Publications by authors named "Crystal Y Koh"

10 Publications

  • Page 1 of 1

Defining IL-6 levels in healthy individuals: A meta-analysis.

J Med Virol 2021 Jun 22;93(6):3915-3924. Epub 2020 Nov 22.

Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India.

Background: Interleukin-6 (IL-6) is produced by and impacts different cell types in human. IL-6 is associated with different diseases and viral infections, including COVID-19. To our knowledge, no normal values were reported for IL-6 in the blood of healthy individuals. We have reviewed and performed a meta-analysis on a total of 140 studies, including 12,421 values for IL-6 in the blood of healthy adult donors. Among these studies, 83 did not report a mean value and the standard deviation. Therefore, for the statistical analysis, we used the values reported in 57 studies, which included 3166 values for IL-6.

Results: The reported values for IL-6 in the blood of healthy donors varied between 0 and 43.5 pg/ml. The pooled estimate of IL-6 was 5.186 pg/ml (95% confidence interval [CI]: 4.631, 5.740). As the age increased by 1 year, IL-6 values increased by 0.05 pg/ml (95% CI: 0.02, 0.09; p < .01). Though the heterogenicity, as determined by I statistics, was high in our study, the differences in IL-6 values are still at the level of a few pg/ml, which might be related to the differences in the conditions that influence IL-6 production in the healthy population.

Conclusions: This is the first meta-analysis reporting the levels of IL-6 in the blood of healthy donors based on a large number of studies and donors. Therefore the 95% CI values determined in our study could well serve as a reference range for quick decision-making in clinical interventions, particularly those aiming to inhibit IL-6, especially urgent interventions, for example, COVID-19.
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http://dx.doi.org/10.1002/jmv.26654DOI Listing
June 2021

Sleep deprivation alters neutrophil functions and levels of Th1-related chemokines and CD4 T cells in the blood.

Sleep Breath 2019 Dec 30;23(4):1331-1339. Epub 2019 Apr 30.

Department of Human & Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box: 35, 123, Muscat, Oman.

Purpose: The state of knowledge about the effect of sleep deprivation on the immune system is scarce and conflicting. It would therefore be useful to investigate the consequences of sleep deprivation on the immune system. We have studied the effect of sleep deprivation on the changes in neutrophil functions, and the ex vivo proliferative pattern of CD4 T lymphocytes in relationship with blood cytokine and chemokine levels due to the crucial role of these cells in mounting potent immune responses.

Methods: Healthy volunteers were followed for 3 weeks. They had normal sleep in weeks 1 and 3 and they were sleep-deprived on week 2, sleeping < 6 h per 24 h, a pattern similar to sleep behaviors of many chronically sleep-deprived individuals. We assessed the levels of Th1/Th2 and inflammatory cytokines and chemokines, CD4 T cells, and the NADPH oxidase activation and phagocytic functions in neutrophils.

Results: Our results suggest that sleep deprivation leads to a decreased neutrophil capacity to phagocytose bacteria and activate NADPH oxidase (p < 0.05). Sleep deprivation was associated with a potential increase in CXCL9 levels and decrease in CXCL10/CXCL9 and CCL5/CXCL9 ratios (p < 0.05). Furthermore, our results suggest that the decrease in CD4 T cell due to sleep deprivation was not associated with changes in their proliferation as observed by Ki67 levels, but rather, it correlated with changes in CXCL10/CXCL9 ratio (p < 0.05).

Conclusions: Sleep deprivation may lead to a decreased phagocytosis and NADPH oxidase activity in neutrophils and a decrease in the levels of CD4 T cells which is related to changes in the Th1-related chemokine balance.
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http://dx.doi.org/10.1007/s11325-019-01851-1DOI Listing
December 2019

Altered blood cytokines, CD4 T cells, NK and neutrophils in patients with obstructive sleep apnea.

Immunol Lett 2017 10 19;190:272-278. Epub 2017 Aug 19.

Department of Human & Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box: 35, 123, Muscat, Oman. Electronic address:

Background: There are contradictory reports on the effects of obstructive sleep apnea (OSA) on the immune system. In order to clarify the effect of OSA on the different components of the immune system, we studied the association of OSA with changes in cytokine and chemokine levels, proliferative patterns of CD4 and CD8 T lymphocytes as well as NK cells ex vivo and neutrophil functions.

Methods: We investigated the association of OSA with potential alterations in 14 Th1/Th2 and inflammatory cytokines and chemokines, CD4 and CD8 T cells, NK cells, and the NADPH oxidase activation and phagocytic functions in neutrophils.

Results: Our results suggest that the increase in CD4 T cell frequency in OSA is associated with an increased expression of the nuclear protein Ki67 (p<0.05; power>0.8), and is correlated with the levels of IL-1β (p<0.05; power>0.8). The levels of IL-1β as well as IL-6 showed a potential increase, while the levels of IFN-γ (p<0.05; power>0.8) and the ratio IFN-γ/IL-4 in the blood were possibly decreased in OSA. Additionally, we observed a potential increase in the expression of Ki67 in CD8 and CD8 NK cells (p<0.05; power>0.8). Our results also suggest that neutrophils have a decreased capacity to phagocytose bacteria and activate NADPH oxidase in OSA patients (p<0.05; power>0.8).

Conclusion: OSA may be associated with inflammatory and pro-Th2 immune responses, an increased proliferative potential of NK and CD4 T cells and a decreased capacity of neutrophils to phagocytose bacteria and produce ROS.
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http://dx.doi.org/10.1016/j.imlet.2017.08.009DOI Listing
October 2017

Increased CD86 but Not CD80 and PD-L1 Expression on Liver CD68+ Cells during Chronic HBV Infection.

PLoS One 2016 27;11(6):e0158265. Epub 2016 Jun 27.

Department of Microbiology and Immunology, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box: 35, Code: 123, Muscat, Oman.

Background: The failure to establish potent anti-HBV T cell responses suggests the absence of an effective innate immune activation. Kupffer cells and liver-infiltrating monocytes/macrophages have an essential role in establishing anti-HBV responses. These cells express the costimulatory molecules CD80 and CD86. CD80 expression on antigen-presenting cells (APCs) induces Th1 cell differentiation, whereas CD86 expression drives the differentiation towards a Th2 profile. The relative expression of CD80, CD86 and PD-L1 on APCs, regulates T cell activation. Few studies investigated CD80 and CD86 expression on KCs and infiltrating monocytes/macrophages in HBV-infected liver and knowledge about the expression of PD-L1 on these cells is controversial. The expression of these molecules together in CD68+ cells has not been explored in HBV-infected livers.

Methods: Double staining immunohistochemistry was applied to liver biopsies of HBV-infected and control donors to explore CD80, CD86 and PD-L1 expression in the lobular and portal areas.

Results: Chronic HBV infection was associated with increased CD68+CD86+ cell count and percentage in the lobular areas, and no changes in the count and percentage of CD68+CD80+ and CD68+PD-L1+ cells, compared to the control group. While CD68+CD80+ cell count in portal areas correlated with the fibrosis score, CD68+CD80+ cell percentage in lobular areas correlated with the inflammation grade.

Conclusion: The upregulation of CD86 but not CD80 and PD-L1 on CD68+ cells in HBV-infected livers, suggests that these cells do not support the induction of potent Th1. Moreover, the expression of CD80 on CD68+ cells correlates with liver inflammation and fibrosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158265PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922653PMC
July 2017

A Potential Inhibitory Profile of Liver CD68+ Cells during HCV Infection as Observed by an Increased CD80 and PD-L1 but Not CD86 Expression.

PLoS One 2016 11;11(4):e0153191. Epub 2016 Apr 11.

Department of Microbiology and Immunology, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box: 35, Code: 123, Muscat, Oman.

Aim: The lack of potent innate immune responses during HCV infection might lead to a delay in initiating adaptive immune responses. Kupffer cells (KCs) and liver-infiltrating monocytes/macrophages (CD68+ cells) are essential to establish effective anti-HCV responses. They express co-stimulatory molecules, CD80 and CD86. CD86 upregulation induces activator responses that are then potentially regulated by CD80. The relative levels of expression of CD80, CD86 and the inhibitory molecule, PD-L1, on CD68+ cells modulate T cell activation. A few studies have explored CD80 and PD-L1 expression on KCs and infiltrating monocytes/macrophages in HCV-infected livers, and none investigated CD86 expression in these cells. These studies have identified these cells based on morphology only. We investigated the stimulatory/inhibitory profile of CD68+ cells in HCV-infected livers based on the balance of CD80, CD86 and PD-L1 expression.

Methods: CD80, CD86 and PD-L1 expression by CD68+ cells in the lobular and portal areas of the liver of chronic HCV-infected (n = 16) and control (n = 14) individuals was investigated using double staining immunohistochemistry.

Results: The count of CD68+ KCs in the lobular areas of the HCV-infected livers was lower than that in the control (p = 0.041). The frequencies of CD68+CD80+ cells and CD68+PD-L1+ cells in both lobular and total areas of the liver were higher in HCV-infected patients compared with those in the control group (p = 0.001, 0.031 and 0.007 respectively). Moreover, in the lobular areas of the HCV-infected livers, the frequency of CD68+CD80+ cells was higher than that of CD68+CD86+ and CD68+PD-L1+ cells. In addition, the frequencies of CD68+CD80+ and CD68+CD86+ cells were higher in the lobular areas than the portal areas.

Conclusions: Our results show that CD68+ cells have an inhibitory profile in the HCV-infected livers. This might help explain the delayed T cell response and viral persistence during HCV infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153191PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827822PMC
August 2016

Genetic diversity and prevalence of CCR2-CCR5 gene polymorphisms in the Omani population.

Genet Mol Biol 2014 Mar 28;37(1):7-14. Epub 2013 Feb 28.

Division of Immunology, Department of Microbiology and Immunology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman .

Polymorphisms in the regulatory region of the CCR5 gene affect protein expression and modulate the progress of HIV-1 disease. Because of this prominent role, variations in this gene have been under differential pressure and their frequencies vary among human populations. The CCR2V64I mutation is tightly linked to certain polymorphisms in the CCR5 gene. The current Omani population is genetically diverse, a reflection of their history as traders who ruled extensive regions around the Indian Ocean. In this study, we examined the CCR2-CCR5 haplotypes in Omanis and compared the patterns of genetic diversity with those of other populations. Blood samples were collected from 115 Omani adults and genomic DNA was screened to identify the polymorphic sites in the CCR5 gene and the CCR2V64I mutation. Four minor alleles were common: CCR5-2554T and CCR5-2086G showed frequencies of 49% and 46%, respectively, whereas CCR5-2459A and CCR5-2135C both had a frequency of 36%. These alleles showed moderate levels of heterozygosity, indicating that they were under balancing selection. However, the well-known allele CCR5Δ32 was relatively rare. Eleven haplotypes were identified, four of which were common: HHC (46%), HHE (20%), HHA (14%) and HHF*2 (12%).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958329PMC
http://dx.doi.org/10.1590/s1415-47572014000100004DOI Listing
March 2014

Lack of correlation between an assay used to determine early marrow allograft rejection and long-term chimerism after murine allogeneic bone marrow transplantation: effects of marrow dose.

Biol Blood Marrow Transplant 2005 Apr;11(4):252-9

Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

The acute rejection of bone marrow (BM) allografts by host effectors can occur within a short period after BM transplantation (BMT) in lethally irradiated mice. Common assays used to ascertain engraftment/resistance involve measuring the growth of granulocyte/monocyte progenitors (colony-forming unit-granulocyte-macrophage) in vitro or splenocyte proliferation assessed by radioisotope incorporation in vivo 5 to 8 days after BMT. However, the correlation of the long-term outcome of BMT with the kinetics of recovery by using the dose of allogeneic BM cells (BMCs) that leads to early rejection as determined by the in vitro assessment has not been extensively studied. Thus, to investigate whether the early rejection of donor BMCs is an indication of a long-term engraftment failure, C57BL/6 (H2b) mice were lethally irradiated and transplanted with various doses of BALB/c (H2d) BMCs. The short-term engraftment of donor precursors (colony-forming unit-granulocyte-macrophage), the kinetics of hematopoietic cell recovery, the extent of donor chimerism, and the proportion of the recipients with long-term survival were determined. The results show that the kinetics and extent of hematopoietic cell recovery were significantly delayed in mice receiving limiting doses of BMCs that were rejected or severely resisted at day 8 after BMT. However, a proportion of these mice survived up to 98 days after BMT with mixed chimerism or donor chimerism. This study demonstrates that early rejection of BM precursors, as assessed by measurement of myeloid progenitors in the spleen after BMT, does not always correlate with the long-term outcome of the marrow allograft and that significant variability is inherent in the extent of chimerism when threshold amounts of BMCs are used.
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http://dx.doi.org/10.1016/j.bbmt.2005.01.006DOI Listing
April 2005

NK-cell purging of leukemia: superior antitumor effects of NK cells H2 allogeneic to the tumor and augmentation with inhibitory receptor blockade.

Blood 2003 Dec 31;102(12):4067-75. Epub 2003 Jul 31.

Department of Microbiology and Immunology, University of Nevada School of Medicine, Applied Research Facility, Bldg 344/MS 199, Reno, NV 89557, USA.

Natural killer (NK) cells are composed of subsets characterized by the expression of inhibitory or activating receptors, or both, specific for different major histocompatibility complex (MHC) class I determinants. We have previously shown that inhibitory receptor blockade of syngeneic NK cells was an effective means of ex vivo purging of leukemia-contaminated bone marrow and that the transplantation of mice with the purged bone marrow cells (BMCs) resulted in long-term, relapse-free survival. We have extended the investigation to assess the antitumor effects mediated by NK cells H2-allogeneic to tumor cells. We demonstrate that various tumor cell lines are more susceptible to lysis by H2-allogeneic NK cells than by syngeneic NK cells in vitro even though comparable percentages of Ly49 NK cells were present. Using allogeneic NK cells to purge leukemia-contaminating BMCs before transplantation resulted in a higher proportion of mice with long-term survival than using syngeneic NK cells. Allogeneic NK cells did not suppress hematopoietic reconstitution as measured by granulocyte/monocyte-colony-forming unit (CFU-GM), complete blood count (CBC), and donor chimerism at various days after transplantation. Inhibitory receptor blockade of allogeneic NK cells also significantly increased these antitumor effects at lower NK/tumor ratios compared with those of syngeneic NK cells. These results demonstrate that H2-allogeneic NK cells mediate more potent antitumor effects than syngeneic NK cells without adverse hematologic effects and thus may be useful in cancer therapy.
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http://dx.doi.org/10.1182/blood-2003-04-1367DOI Listing
December 2003

The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP.

Blood 2003 Jul 13;102(1):303-10. Epub 2003 Mar 13.

Basic Sciences Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute/NIH, Bldg 560, Rm 31-30, Frederick, MD 21702-1201, USA.

Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor kappaB (NF-kappaB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis.
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http://dx.doi.org/10.1182/blood-2002-09-2975DOI Listing
July 2003

NK inhibitory-receptor blockade for purging of leukemia: effects on hematopoietic reconstitution.

Biol Blood Marrow Transplant 2002 ;8(1):17-25

Transplantation Biology Laboratory, Laboratory of Molecular Immunoregulation, National Cancer Institute at Frederick, Maryland, USA.

One of the obstacles of BMT that limits its efficacy is failure to eradicate the original tumor. The incidence of tumor relapse is particularly high after autologous BMT. Natural killer (NK) cells comprise various subsets that can express inhibitory receptors for MHC class I determinants. We have recently demonstrated that blockade of NK-cell inhibitory receptors can augment antitumor effects in vitro and in vivo. However, breakdown of tolerance and autoreactivity may occur as a result of the inhibition of NK-cell inactivation to self MHC determinants. We have utilized F(ab')2 fragments of monoclonal antibody, 5E6, against Ly49C/I inhibitory receptors, which are expressed on 35% to 60% of NK cells in H2b strains of mice and are specific for H2Kb, to investigate the effect of inhibitory-receptor blockade on syngeneic bone marrow cell (BMC) and tumor cell growth. We show that treatment of interleukin 2-activated C57BL/6 (B6, H2b) SCID-mouse NK cells with 5E6 F(ab')2 fragments during 48-hour coculture resulted in autoreactivity against syngeneic BMCs as demonstrated by suppression of myeloid reconstitution on day 14 post-BMT. However, this suppressive effect was transient and normalized by day 21 post-BMT. In contrast, blockade of inhibitory receptors during 24-hour coculture had no adverse effects on myeloid reconstitution after BMT. Furthermore, under the same coculture conditions, NK cell-mediated purging of C1498 leukemia cells contaminating syngeneic BMCs was more effective with inhibitory-receptor blockade, leading to a significantly higher proportion of animals with long-term survival compared to the control recipients. These results demonstrate that short-term in vitro blockade of inhibitory receptors can augment antitumor activity without long-term inhibitory effects on BMCs and thus may be of potential use in the purging of contaminating tumor cells prior to autologous BMT.
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http://dx.doi.org/10.1053/bbmt.2002.v8.pm11846352DOI Listing
July 2003