposure has largely been unexplored and neglected. What is the main finding and its importance? Using blood-derived mononuclear cells and semi-professional mixed martial artists, we show that acute and repetitive cryotherapy reduces the in vitro and in vivo T-cell and monocyte activation response whilst remaining independent of the physical performance of elite athletes. We investigated the effect of repetitive cryotherapy on the in vitro (cold exposure) and in vivo (cold water immersion) activation of blood-derived mononuclear cells following high-intensity exercise. Single and repeated cold exposure (5°C) of a mixed cell culture (T cells and monocytes) was investigated using in vitro tissue culture experimentation for total neopterin production (neopterin plus 7,8-dihydroneopterin). Fourteen elite mixed martial art fighters were also randomly assigned to either a cold water immersion (15 min at 10°C) or passive recovery protocol, which they completed three times per week during a 6 week training camp. Urine was collected and analysed for neopterin and total neopterin three times per week, and perceived soreness, fatigue, physical performance (broad jump, push-ups and pull-ups) and training performance were also assessed. Single and repetitive cold exposure significantly (P T-cell and monocyte activation. This may explain the disparity in in vivo neopterin and total neopterin between cold water immersion and passive recovery following repetitive exposure during a high-intensity physical impact sport that remains independent of physical performance.
    Matched MeSH terms: T-Lymphocytes/metabolism
  11. Fulltext Long non-coding RNA expression in primary human monocytes
    Mirsafian H, Manda SS, Mitchell CJ, Sreenivasamurthy S, Ripen AM, Mohamad SB, et al.
    Genomics, 2016 07;108(1):37-45.
    PMID: 26778813 DOI: 10.1016/j.ygeno.2016.01.002
    Long non-coding RNAs (lncRNAs) have been shown to possess a wide range of functions in both cellular and developmental processes including cancers. Although some of the lncRNAs have been implicated in the regulation of the immune response, the exact function of the large majority of lncRNAs still remains unknown. In this study, we characterized the lncRNAs in human primary monocytes, an essential component of the innate immune system. We performed RNA sequencing of monocytes from four individuals and combined our data with eleven other publicly available datasets. Our analysis led to identification of ~8000 lncRNAs of which >1000 have not been previously reported in monocytes. PCR-based validation of a subset of the identified novel long intergenic noncoding RNAs (lincRNAs) revealed distinct expression patterns. Our study provides a landscape of lncRNAs in monocytes, which could facilitate future experimental studies to characterize the functions of these molecules in the innate immune system.
    Matched MeSH terms: T-Lymphocytes/metabolism
  12. Increased level of activated gamma delta lymphocytes correlates with disease severity in HIV infection
    Norazmi MN, Arifin H, Jamaruddin MA
    Immunol Cell Biol, 1995 Jun;73(3):245-8.
    PMID: 7590898
    The lymphocyte subset expressing the gamma delta T cell receptor is increased in several infectious diseases including HIV infection. In this study the expression on gamma delta lymphocytes of the T cell activation markers CD25, HLA-DR and CD38, as well as the two isoforms of CD45, namely CD45RA and CD45RO, was determined in the peripheral blood of 56 HIV-infected intravenous drug users and 34 HIV-seronegative blood donors by two-colour flow cytometry. The percentage of gamma delta lymphocytes expressing HLA-DR and CD38 was higher than those in HIV-seronegative controls (P < 0.001 and P < 0.0001, respectively). Furthermore the HLA-DR+gamma delta+ lymphocytes correlated inversely with CD4+ T lymphocyte absolute count (P < 0.02 for both). The levels of gamma delta lymphocytes expressing CD25, CD45RA and CD45RO were similar to those in HIV-seronegative controls. Activated gamma delta lymphocytes may play a role in the HIV disease process and could provide a useful marker for disease progression.
    Matched MeSH terms: CD4-Positive T-Lymphocytes/metabolism*
  13. Fulltext Identification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a binding protein for a 68-kDa Bacillus thuringiensis parasporal protein cytotoxic against leukaemic cells
    Krishnan K, Ker JE, Mohammed SM, Nadarajah VD
    J Biomed Sci, 2010;17:86.
    PMID: 21073742 DOI: 10.1186/1423-0127-17-86
    Bacillus thuringiensis (Bt), an ubiquitous gram-positive spore-forming bacterium forms parasporal proteins during the stationary phase of its growth. Recent findings of selective human cancer cell-killing activity in non-insecticidal Bt isolates resulted in a new category of Bt parasporal protein called parasporin. However, little is known about the receptor molecules that bind parasporins and the mechanism of anti-cancer activity. A Malaysian Bt isolate, designated Bt18 produces parasporal protein that exhibit preferential cytotoxic activity for human leukaemic T cells (CEM-SS) but is non-cytotoxic to normal T cells or other cancer cell lines such as human cervical cancer (HeLa), human breast cancer (MCF-7) and colon cancer (HT-29) suggesting properties similar to parasporin. In this study we aim to identify the binding protein for Bt18 in human leukaemic T cells.
    Matched MeSH terms: T-Lymphocytes/metabolism
  14. Fulltext Biomarkers of severe dengue disease - a review
    John DV, Lin YS, Perng GC
    J Biomed Sci, 2015;22:83.
    PMID: 26462910 DOI: 10.1186/s12929-015-0191-6
    Dengue virus infection presents a wide spectrum of manifestations including asymptomatic condition, dengue fever (DF), or severe forms, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) in affected individuals. The early prediction of severe dengue in patients without any warning signs who may later develop severe DHF is very important to choose appropriate intensive supportive therapy since available vaccines for immunization are yet to be approved. Severe dengue responses include T and B cell activation and apoptosis, cytokine storm, hematologic disorders and complement activation. Cytokines, complement and other unidentified factors may transiently act on the endothelium and alter normal fluid barrier function of the endothelial cells and cause plasma leakage. In this review, the host factors such as activated immune and endothelial cells and their products which can be utilized as biomarkers for severe dengue disease are discussed.
    Matched MeSH terms: T-Lymphocytes/metabolism*
  15. Differential transcriptional expression of PPARalpha, PPARgamma1, and PPARgamma2 in the peritoneal macrophages and T-cell subsets of non-obese diabetic mice
    Yaacob NS, Kaderi MA, Norazmi MN
    J Clin Immunol, 2009 Sep;29(5):595-602.
    PMID: 19472040 DOI: 10.1007/s10875-009-9300-1
    BACKGROUND: The peroxisome proliferator-activated receptors (PPARs) have been implicated in immune regulation. We determined the transcriptional expression of the three isoforms, PPARalpha, PPARgamma1, and PPARgamma2 in the peritoneal macrophages, CD4- and CD8-positive lymphocytes in non-obese diabetic (NOD) mice at 5 and 10 weeks of age as well as at diabetic stage.

    RESULTS: Compared to the non-obese diabetic resistant (NOR) mice, the peritoneal macrophages of NOD mice expressed increased levels of PPARalpha but reduced levels of PPARgamma2, while PPARgamma1 expression was unchanged in all age groups. CD4-positive lymphocytes expressed low levels of PPARalpha in diabetic NOD mice and greatly reduced expression of PPARgamma2 in all age groups. Unlike peritoneal macrophages and CD4-positive cells, the CD8-positive cells expressed low levels of PPARgamma1 in diabetic NOD mice but no difference in PPARalpha and PPARgamma2 expression was observed compared to NOR mice.

    CONCLUSION: The current findings may suggest an important regulatory role of PPARs in the pathogenesis of autoimmune diabetes.

    Matched MeSH terms: CD4-Positive T-Lymphocytes/metabolism; CD8-Positive T-Lymphocytes/metabolism*
  16. Fulltext Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment
    Looi CK, Chung FF, Leong CO, Wong SF, Rosli R, Mai CW
    J Exp Clin Cancer Res, 2019 Apr 15;38(1):162.
    PMID: 30987642 DOI: 10.1186/s13046-019-1153-8
    BACKGROUND: Pancreatic cancer is one of the most lethal type of cancers, with an overall five-year survival rate of less than 5%. It is usually diagnosed at an advanced stage with limited therapeutic options. To date, no effective treatment options have demonstrated long-term benefits in advanced pancreatic cancer patients. Compared with other cancers, pancreatic cancer exhibits remarkable resistance to conventional therapy and possesses a highly immunosuppressive tumor microenvironment (TME).

    MAIN BODY: In this review, we summarized the evidence and unique properties of TME in pancreatic cancer that may contribute to its resistance towards immunotherapies as well as strategies to overcome those barriers. We reviewed the current strategies and future perspectives of combination therapies that (1) promote T cell priming through tumor associated antigen presentation; (2) inhibit tumor immunosuppressive environment; and (3) break-down the desmoplastic barrier which improves tumor infiltrating lymphocytes entry into the TME.

    CONCLUSIONS: It is imperative for clinicians and scientists to understand tumor immunology, identify novel biomarkers, and optimize the position of immunotherapy in therapeutic sequence, in order to improve pancreatic cancer clinical trial outcomes. Our collaborative efforts in targeting pancreatic TME will be the mainstay of achieving better clinical prognosis among pancreatic cancer patients. Ultimately, pancreatic cancer will be a treatable medical condition instead of a death sentence for a patient.

    Matched MeSH terms: T-Lymphocytes/metabolism
  17. Appraisal of immunomodulatory potential of Spirulina fusiformis: an in vivo and in vitro study
    Rasool M, Sabina EP
    J Nat Med, 2009 Apr;63(2):169-75.
    PMID: 19093070 DOI: 10.1007/s11418-008-0308-2
    In recent years, Spirulina has gained more and more attention from medical scientists as a nutraceutical and a source of potential pharmaceuticals. The present study was conducted to elucidate the immunomodulatory effect of Spirulina fusiformis (a cyanobacterium of the family Oscillatoriaceae) in vivo and in vitro. The in vivo effect of S. fusiformis (400 or 800 mg/kg body wt.) on humoral immune response, cell-mediated immune response and tumour necrosis factor alpha was investigated in mice. We also evaluated the effect of S. fusiformis (50 or 100 microg/ml) in vitro on mitogen (phytohaemagglutinin)-induced T lymphocyte proliferation in heparinized human peripheral blood. For comparison, dexamethasone was used as a standard. In mice, S. fusiformis (400 or 800 mg/kg body wt.) administration significantly inhibited the humoral immune response, cell-mediated immune response (delayed-type hypersensitivity reaction (DTH)) and tumour necrosis factor alpha in a dose-dependent manner. In vitro, S. fusiformis (50 or 100 microg/ml) decreased the mitogen (phytohaemagglutinin)-induced T lymphocyte proliferation in a concentration-dependent manner when compared with control cells. These observations clearly suggest that S. fusiformis has a remarkable immunosuppressive effect, which provides a scientific validation for the popular use of this drug, and helped us in further work on investigating its complete mechanism of action.
    Matched MeSH terms: T-Lymphocytes/metabolism
  18. Computational Analysis of Protein-Protein Interactions in Motile T-Cells
    Kumar S, Fazil MHUT, Ahmad K, Tripathy M, Rajapakse JC, Verma NK
    Methods Mol Biol, 2019;1930:149-156.
    PMID: 30610609 DOI: 10.1007/978-1-4939-9036-8_18
    Analysis of protein-protein interactions is important for better understanding of molecular mechanisms involved in immune regulation and has potential for elaborating avenues for drug discovery targeting T-cell motility. Currently, only a small fraction of protein-protein interactions have been characterized in T-lymphocytes although there are several detection methods available. In this regard, computational approaches garner importance, with the continued explosion of genomic and proteomic data, for handling protein modeling and protein-protein interactions in large scale. Here, we describe a computational method to identify protein-protein interactions based on in silico protein design.
    Matched MeSH terms: T-Lymphocytes/metabolism*
  19. Immunomodulation by melatonin: its significance for seasonally occurring diseases
    Srinivasan V, Spence DW, Trakht I, Pandi-Perumal SR, Cardinali DP, Maestroni GJ
    Neuroimmunomodulation, 2008;15(2):93-101.
    PMID: 18679047 DOI: 10.1159/000148191
    Melatonin is not only synthesized by the pineal gland but also in many other organs and tissues of the body, particularly by lymphoid organs such as the bone marrow, thymus and lymphocytes. Melatonin participates in various functions of the body, among which its immunomodulatory role has assumed considerable significance in recent years. Melatonin has been shown to be involved in the regulation of both cellular and humoral immunity. Melatonin not only stimulates the production of natural killer cells, monocytes and leukocytes, but also alters the balance of T helper (Th)-1 and Th-2 cells mainly towards Th-1 responses and increases the production of relevant cytokines such as interleukin (IL)-2, IL-6, IL-12 and interferon-gamma. The regulatory function of melatonin on immune mechanisms is seasonally dependent. This fact may in part account for the cyclic pattern of symptom expression shown by certain infectious diseases, which become more pronounced at particular times of the year. Moreover, melatonin-induced seasonal changes in immune function have also been implicated in the pathogenesis of seasonal affective disorder and rheumatoid arthritis. The clinical significance of the seasonally changing immunomodulatory role of melatonin is discussed in this review.
    Matched MeSH terms: T-Lymphocytes/metabolism
  20. Fulltext Suppression of Human T Cell Proliferation Mediated by the Cathepsin B Inhibitor, z-FA-FMK Is Due to Oxidative Stress
    Rajah T, Chow SC
    PLoS One, 2015;10(4):e0123711.
    PMID: 25915766 DOI: 10.1371/journal.pone.0123711
    The cathepsin B inhibitor, benzyloxycarbonyl-phenylalanine-alanine-fluoromethyl ketone (z-FA-FMK) readily inhibits anti-CD3-induced human T cell proliferation, whereas the analogue benzyloxycarbonyl-phenylalanine-alanine-diazomethyl ketone (z-FA-DMK) had no effect. In contrast, benzyloxycarbonyl-phenylalanine-alanine-chloromethyl ketone (z-FA-CMK) was toxic. The inhibition of T cell proliferation mediated by z-FA-FMK requires not only the FMK moiety, but also the benzyloxycarbonyl group at the N-terminal, suggesting some degree of specificity in z-FA-FMK-induced inhibition of primary T cell proliferation. We showed that z-FA-FMK treatment leads to a decrease in intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) levels in activated T cells. The inhibition of anti-CD3-induced T cell proliferation mediated by z-FA-FMK was abolished by the presence of low molecular weight thiols such as GSH, N-acetylcysteine (NAC) and L-cysteine, whereas D-cysteine which cannot be metabolised to GSH has no effect. The inhibition of anti-CD3-induced up-regulation of CD25 and CD69 expression mediated by z-FA-FMK was also attenuated in the presence of exogenous GSH. Similar to cell proliferation, GSH, NAC and L-cysteine but not D-cysteine, completely restored the processing of caspase-8 and caspase-3 to their respective subunits in z-FA-FMK-treated activated T cells. Our collective results demonstrated that the inhibition of T cell activation and proliferation mediated by z-FA-FMK is due to oxidative stress via the depletion of GSH.
    Matched MeSH terms: T-Lymphocytes/metabolism
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