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1
Kobie, James, David Spencer, Philip Barnette, Shilpi Pandey, Madhubanti Basu, William Sutton, Javier Rangel-Moreno, Nancy Logan Haigwood, Ann Jones Hessell, and Sanghita Sarkar. "Targeting tonsillar B cells with IL-9 and IL-33 enhances the rhesus macaque humoral response to DNA/protein-based HIV envelope vaccine." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 114.25. http://dx.doi.org/10.4049/jimmunol.208.supp.114.25.
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Abstract Development of an effective HIV vaccine is dependent on the quantity and quality of HIV Envelope specific antibody at the mucosal sites. Priming of the oral mucosa is a promising approach to generate mucosal antibody at HIV entry sites. Our recent work in mice has demonstrated the ability of IL-9 and IL-33, known regulators of mucosal immunity, to promote robust development of HIV Env-specific IgG; in addition they increase the breadth, magnitude, and durability of the Env-specific IgG response when combined with the DNA/protein HIV Env immunogen platform VC10014, which elicits Tier 2 neutralizing antibody in rhesus macaques. We hypothesized that conditioning the tonsil microenvironment with IL-9 or IL-33 would enable the rapid induction of durable and effective mucosal humoral immunity by the VC10014 DNA/protein HIV vaccine platform. Rhesus macaques were primed with VC10014 gp160 DNA plasmids in the absence or presence of IL-9 or IL-33 intra-tonsillar (IT), followed by intramuscular (IM) boosting with the DNA/protein HIV vaccine regimen. IT immunization with IL-9 or IL33 induced plasma Env-specific IgG that was present as early as week 6, mucosal Env-specific IgG and heterologous plasma neutralizing antibody. IL-33 treated animals exhibited the greatest number of germinal centers (GCs) and largest GCs following the first IM boost whereas IL-9 treated animals showed the greatest number of GCs following the second IM boost in the draining lymph nodes. The difference in kinetics, with IL-33 promoting an earlier B cell response, and IL-9 promoting greater magnitude later, may suggest that IL-9 and IL-33 promote the development of qualitatively different B cells subsets and may have synergistic potential in HIV vaccine development. Supported by a grant from NIH (R01DE027245).
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Younas, Mehwish, Christina Psomas, Vikram Mehraj, Renaud Cezar, Pierre Portales, Edouard Tuaillon, Adeline Guigues, Jacques Reynes, Pierre Corbeau, and Jean-Pierre Routy. "Plasma Level of Soluble ST2 in Chronically Infected HIV-1 Patients with Suppressed Viremia." Open AIDS Journal 11, no. 1 (April 26, 2017): 32–35. http://dx.doi.org/10.2174/1874613601711010032.
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Introduction: Interleukin-33 (IL-33) is a cell damage-induced alarmin. The plasma concentration of suppression of tumorogenicity (sST2), a surrogate marker of IL-33 production, is a prognostic marker of cardiovascular disease. Observation: Recently, we reported that sST2 plasma levels were elevated in early HIV-1 infection and linked to markers of microbial translocation and of T cell activation. Results: Here we show that it is not the case in patients with suppressed viremia. Thus, IL-33 plays its alarmin role only during the early phase of the infection.
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Jalbert, Emilie, Nisha Parikh, Todd Seto, Dominic Chow, Cecilia Shikuma, Lishomwa Ndhlovu, and Jason Barbour. "Elevated proinflammatory cytokine production by monocytes in HIV(+) individuals at risk for cardiovascular disease (P3033)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 55.17. http://dx.doi.org/10.4049/jimmunol.190.supp.55.17.
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Abstract Despite virologic suppression by HIV antiretroviral therapy, residual inflammation associated with chronic HIV infection increases the risk of developing cardiovascular disease. Monocytes have been shown to be major players in the development of atherosclerosis due to their proinflammatory responses to oxidized Low Density Lipoproteins. Our study sought to assess the functional properties of monocytes from peripheral blood of HIV-infected individuals. The cohort consisted of 33 HIV(+) subjects on HAART and 14 HIV(-) risk- and age- matched subjects. Our flow cytometry-based functional assay measured monocyte production of IL-1β, IL-8 and IL-6 in the absence of stimulation and in response to LPS or oxLDL. Without stimulation, HIV(+) subjects had a greater frequency of cells producing IL-1β and IL-8. In the presence of either oxLDL or LPS, both groups increased the frequency of responding cells compared to no stimulation, but HIV(+) subjects maintained a higher frequency of IL-1β(+) and IL-8(+) cells compared to HIV(-). There was no IL-6 production in either group in the absence of stimulation, but upon stimulation with either oxLDL or LPS, there was a higher frequency of IL-6 producing cells in the HIV(+) group. The higher level of inflammatory cytokine production in HIV(+) adults compared to HIV(-), both at rest and in the presence of stimulation, may in part account for increased risk of cardiovascular disease seen in the HIV(+) population.
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Kobie, James, Sanghita Sarkar, Michael Piepenbrink, Madhubanti Basu, Michael Keefer, Juilee Thakar, Ann Jones Hessell, and Nancy Logan Haigwood. "IL-33 enhances the induction, durability, and breadth of the antibody response to a DNA/protein-based HIV Env vaccine." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 225.16. http://dx.doi.org/10.4049/jimmunol.198.supp.225.16.
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Abstract Induction of a sustained and broad antibody (Ab) response is a major goal in developing a protective HIV vaccine. DNA is an attractive priming strategy when combined with protein or viral vector boosting; however, DNA priming alone fails to induce a substantial Ab response, limiting its potential as a stand-alone immunogen. Using the VC10014 DNA/protein vaccine consisting of gp160 plasmids and gp140 proteins derived from an HIV clade B infected subject who developed broadly neutralizing serum Abs, and which has been previously shown to induce Tier 2 heterologous neutralizing Abs in rhesus macaques, we screened a panel of factors in C57BL/6 mice for their ability to enhance the Env-specific Ab response. IL-33, an alarmin, emerged as the lead candidate. The addition of recombinant IL-33 during the gp160 DNA priming phase dramatically changed the kinetics of the Ab response, inducing serum gp120-specific IgG (>1:12,500 titer) after a single DNA immunization, which was not detectable in mice that did not receive IL-33 (p<0.0001). Then following boosting with DNA/protein coimmunization in Alum, gp120-specific IgG levels were extraordinarily durable, remaining stable even at 6 weeks after final immunization compared to mice not receiving IL-33 (p<0.0001), in which they rapidly declined. IL-33 also increased the cross-clade breadth and avidity of the serum gp120-specific IgG response. Analysis of the Env-specific B cell immunoglobulin repertoire and the IL-33 mechanism of action is ongoing. These results demonstrate the profound effect that priming conditions can have on the quality of the Env-specific antibody response.
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Carreto-Binaghi, Laura E., Eda P. Tenorio, Fernando R. Morales-Villarreal, El Moukhtar Aliouat, Edgar Zenteno, José-Arturo Martínez-Orozco, and Maria-Lucia Taylor. "Detection of Cytokines and Collectins in Bronchoalveolar Fluid Samples of Patients Infected with Histoplasma capsulatum and Pneumocystis jirovecii." Journal of Fungi 7, no. 11 (November 4, 2021): 938. http://dx.doi.org/10.3390/jof7110938.
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Histoplasmosis and pneumocystosis co-infections have been reported mainly in immunocompromised humans and in wild animals. The immunological response to each fungal infection has been described primarily using animal models; however, the host response to concomitant infection is unknown. The present work aimed to evaluate the pulmonary immunological response of patients with pneumonia caused either by Histoplasma capsulatum, Pneumocystis jirovecii, or their co-infection. We analyzed the pulmonary collectin and cytokine patterns of 131 bronchoalveolar lavage samples, which included HIV and non-HIV patients infected with H. capsulatum, P. jirovecii, or both fungi, as well as healthy volunteers and HIV patients without the studied fungal infections. Our results showed an increased production of the surfactant protein-A (SP-A) in non-HIV patients with H. capsulatum infection, contrasting with HIV patients (p < 0.05). Significant differences in median values of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, IL-33, IL-13, and CXCL8 were found among all the groups studied, suggesting that these cytokines play a role in the local inflammatory processes of histoplasmosis and pneumocystosis. Interestingly, non-HIV patients with co-infection and pneumocystosis alone showed lower levels of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, and IL-23 than histoplasmosis patients, suggesting an immunomodulatory ability of P. jirovecii over H. capsulatum response.
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Stefanie, Sammet, Michael Koldehoff, Pia Schenk-Westkamp, Peter A. Horn, Stefan Esser, and Monika Lindemann. "T Cell Responses against Orthopoxviruses in HIV-Positive Patients." Vaccines 12, no. 2 (January 27, 2024): 131. http://dx.doi.org/10.3390/vaccines12020131.
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A global outbreak of predominantly sexually transmitted mpox infections, outside endemic regions, was reported in May 2022. Thereafter, risk groups were vaccinated against smallpox, a structurally related orthopoxvirus. In the current study, we analyzed T cell responses against peptides derived from orthopoxviruses in 33 HIV-positive patients after two vaccinations against smallpox and in 10 patients after mpox infection. We established an ELISpot assay, detecting either the secretion of the pro-inflammatory cytokine interferon (IFN)-γ or interleukin (IL)-2. After vaccination, 21 out of 33 patients (64%) showed specific IFN-γ secretion and 18 (55%) specific IL-2 secretion, defined as >3-fold higher specific value than negative control and at least 4 spots above the negative control. After mpox infection, all patients showed specific IFN-γ secretion and 7 out of 10 (70%) IL-2 secretion. In vaccinated patients, IFN-γ responses were significantly lower than in patients with mpox infection (median response 4.5 vs. 21.0 spots, p < 0.001). The same trend was observed for IL-2 responses. After mpox infection, IL-2 ELISpot results positively correlated with CD8+ T cells (p < 0.05). Thus, T cell responses were detectable in two thirds of HIV-positive patients after vaccination and were even more abundant and vigorous after mpox infection.
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Mitchell, Brooks I., Elizabeth I. Laws, Dominic C. Chow, Ivo N. Sah Bandar, Louie Mar A. Gangcuangco, Cecilia M. Shikuma, and Lishomwa C. Ndhlovu. "Increased Monocyte Inflammatory Responses to Oxidized LDL Are Associated with Insulin Resistance in HIV-Infected Individuals on Suppressive Antiretroviral Therapy." Viruses 12, no. 10 (October 5, 2020): 1129. http://dx.doi.org/10.3390/v12101129.
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Despite long term antiretroviral therapy (ART), insulin resistance (IR) is common among people living with HIV/AIDS (PLWHA) exposing this population to a greater risk of cardiometabolic complications when compared to their uninfected counterparts. We previously identified an expansion in monocyte subpopulations in blood that were linked to the degree of IR in persons with HIV on stable ART. In this study, we directly assessed monocyte inflammatory functional properties from PLWHA on ART (n = 33) and HIV-uninfected controls (n = 14) of similar age, gender, and cardiovascular disease risk and determined the relationship with IR (homeostatic model assessment-insulin resistance (HOMA-IR)), calculated from fasting blood glucose and insulin measurements. Peripheral blood mononuclear cells were stimulated with oxidized low-density lipoproteins (oxLDL) and polyfunctional monocyte cytokine responses (IL-1β, IL-6, IL-8, or TNF-α) were determined by flow cytometry. Higher monocyte IL-1β and IL-8 responses to oxLDL were associated with higher IR in PLWHA but not in the control group. We observed that higher basal monocyte cytokine responses were associated with both duration since HIV diagnosis and ART initiation. In the management of IR in chronic HIV, strategies lowering monocyte IL-1β and IL-8 responses should be considered in addition to ART in order to limit adverse cardio-metabolic outcomes.
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Menezes, Silvio Augusto Fernandes de, Tatiany Oliveira de Alencar Menezes, Tânia Maria de Souza Rodrigues, Brenna Magdalena Lima Nogueira, and Ricardo Roberto de Souza Fonseca. "Analysis of IL-10 in HIV-1 patients with chronic periodontitis in northern Brazil." Brazilian Journal of Oral Sciences 16 (December 15, 2017): 1–9. http://dx.doi.org/10.20396/bjos.v16i0.8651054.
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Aim: The objective of this study was to investigate the levels of IL-10 in the gingival crevicular fluid in HIV-1 positive patients with chronic periodontitis and to compare with HIV-1 negative patients with chronic periodontitis, also to correlate clinical periodontal parameters, viral load and count of CD4+ and CD8+ lymphocytes (LTCD4+ and LTCD8+). Methods: 33 patients were selected and splitted into two groups: 16 HIV-1 positive patients and 17 HIV-1 negative patients and all with chronic periodontitis. The clinical periodontal parameters recorded were: Probing Depth (PD) and Clinical Attachment Level (CAL); the sistemical parameters LTCD4+, LTCD8+ and viral load were analized by the gingival crevicular fluid collected from all patients. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentrations of Interleukin (IL)-10. For the statistical analysis the Student t, Mann-Whitney and Spearman tests were performed. IL-10 levels were significantly lower in both patients groups. Results: There was statistical difference betwen groups for probing depth (p=0.015) and clinical attachment level (p=0.011), no significant correlation was found among the analyzed variables. Conclusion: The IL-10 levels in HIV-1 positive patients had no influence in periodontal and medical parameters.
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He, B., L. Zheng, H. Zhou, Y. He, Z. Chen, S. Xiao, H. Wang, Y. Ling, and Y. Zheng. "Dynamic observation of IL-33 and its receptors in HIV patients who received HAART." Cellular and Molecular Biology 63, no. 3 (March 31, 2017): 73. http://dx.doi.org/10.14715/cmb/2017.63.3.14.
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Olaniyan, Mathew F., Alade A. Ogunlade, and David Atere. "Possible Immunological Alterations in the Plasma Levels of TNF-α and IL-10 in the Traditional Application of Vernonia Amygdalina (Ewuro) Leaves in the Treatment of Diabetes Mellitus." Recent Advances in Biology and Medicine 5 (2019): 1. http://dx.doi.org/10.18639/rabm.2019.743583.
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Diabetes mellitus can induce release of free radicals and oxidative stress, which can trigger production of cytokines. Vernonia amygdalina has antidiabetic activity due to its phytochemical constituents. This work was designed to determine possible immunological alterations in the plasma levels of TNF-α and Interleukin-10 (IL-10) in the traditional application of V. amygdalina (Ewuro) leaves in the treatment of diabetes mellitus. The study populations include all 33 diabetes mellitus patients (51-67 years; male, 21; female, 12) who had not commenced any form of medication or treatment and received herbal treatment in 10 herbal homes of Saki West, a local government area in Nigeria. Twenty-seven agematched volunteers who were treated on insulin medication in the hospital almost within the same period were also investigated. Patients who were positive to acid-fast bacilli sputum test, Plasmodium spp., identification, HBsAg, anti-HCV, and HIV-1 p24 assays were not included. Plasma TNF-α, IL-10, HBsAg, anti-HCV, and HIV-1 p24 were determined in the patients by ELISA while identification of acid-fast bacilli and Plasmodium spp. were carried out by Ziehl-Neelsen and Giemsa thick blood-film staining, respectively. There was a significant decrease in the plasma levels of TNF-α, IL-10, and glucose in diabetes mellitus patients after the administration of raw liquid extract of V. amygdalina and insulin compared to their basal samples before the commencement of the treatment (p < 0.05). The work revealed a significant increase in plasma TNF-α, IL-10, and glucose in diabetes patients, which returned to normal plasma values after treatment using raw liquid extract of V. amygdalina leaves and insulin.
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Chen, Marcelo, Chung-Lieh Hung, Chun-Ho Yun, Allison R. Webel, and Chris T. Longenecker. "Sex Differences in the Association of Fat and Inflammation Among People with Treated HIV Infection." Pathogens and Immunity 4, no. 1 (August 19, 2019): 163. http://dx.doi.org/10.20411/pai.v4i1.304.
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Introduction: Ectopic fat deposition may contribute to chronic inflammation in people with HIV (PWH). To inform future mechanistic studies of metabolic risk in this population, we sought to determine which fat measures relate more strongly to inflammation and whether the fat-inflammation relationship is modified by sex or HIV status.Methods: We conducted a cross-sectional study of 105 PWH and 20 age- and sex-matched HIV-negative controls. Interleukin-6 (IL-6) and high-sensitivity C reactive protein (hs-CRP) levels were measured from plasma. Pericardial fat (PCF) and thoracic periaortic adipose tissue (TAT) volumes and peri-right coronary artery (RCA), left atrium (LA) roof and liver densities were measured from cardiac CT scans. Unadjusted and multivariate adjusted linear regression models were used to determine the relationship between ectopic fat measures and inflammation biomarkers.Results: Forty subjects had BMI <25, 33 had BMI 25-30, and 52 had BMI >30. Systolic blood pressure and insulin resistance increased with BMI. Subjects with higher BMI had higher CD4+ count. In models adjusted for demographics, HIV status and metabolic risk factors, BMI was positively associated with IL-6 and hs-CRP. Ectopic PCF and TAT volumes were positively associated with IL-6 and hs-CRP; however, these relationships were somewhat attenuated in adjusted models. LA roof (but not peri-RCA) fat radiodensity was inversely associated with hs-CRP in fully adjusted models and the association with IL-6 was borderline statistically significant. IL-6 was more strongly associated with BMI and LA roof density in women than in men (p for interaction=0.05).Conclusions: Among PWH on antiretroviral therapy, higher BMI and excessive visceral fat burden were associated with circulating markers of systemic inflammation, and this relationship appears to be stronger in women compared to men.
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Reddy, Pichili Vijaya Bhaskar, Sudheesh Pilakka-Kanthikeel, Shailendra K. Saxena, Zainulabedin Saiyed, and Madhavan P. N. Nair. "Interactive Effects of Morphine on HIV Infection: Role in HIV-Associated Neurocognitive Disorder." AIDS Research and Treatment 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/953678.
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HIV epidemic continues to be a severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV. The frequency of drug abuse among HIV infected patients is rapidly increasing and is another major issue since injection drug users are at a greater risk of developing HIV associated neurocognitive dysfunctions compared to non-drug users infected with HIV. Brain is a major target for many of the recreational drugs and HIV. Evidences suggest that opiate drug abuse is a risk factor in HIV infection, neural dysfunction and progression to AIDS. The information available on the role of morphine as a cofactor in the neuropathogenesis of HIV is scanty. This review summarizes the results that help in understanding the role of morphine use in HIV infection and neural dysfunction. Studies show that morphine enhances HIV-1 infection by suppressing IL-8, downregulating chemokines with reciprocal upregulation of HIV coreceptors. Morphine also activates MAPK signaling and downregulates cAMP response element-binding protein (CREB). Better understanding on the role of morphine in HIV infection and mechanisms through which morphine mediates its effects may help in devising novel therapeutic strategies against HIV-1 infection in opiate using HIV-infected population.
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Valdez, Michael, Leila Moosavi, and Arash Heidari. "Concomitant Central Nervous System Toxoplasmosis and Seronegative Disseminated Coccidioidomycosis in a Newly Diagnosed Acquired Immune Deficiency Syndrome Patient." Journal of Investigative Medicine High Impact Case Reports 7 (January 2019): 232470961986937. http://dx.doi.org/10.1177/2324709619869372.
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Opportunistic infections (OIs) are a significant cause of morbidity and mortality in immunosuppressed patients and may be due to bacteria, virus, protozoa, or fungi. Toxoplasmosis is a common cause of central nervous system infection in human immunodeficiency virus (HIV) patients. Coccidioidomycosis is a relatively common fungal infection that may lead to disseminated disease and fungemia in immune-compromised hosts living in endemic regions. This single-patient case report documents the presentation, diagnosis, management, and outcome of concomitant central nervous system toxoplasmosis and diffuse miliary pneumonia with fungemia due to disseminated seronegative Coccidioides immitis in a 33-year-old male patient recently diagnosed with chronic advanced HIV. Impaired cellular immune function, such as defects in the IL-12/IFN-γ pathway or T-helper IL-17-mediated response, is associated with increased severity of coccidioidomycosis. Fungemia and acute respiratory distress syndrome are both associated with very high mortality in coccidioidomycosis. In HIV hosts, negative Coccidioides serology can be seen in up to 25% of cases and therefore other diagnostic modalities should be initiated promptly and simultaneously. This case demonstrates simultaneous OI in the setting of advanced acquired immune deficiency syndrome and emphasizes the need for early diagnosis of HIV and OI in order to ensure prompt initiation of antiretroviral therapy, prophylactic, and therapeutic medications.
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Benson, D. M., M. Shah, A. Freud, A. Ferketich, B. J. Dezube, Z. P. Bernstein, and M. A. Caligiuri. "A phase I study of ultra low dose interleukin-2 (IL-2) and stem cell factor (SCF) in patients with cancer and or HIV infection." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 2503. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.2503.
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2503 Background: HIV infection depletes crucial lymphocyte subsets and often culminates in patients’ demise due to infectious or malignant complications. We have shown in previous work that ultra low dose interleukin-2 (IL-2) expands natural killer (NK) cells and other lymphocyte subsets in patients with AIDS-associated malignancies. Preclinical work by our group has demonstrated that CD56bright NK cells, an important source of interferon-γ, constitutively express the c-kit receptor and proliferate synergistically in vitro and in vivo in response to IL-2 and stem cell factor (SCF) presented together. To determine the safety, toxicity, and immune modulatation of IL-2 and SCF in patients, we report a first-in-man Phase I trial of this combination of cytokines in patients with HIV and HIV-associated malignancies. Methods: Eligible adults had a history of cancer and HIV or an AIDS defining illness, Karnofsky score > 70%, CD4 T-cell count > 20/mm3, and had to be on HAART therapy. Patients received IL-2 subcutaneously (SQ) daily at 900,000 IU/m2 (cohort 1) or 450,000 IU/m2 (cohorts 2 and 3) except Sunday and SCF (SQ) three times a week (at 5 mcg/kg/d or 10 mcg/kg/d) for 8 weeks. Toxicities and side effects of therapy were closely monitored. Changes in lymphocyte subsets were assessed by flow cytometry. Results: 13 patients (median age = 42, range 33–62) with cancer and HIV (5) or AIDS (8) were enrolled. 10 patients completed therapy, whereas three exhibited the grade 3 dose limiting toxicity (DLT) of fatigue and withdrew. Treatment led to statistically significant increases in NK cells (2.2-fold, p = 0.02) and regulatory T cells (Tregs) (6-fold, 0.005). These were similar to a previous study using a slightly higher dose of IL-2 alone (1 million IU/m2) in which NK were expanded 1.6 fold (p = 0.02) and Treg were expanded nearly 9-fold (p = 0.0003). Conclusions: Simultaneous administration of IL-2 and SCF is safe and well tolerated. The maximum tolerated doses of IL-2 and SCF were 450,000 IU/m2 and 5 mcg/kg/d respectively. Fatigue was the DLT. A trend towards preferential expansion of CD56bright NK cells as opposed to Tregs was seen; however, these changes were not significantly different from changes in response to a similar ultra low dose of IL-2 alone. No significant financial relationships to disclose.
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Pour, Navaz Karimian, and Micheline Piquette-Miller. "Endotoxin Modulates the Expression of Renal Drug Transporters in HIV-1 Transgenic Rats." Journal of Pharmacy & Pharmaceutical Sciences 21, no. 1s (July 16, 2018): 117s—129s. http://dx.doi.org/10.18433/jpps30017.
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PURPUSE: Bacterial co-infections and low grade endotoxemia are common in HIV patients. Inflammation due to endotoxin or HIV may influence the expression and activity of transporters. Kidney transporters influence renal drug clearances including many antiretroviral agents. Our objective was to study the effect of endotoxin and HIV on the renal expression of drug transporters in an HIV-transgenic (HIV-Tg) rat model. These rats develop immune dysfunction and AIDS-associated conditions like humans. METHODS: Endotoxin or saline was administered intraperitoneally to HIV-Tg or wild type (WT) littermates and kidneys were collected 18 hours later. Expression of transporters and cytokines were measured by qRT-PCR and Western blots. Serum cytokine levels were measured by ELISA. RESULTS: Endotoxin induced serum levels of IL-6, TNF-α and IFN-γ in both HIV-Tg and WT animals. The basal mRNA expression of Oct2, Oct3, Octn1, Mate1, Urat1 and Ent1was significantly lower (33-60%) and the expression of Ent2 and Pept2 was significantly higher (33-45%) in HIV-Tg as compared to WT. While endotoxin significantly downregulated the mRNA expression of Mdra1 and Pept2 in both HIV and WT groups (69-78%), it imposed a significant reduction on the mRNA expression of Oct2, Oct3, Octn1, Mate1, Oat2, urat1, and Ent1 (54-83%) only in the WT group. Endotoxin significantly increased the mRNA expression of Pept1 (140%) in both WT and HIV groups. CONCLUSIONS: HIV and endotoxin each imposed alterations in the expression of many clinically important renal drug transporters although co-infection did not augment this effect. Viral and/or bacterial infections may impact the renal clearance of drug substrates in patients and could potentially be a source of drug-disease interactions.
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Yndart, Adriana, Ajeet Kaushik, Marisela Agudelo, Andrea Raymond, Venkata S. Atluri, Shailendra K. Saxena, and Madhavan Nair. "Investigation of Neuropathogenesis in HIV-1 Clade B and C Infection Associated with IL-33 and ST2 Regulation." ACS Chemical Neuroscience 6, no. 9 (July 15, 2015): 1600–1612. http://dx.doi.org/10.1021/acschemneuro.5b00156.
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Miyagaki, Tomomitsu, Makoto Sugaya, Hitomi Yokobayashi, Toyoaki Kato, Hanako Ohmatsu, Hideki Fujita, Hidehisa Saeki, Yoshiki Kikuchi, Takeshi Tamaki, and Shinichi Sato. "High Levels of Soluble ST2 and Low Levels of IL-33 in Sera of Patients with HIV Infection." Journal of Investigative Dermatology 131, no. 3 (March 2011): 794–96. http://dx.doi.org/10.1038/jid.2010.366.
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Routy, J. P., V. Mehraj, R. Thomas, J. G. Baril, R. Leblanc, B. Lebouche, C. Costiniuk, C. Tremblay, and M. A. Jenabian. "32 Alarmin IL-33/ST2 pathway as an inductor of T-cell dependent response in acute and early HIV-infected patients." Journal of Virus Eradication 2 (July 2016): 19–20. http://dx.doi.org/10.1016/s2055-6640(20)30977-8.
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Sarkar, Sanghita, Michael S. Piepenbrink, Madhubanti Basu, Juilee Thakar, Michael C. Keefer, Ann J. Hessell, Nancy L. Haigwood, and James J. Kobie. "IL-33 enhances the kinetics and quality of the antibody response to a DNA and protein-based HIV-1 Env vaccine." Vaccine 37, no. 17 (April 2019): 2322–30. http://dx.doi.org/10.1016/j.vaccine.2019.03.044.
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Tunggal, Hillary Claire, Paul Veness Munson, Megan Ashley O’Connor, Nika Hajari, Sandra Elizabeth Dross, Debra Bratt, James Thomas Fuller, Kenneth Bagley, and Deborah Heydenburg Fuller. "Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs." PLOS ONE 16, no. 6 (June 17, 2021): e0253265. http://dx.doi.org/10.1371/journal.pone.0253265.
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A therapeutic vaccine that induces lasting control of HIV infection could eliminate the need for lifelong adherence to antiretroviral therapy. This study investigated a therapeutic DNA vaccine delivered with a single adjuvant or a novel combination of adjuvants to augment T cell immunity in the blood and gut-associated lymphoid tissue in SIV-infected rhesus macaques. Animals that received DNA vaccines expressing SIV proteins, combined with plasmids expressing adjuvants designed to increase peripheral and mucosal T cell responses, including the catalytic subunit of the E. coli heat-labile enterotoxin, IL-12, IL-33, retinaldehyde dehydrogenase 2, soluble PD-1 and soluble CD80, were compared to mock-vaccinated controls. Following treatment interruption, macaques exhibited variable levels of viral rebound, with four animals from the vaccinated groups and one animal from the control group controlling virus at median levels of 103 RNA copies/ml or lower (controllers) and nine animals, among all groups, exhibiting immediate viral rebound and median viral loads greater than 103 RNA copies/ml (non-controllers). Although there was no significant difference between the vaccinated and control groups in protection from viral rebound, the variable virological outcomes during treatment interruption enabled an examination of immune correlates of viral replication in controllers versus non-controllers regardless of vaccination status. Lower viral burden in controllers correlated with increased polyfunctional SIV-specific CD8+ T cells in mesenteric lymph nodes and blood prior to and during treatment interruption. Notably, higher frequencies of colonic CD4+ T cells and lower Th17/Treg ratios prior to infection in controllers correlated with improved responses to ART and control of viral rebound. These results indicate that mucosal immune responses, present prior to infection, can influence efficacy of antiretroviral therapy and the outcome of immunotherapeutic vaccination, suggesting that therapies capable of modulating host mucosal responses may be needed to achieve HIV cure.
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Gaya, Anna, Alvaro Urbano-Ispizua, Alfons Navarro, Aina Pons, Pau Abrisqueta, Carmen Martinez, Miquel Granell, et al. "Effect of Germline Polymorphisms on Clinical Outcome in Hodgkin’s Lymphoma (HL)." Blood 108, no. 11 (November 1, 2006): 2267. http://dx.doi.org/10.1182/blood.v108.11.2267.2267.
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Abstract In this study, we investigated whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways (GSTT1, GSTP1, GSTM1, SULT1C2, TOP2A, SXR-1), DNA repair (XPD, XPA, ERCC1, ERCC5, XRCC1, XRCC4, XRCC5), apoptosis and inflammatory cytokines (FAS, FASL, IL-10), and multidrug resistance (MDR1-2, MDR1-6) predict clinical outcome in patients with HL. One hundred and twenty-seven adult patients (median age, 33 yrs; range, 15–80; males 53%) diagnosed with HL at a single institution between September 1995 and June 2005 have been studied. Seventeen patients (13.4%) were HIV+. Distribution according to histological subtypes was: nodular sclerosis (56.7%), mixed cellularity (20.5%), lymphocytic predominance (5.6%), and lymphoid depletion (5.6%). Epstein-Barr Virus (EBV) was present in 35.4% of the samples. First-line treatment consisted of CMOPP/ABV (39.4%) or ABVD (52.8%). Allelic discrimination of single nucleotide polymorphisms (SNPs) (ABI Prism 7500; TaqMan) of DNA obtained from formalin fixed paraffin embedded lymph nodes was performed. The characteristics considered were: age (<45 years vs. ≥45), ECOG, Hasenclever prognostic index (≤1 vs 2–4 vs ≥5), HIV status, Ann Arbor (I–II vs. III–IV), WHO histological classification, bulky disease, EBV (LMP1+ vs LMP1−), ESR (EORTC criteria), and polymorphisms of the above-mentioned genes. Clinical outcomes analyzed were probability to achieve complete remission (CR), toxicity due to the treatment, relapse rate, disease-free survival (DFS) and overall survival (OS). Out of 127 patients, 101 (79.5%) achieved CR, 7 (5.5%) partial response, 9 (7.1%) were chemoresistant, and 5 (3.9%) died during the initial treatment. After a median follow-up of 43 months (1–128), OS was 81.1% and DFS 62.6%. In the multivariate analysis, the only adverse prognostic factor for the achievement of CR was FASL -844 T>C polymorphism (RR=1.7; p=0.01) and the only adverse prognostic factor for relapse was IL-10 -1082 A>G polymorphism (RR=2.1; p=0.02). A lower probability of DFS was associated with HIV+ status (RR=11.4; p=0.03), and a lower probability of OS to higher Hasenclever prognostic index (RR=2.3; p=0.02). Moreover, a close association between Asp5Glu genotype of the phase II drug-metabolizing enzyme SULT1C2 and pulmonary toxicity was found; thus, all eight patients with pulmonary toxicity due to bleomicine had the wild type SULT1C2 genotype (p=0.006). In conclusion, germline polymorphisms in FASL, IL-10 and SULT1C2, which can easily be analyzed in paraffin embedded samples, have prognostic value in patients with HL.
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Thiruvalluvan, E. "Family Burden and Health Related Quality of Life of HIV Infected Individuals in Madurai, South India." SAARC Journal of Tuberculosis, Lung Diseases and HIV/AIDS 13, no. 1 (March 9, 2017): 1–8. http://dx.doi.org/10.3126/saarctb.v13i1.16922.
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Introduction: With the advent of Highly Active Antiretroviral Therapy (HAART) in 1996, HIV-infected patients are living longer and are concerned not only with treatment’s ability to extend their life butalso with the quality of the life they are able to lead, because, efficacy of treatment is strongly relatedto meaningful outcome i.e., better Quality of Life. Especially Health related quality of life has not been studied well. Hence, this study was necessitated with the objectives to evaluate Health Related Quality of Life (HRQoL) in HIV infected persons on ART. The secondary objectives were to assess the family burden experienced by the families of HIV infected, and measure influence of family burden on overall quality of life.Methodology: The HIV infected individuals who were started on treatment six months prior to date of interview were considered for the study The SF36 (Short Form with 36 questions) was used to evaluate function and mental Health while Pai and Kapur’s Family Burden Interview schedule was used to assess family burden. Interview schedule was pre-tested on 10 HIV infected individuals for consistency. Data analysis was performed using SPSS version 11 (SPSS inc. Chicago, IL, USA). Pearson product moment Correlation were computed to explore the relationships of SF36 with SLI, Family Burden and BMI. Further, Independent student “t” – test was performed to see the association between HRQoL and gender.Results: Of 91 participants interviewed 51.6% were women. Median age (years) of the respondents was 33. The overall mean score for Physical health was 45.13 SD (12.40) and for Mental health 56.91 SD (15.52). Age of HIV infected persons had significant influence in scores in social functioning (p-value .015), emotional well being scores (.015), and Mental health (.010). Socio life Index was directly related to physical health, mental health, Vitality, social functioning and emotional scores on HRQoL. Physicalhealth score was negatively affected by the Family burden score. Similarly, BMI status of the respondents correlated with Mental health, Body Pain, Vitality and Role emotional scores of HRQoL scale SF 36.Conclusion: Socio Life Index and BMI appear to be the two important predictors of HRQoL. Therefore, special attention may be required to HIV infected persons with lower SLI and BMI. Nutritional supplements, in addition to ART drugs, may be provided to ensure some improvements in physical functioning.SAARC J TUBER LUNG DIS HIV/AIDS, 2016; XIII(1), Page: 1-8
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Sattler, Fred Richard, Daniel Chelliah, Xingye Wu, Alejandro Sanchez, Michelle A. Kendall, Evelyn Hogg, David Lagat, et al. "Biomarkers Associated with Death After Initiating Treatment for Tuberculosis and HIV in Patients with Very Low CD4 Cells." Pathogens and Immunity 3, no. 1 (April 26, 2018): 46. http://dx.doi.org/10.20411/pai.v3i1.235.
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Background: The risk of short-term death for treatment naive patients dually infected with Mycobacterium tuberculosis and HIV may be reduced by early anti-retroviral therapy. Of those dying, mechanisms responsible for fatal outcomes are unclear. We hypothesized that greater malnutrition and/or inflammation when initiating treatment are associated with an increased risk for death.Methods: We utilized a retrospective case-cohort design among participants of the ACTG A5221 study who had baseline CD4 < 50 cells/mm3. The case-cohort sample consisted of 51 randomly selected participants, whose stored plasma was tested for C-reactive protein, cytokines, chemokines, and nutritional markers. Cox proportional hazards models were used to assess the association of nutritional, inflammatory, and immunomodulatory markers for survival.Results: The case-cohort sample was similar to the 282 participants within the parent cohort with CD4 < 50 cells/mm3. In the case cohort, 7 (14%) had BMI < 16.5 (kg/m2) and 17 (33%) had BMI 16.5-18.5(kg/m2). Risk of death was increased per 1 IQR width higher of log10 transformed level of C-reactive protein (adjusted hazard ratio (aHR) = 3.42 [95% CI = 1.33-8.80],P = 0.011), interferon gamma (aHR = 2.46 [CI = 1.02-5.90], P = 0.044), MCP-3 (3.67 [CI = 1.08-12.42], P = 0.037), and with IL-15 (aHR = 2.75 [CI = 1.08-6.98], P = 0.033) and IL-17 (aHR = 3.99 [CI = -1.06-15.07], P = 0.041). BMI, albumin, hemoglobin, and leptin levels were not associated with risk of death.Conclusions: Unlike patients only infected with M. tuberculosis for whom malnutrition and low BMI increase the risk of death, this relationship was not evident in our dually infected patients. Risk of death was associated with significant increases in markers of global inflammation along with soluble biomarkers of innate and adaptive immunity.
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Nitsotolis, Thomas, Konstantinos G. Kyriakoulis, Anastasios Kollias, Alexia Papalexandrou, Helen Kalampoka, Elpida Mastrogianni, Dimitrios Basoulis, and Mina Psichogiou. "Comparison of Integrase Strand Transfer Inhibitors (INSTIs) and Protease-Boosted Inhibitors (PIs) on the Reduction in Chronic Immune Activation in a Virally Suppressed, Mainly Male Population Living with HIV (PLWH)." Medicina 60, no. 2 (February 15, 2024): 331. http://dx.doi.org/10.3390/medicina60020331.
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Background and Objectives: The success of combined antiretroviral therapy (cART) has led to a dramatic improvement in the life expectancy of people living with HIV (PLWH). However, there has been an observed increase in cardiometabolic, bone, renal, hepatic, and neurocognitive manifestations, as well as neoplasms, known as serious non-AIDS events/SNAEs, compared to the general population of corresponding age. This increase is linked to a harmful phenomenon called inflammaging/immunosenescence, which is driven by chronic immune activation and intestinal bacterial translocation. In this study, we examined immunological and metabolic parameters in individuals receiving current cART. Materials and Methods: The study was conducted at Laiko General Hospital in Athens, Greece. Plasma concentrations of sCD14, IL-6, SuPAR, I-FABP, and LBP were measured in virally suppressed PLWH under cART with at least 350 CD4 lymphocytes/μL. We compared these levels between PLWH receiving integrase strand transfer inhibitors (INSTIs) and protease inhibitors (PIs) and attempted to correlate them with chronic immune activation and metabolic parameters. Results: Data from 28 PLWH were analyzed, with a mean age of 52 and 93% being males. Among the two comparison groups, IL-6 levels were higher in the PIs group (5.65 vs. 7.11 pg/mL, p = 0.03). No statistically significant differences were found in the other measured parameters. A greater proportion of PLWH under INSTIs had normal-range LBP (33% vs. 0%, p = 0.04). When using inverse probability of treatment weighting, no statistically significant differences in the measured parameters were found between the two groups (sCD14 p = 0.511, IL-6 p = 0.383, SuPAR p = 0.793, I-FABP p = 0.868, and LBP p = 0.663). Glucose levels were found to increase after viral suppression in the entire sample (92 mg/dL vs. 98 mg/dL, p = 0.009). Total (191 mg/dL vs. 222 mg/dL, p = 0.005) and LDL cholesterol (104 mg/dL vs. 140 mg/dL, p = 0.002) levels were higher in the PIs group. No significant differences were observed in liver and renal function tests. Conclusions: Further investigation is warranted for PLWH on cART-containing INSTI regimens to explore potential reductions in chronic immune activation and intestinal bacterial translocation.
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Warr, Alex Jay, Javeed Shah, Sylvia LaCourse, Jon Kinuthia, Elizabeth Maleche-Obimbo, Lisa Cranmer, Felicia Nguyen, Daniel Matemo, Grace John-Stewart, and Thomas Hawn. "M. tuberculosis antigen-specific T-cell function in breast milk of HIV-infected mothers." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 66.10. http://dx.doi.org/10.4049/jimmunol.202.supp.66.10.
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Abstract Objective Breast milk (BM) is a mucosal compartment containing T cells, however, little is known regarding BM T-cell functional capacity or role in infant immunity. We hypothesized that BM T cells have M. tuberculosis (Mtb)-specific Th1 responses that are compartment-specific and differ from peripheral blood (PB) responses. Methods HIV-infected mothers and their infants were enrolled in a randomized clinical trial of isoniazid to prevent Mtb infection in Kisumu, Kenya. Maternal BM and PB were collected at 6–10 weeks postpartum. Cells were stimulated with Mtb whole cell lysate and controls. We measured frequencies of T cells expressing CD4 and CD8 and intracellular cytokines IFN-γ, IL-2, and TNF-α. Results Among 12 mothers with >1000 CD3+ cells evaluable, 33% had Mtb-specific IFNγ responses, 66% had Mtb-specific IL2 responses, 66% had Mtb-specific TNF responses, and 25% had combined IFNγ, IL2, and TNF responses. The most common Mtb-specific CD4 cytokine profile was IFNγ-IL2+TNF+ (66%) and the most common CD8 profile was IFNγ+IL2-TNF+ (58%). When compared to PB profiles (N=25), BM had higher polyfunctional CD4 cells expressing IFNγ-IL2+TNF+ (median 0.11 BM vs 0.0 PB, p=.005) and lower frequencies of IFNγ+IL2-TNF− CD4 cells (median 0.0 BM vs 0.03 PB, p=.002). CD8 cells in BM had higher frequencies of IFNγ+IL2-TNF+ cells compared to PB (median 0.05 BM vs 0.0 PB, p=.0002). Conclusions Our data demonstrate the presence of Mtb antigen-specific Th1 cells in BM with cytokine profiles distinct from PB responses. Defining BM Mtb-specific immune responses may inform novel vaccine strategies. Studies are ongoing to examine correlations between maternal BM and PB Mtb-specific T-cell responses and infant responses to BCG vaccination.
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Lurain, Kathryn, Thomas S. Uldrick, Priscila H. Goncalves, Ramya Ramaswami, Mark N. Polizzotto, Anaida Widell, Seth M. Steinberg, et al. "Radiation-Sparing Treatment of HIV-Related Primary Central Nervous System Lymphoma with Antiretroviral Therapy, Rituximab and High-Dose Methotrexate." Blood 132, Supplement 1 (November 29, 2018): 2963. http://dx.doi.org/10.1182/blood-2018-99-112169.
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Abstract BACKGROUND: HIV-associated primary central nervous system lymphoma (HIV-PCNSL) is an AIDS-defining cancer. Tumors occur in patients with very low CD4+ counts, and tumors are almost always Epstein-Barr virus (EBV) infected. Overall survival (OS) has improved over time with antiretroviral therapy (ART)-associated immune reconstitution but is still generally less than 1 year. Treatment has traditionally included whole brain radiation, which can lead to devastating long-term neurotoxicity, including cognitive decline. ART has made it possible to treat patients with curative-intent, but radiation-sparing approaches have not been studied prospectively in HIV-PCNSL. METHODS: In a prospective phase II pilot study conducted in the HIV & AIDS Malignancy Branch at the National Cancer Institute, we evaluated curative-intent radiation-sparing immunochemotherapy in patients with untreated HIV-PCNSL (NCT00267865). Patients with HIV-PCNSL received ART, rituximab (375 mg/m2) and HD-MTX (6 g/m2) with leucovorin rescue (R-HD-MTX). Responses were evaluated by modified International Working Group Response Criteria for PCNSL after 6 cycles of induction R-HD-MTX and patients with a complete response (CR) received 2 consolidation cycles of R-HD-MTX. Patients with poor renal or cardiac function who were not eligible to receive HD-MTX at enrollment, received ART, rituximab and best-available radiation-sparing care. The primary objective of the study was to estimate the percentage of patients receiving ART and R-HD-MTX alive without recurrent lymphoma at two years. Response to treatment, immune reconstitution, and OS were evaluated using descriptive statistics and Kaplan-Meier methodology. RESULTS: Twelve patients were enrolled between September 2006 and June 2016. One enrolled patient was initially ineligible to receive HD-MTX due to renal dysfunction and received rituximab with temozolomide (TMZ) 150 mg/m2 for 5 days for one cycle followed by 6 cycles of R-HD-MTX + TMZ and 2 consolidation cycles of R-HD-MTX. Patient characteristics: 9 men, 3 women; median (med) age 33 years (range: 21-55); 8 African-American, 3 Hispanic, 1 white non-Hispanic; med Eastern Cooperative Oncology Group performance status 2 (1-3); med baseline Mini Mental State Examination (MMSE, maximum score = 30) was 22 (range: 5-29). Only 4 patients were on ART prior to diagnosis, and all but 1 had been on ART less than 4 months. Med time from HIV infection to PCNSL diagnosis was 30 weeks (range: 0-23 years). Med CD4+ T-cell count at PCNSL diagnosis was 16 cells/µL (0-409). Diagnosis of PCNSL was biopsy-confirmed (11) or made by 18fludeoxyglucose positron emission tomography/cerebral spinal fluid (CSF) EBV viral load criteria (1). 11/12 tumors were EBV positive. Flow cytometry showed leptomeningeal disease in 4 patients. Three had concurrent CNS infections, including Cryptococcus, histoplasmosis, and CMV retinitis. Ten were evaluable for response to R-HD-MTX induction. Two patients received only 1 cycle of therapy and were not evaluable due to treatment failure (TF). Responses after R-HD-MTX induction: CR (5), partial response (PR) (4) and progressive disease (PD) (1). Two patients with a PR received second-line TMZ at end of R-HD-MTX and obtained a subsequent CR. The patient with PD received second-line therapy with the Cancer and Leukemia Group B 50202 induction regimen and obtained a subsequent CR. There were 4 deaths on study: 1 pulmonary embolism, 1 CNS fungal infection in setting of PD, 2 TF. Eight patients (67%), including 3 patients who received second line therapy, obtained a durable CR. Med CD4+ T-cell increase following R-HD-MTX induction was +35 cells/uL (range: -54 - +369). In surviving patients, med MMSE after R-HD-MTX was 28 (27-30). For all patients, estimated 60-month OS was 66% (95% CI: 32-86%) with med potential follow-up of 82 months. Med OS was not reached. CONCLUSIONS:Treatment with ART and R-HD-MTX is associated with a high response rate, CD4+ immune reconstitution, preserved cognition, and improved OS, even in a high-risk patient population. Disclosures Uldrick: Celgene: Patents & Royalties: 10,001,483 B2; Celgene: Research Funding; Merck: Research Funding. Yarchoan:NIH: Patents & Royalties: Patents on IL-12 for KS and cereblon-binding drugs for KSHV diseases. Spouse has patent on KSHV IL-6. Patents assigned to DHHS/NIH.; Celgene Corp.: Research Funding.
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Tomioka, Yuichiro, You‐Na Sung, Ryuichiro Sawada, Seung‐Mo Hong, Masayuki Akita, Tomoo Itoh, Tetsuo Ajiki, Takumi Fukumoto, and Yoh Zen. "IL‐33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction." Histopathology 75, no. 3 (July 2, 2019): 365–75. http://dx.doi.org/10.1111/his.13863.
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Gao, Xiuzhu, Xiumei Chi, Xiaomei Wang, Ruihong Wu, Hongqin Xu, MengRu Zhan, Dong Li, Yanhua Ding, Damo Xu, and Junqi Niu. "IL-33 Inhibits Hepatitis B Virus through Its Receptor ST2 in Hydrodynamic HBV Mouse Model." Mediators of Inflammation 2020 (April 28, 2020): 1–9. http://dx.doi.org/10.1155/2020/1403163.
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Interleukin-33 has been demonstrated to be associated with liver damage. However, its potential value in hepatitis B virus (HBV) infection remains unknown. This study was designed to investigate the role of IL-33 in hydrodynamic HBV mouse model. Different doses of IL-33 were used to treat HBV wild-type, ST2 knockout, CD8+ T depletion, NK depletion C57BL/6 mice and C.B-17 SCID and nod SCID mouse, respectively. The concentrations of HBV DNA, HBsAg, HBeAg, and molecules related to liver function were detected in the collected serum at different time points from model mice. Intrahepatic HBcAg was visualized by immunohistochemical staining of liver tissues. In vitro, hepG2 cells were transfected with pAAV-HBV 1.2, then treated with IL-33. The results showed that IL-33 significantly reduced HBV DNA and HBsAg in a dose-dependent manner in HBV wild-type mice. However, in the IL-33 specific receptor ST2 knockout mice, their antiviral effects could not be exerted. Through immunodeficient animal models and in vivo immune cell depletion mouse model, we found that IL-33 could not play antiviral effects without NK cells. Moreover, IL-33 could reduce the levels of HBsAg and HBeAg in the supernatant of HBV-transfected hepG2 cells in vitro. Our study revealed that IL-33 could inhibit HBV through ST2 receptor in the HBV mouse model, and this effect can be impaired without NK cell. Additionally, IL-33 had the direct anti-HBV effect in vitro, indicating that IL-33 could be a potent inducer of HBV clearance and a promising drug candidate.
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Wang, Juan, Pingwei Zhao, Hui Guo, Xiguang Sun, Zhenyu Jiang, Lijun Xu, Junyan Feng, Junqi Niu, and Yanfang Jiang. "Serum IL-33 Levels Are Associated with Liver Damage in Patients with Chronic Hepatitis C." Mediators of Inflammation 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/819636.
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Interleukin-33 (IL-33) is associated with the development of Th2 responses. This study examined the potential role of IL-33 in the pathogenic process of chronic hepatitis C (CHC) in Chinese patients. The levels of serum IL-33 and sST2 in 154 patients with CHC, 24 with spontaneously resolved HCV (SR-HCV) infection and 20 healthy controls (HC), were analyzed by ELISA. The concentrations of serum IL-2, IFN-γ, TNF-α, IL-4, IL-6, and IL-10, HCV loads, ALT, AST, and HCV-Ab were measured. We found that the levels of serum IL-33 in CHC patients were significantly higher than those of SR-HCV and HC but decreased after treatment with interferon for 12 weeks. More importantly, the levels of serum IL-33 were correlated with the concentrations of ALT and AST in CHC patients. The levels of serum sST2, as a decoy receptor of IL-33, were significantly higher in CHC and SR-CHC patients than those in HC, and there was no correlation between the levels of serum sST2 and IL-33. The concentrations of serum IFN-γ and IL-6 in CHC patients were significantly lower than those of SR-HCV. These data suggest that IL-33 may be a pathogenic factor contributing to CHC-related liver injury.
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Hansra, Damien, Jorge Antunez de Mayolo, Arfa Malik, Lisellet Morin, Abraham Jaguan, Jason Kosove, and Maureen Cioffi-Lavina. "Rare Case of an Immunocompetent Patient with Multicentric Castleman's Disease and Pure Nodal Kaposi's Sarcoma Achieving Complete Remission Using Rituximab and Liposomal Doxorubicin." Blood 128, no. 22 (December 2, 2016): 5319. http://dx.doi.org/10.1182/blood.v128.22.5319.5319.
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Abstract Top of Form Kaposi's Sarcoma (KS) and Multicentric Castleman's Disease (MCD) can infrequently occur simultaneously in immunocompromised patients. Here we present a rare case of HIV negative, HHV8 positive, EBV positive MCD with simultaneous pure nodal KS in an immunocompetent patient. A 69 year old female with no past medical history presented in June 2015 with neck pains, night sweats, and 20 pound weight loss. Physical examination revealed bilateral cervical, inguinal lymphadenopathy. She also had bulky bilateral axillary lymphadenopathy. No skin lesions were noted. Excisional lymph node axillary biopsy performed 7/16/15 revealed follicular hyperplasia with intense follicular expansion of plasma cells (figure 1, 2). Some follicles showed transformed germinal centers with expanded mantle zones and occasionally more than one germinal cell within a single mantle (figure 1, 2). By Immunohistochemical stains, CD20 highlighted the follicular B-cells and expanded mantle zone B-cells. CD3 highlighted small interfollicular T-cells. CD138 highlighted interfollicular expansion of plasma cells that were positive for kappa and lambda light chains in the interfollicular areas by in-situ hybridization. The plasmablastic cells in the mantle zone showed lambda light chain restriction and HHV-8 positivity. HHV-8 additionally highlighted the nuclei of the spindle cell proliferation (figure 3). PET CT 7/14/15 showed bilateral axillary adenopathy with SUV 8.0, mild hilar adenopathy with SUV 6.0 (Figure 4) and prominent adenopathy of pelvic sidewall and inguinal regions with SUV ranging 3.0-8.0. Baseline labs 7/14/15: HIV (-), HHV8 DNA (-), EBV IgG 7.7 AI (+), EBV DNA (+), IL-6 elevated 7.91 pg/mL and CRP 3.64 mg/dL (high). CBC and CMP were normal. Serum immunoglobulins: IgA 653m/dL (high), IgG 3210 mg/dL (high), IgM 33 mg/dL (low). SPEP with immunofixation showed hypergammaglobulinemia with slight peak asymmetry of the gamma globulins without evidence of monoclonality. LDH was normal at 127 U/L. The patient was given Rituximab 375m/m2 IV day 1 and Liposomal Doxorubicin 20 mg/m2 IV day 1 (R-Dox) every 3 weeks for 4 cycles between 8/7/15 - 10/5/15 with complete resolution of lymphadenopathy clinically and by PET CT 10/15/15. Patient has been doing well without evidence of recurrence as of last clinic visit 3/14/16. Figure 1 Low power (5X magnification) showing targetoid pattern of follicles and prominent interfollicular stroma with prominent capillaries consistent with Castleman's and a spindle cell proliferation towards the bottom consistent with Kaposi Sarcoma Figure 1. Low power (5X magnification) showing targetoid pattern of follicles and prominent interfollicular stroma with prominent capillaries consistent with Castleman's and a spindle cell proliferation towards the bottom consistent with Kaposi Sarcoma Figure 2 Higher magnification (10X) shows a prominent follicle with concentric layering of peripheral lymphocytes that resembles onion-skin. To the right, the KS shows spindle cells forming slits with extravasated red blood cells. Figure 2. Higher magnification (10X) shows a prominent follicle with concentric layering of peripheral lymphocytes that resembles onion-skin. To the right, the KS shows spindle cells forming slits with extravasated red blood cells. Figure 3 HHV-8 nuclear immunostain highlights KS cells with nuclear staining. Figure 3. HHV-8 nuclear immunostain highlights KS cells with nuclear staining. Disclosures No relevant conflicts of interest to declare.
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Koma, Mousa Komai. "NUCLEAR FUNCTION AND RELEASE OF IL-33." Professional Medical Journal 21, no. 03 (June 10, 2014): 503–8. http://dx.doi.org/10.29309/tpmj/2014.21.03.2135.
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Interleukin-33 (IL-33) is the most attractive novel cytokine identified as an IL-1family member. IL-33 was first named NF-HEV (nuclear factor from high endothelial venules), as itwas known to interact with nuclear chromatin although its exact intracellular functions are still tobe clarified. IL-33 is now recognized as the specific ligand for the orphan IL-1 receptor familymember ST2 and to be involved in polarization of T cells towards T helper 2-cell phenotype and inactivation of mast cells, basophils, eosinophils and natural killer cells. It is essential for IL-33 to beextracellularly released in order to bind to the ST2 receptor and consequently play a crucial role ininflammatory, infectious and autoimmune diseases. However, like the IL-1 family members, IL-1beta and IL-18, IL-33 mRNA is translated without a signal sequence for secretion. Additionally, IL-33 cannot be released by the processing and secretion mechanism shared by IL-1beta and IL-18as IL-33 is not a substrate of caspase-1 and does not require proteolysis for activation. In contrast,IL-33 can be inactivated by apoptotic caspases. Accordingly, IL-33 is proposed to be released asan alarmin from necrotic cells but deleted during apoptosis. Besides the known autocrine,paracrine mechanisms of cellular interaction with cytokines, release by necrotic cells is anotherpathway for a cytokine to display its function, which we suggest might be called 'necrocrine'.
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Baay-Guzman, Guillermina J., Aaron Pavel Rodríguez-Hernández, D. Anaya Estrada, M. Jimenez Rodriguez, JE Cocoletzi Bautista, D. Hernández Cueto, and R. Luria Perez. "Regulación de la expresión de IL-33 e IL-17 por la modulación farmacológica de HIF-1 en un modelo murino de inflamación alérgica pulmonar." Revista Alergia México 70, no. 3 (August 21, 2023): 190. http://dx.doi.org/10.29262/ram.v70i3.1273.
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Objetivo: Evaluar el efecto de la modulación farmacológica de HIF-1 en la expresión de IL-33 e IL-17 en un modelo murino de inflamación alérgica pulmonar (IAP) con diferentes grados de severidad. Métodos: 5 ratones/grupo recibieron ovoalbúmina (OVA) 1(leve), 2(moderada) o 3(severa) retos vía i.t. previa sensibilización como alergeno, además los grupos de inducción o inhibición de HIF-1α, recibieron EDHB (OVA+EDHB) i.p. o 2ME (OVA+2ME) i.t. respectivamente. Los grupos controles recibieron solución salina (SS) de igual forma. Se realizaron tinciones de HE (infiltrado inflamatorio), PAS (producción de moco) e inmunohistoquímicas de HIF-1α, IL-33, IL-17, analizando cuantitativamente por patología digital. Resultados: Obtuvimos diferentes grados de severidad a mayor número de retos, incrementando la expresión de HIF-1, correlacionando con la expresión de IL- 33/IL-17. Aumentando o disminuyendo, respectivamente por la modulación farmacológica. Conclusiones: Lo anterior sugiere que la alta expresión de HIF-1 favorece la producción de IL-33 e IL-17 contribuyendo al daño en el tejido pulmonar y la severidad de la enfermedad y estas pueden ser reguladas a través de la modulación de HIF-1.
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Askoura, Momen, Hisham A. Abbas, Hadeel Al Sadoun, Wesam H. Abdulaal, Amr S. Abu Lila, Khaled Almansour, Farhan Alshammari, El-Sayed Khafagy, Tarek S. Ibrahim, and Wael A. H. Hegazy. "Elevated Levels of IL-33, IL-17 and IL-25 Indicate the Progression from Chronicity to Hepatocellular Carcinoma in Hepatitis C Virus Patients." Pathogens 11, no. 1 (January 3, 2022): 57. http://dx.doi.org/10.3390/pathogens11010057.
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Hepatitis C virus (HCV) is one of the most epidemic viral infections in the world. Three-quarters of individuals infected with HCV become chronic. As a consequence of persistent inflammation, a considerable percentage of chronic patients progress to liver fibrosis, cirrhosis, and finally hepatocellular carcinoma. Cytokines, which are particularly produced from T-helper cells, play a crucial role in immune protection against HCV and the progression of the disease as well. In this study, the role of interleukins IL-33, IL-17, and IL-25 in HCV patients and progression of disease from chronicity to hepatocellular carcinoma will be characterized in order to use them as biomarkers of disease progression. The serum levels of the tested interleukins were measured in patients suffering from chronic hepatitis C (CHC), hepatocellular carcinoma (HCC), and healthy controls (C), and their levels were correlated to the degree of liver fibrosis, liver fibrosis markers and viral load. In contrast to the IL-25 serum level, which increased in patients suffering from HCC only, the serum levels of both IL-33 and IL-17 increased significantly in those patients suffering from CHC and HCC. In addition, IL-33 serum level was found to increase by liver fibrosis progression and viral load, in contrast to both IL-17 and IL-25. Current results indicate a significant role of IL-33 in liver inflammation and fibrosis progress in CHC, whereas IL-17 and IL-25 may be used as biomarkers for the development of hepatocellular carcinoma.
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Abebayehu, Daniel, Andrew Spence, Amina Abdul Qayum, Marcela T. Taruselli, Jamie J. McLeod, Heather Caslin, Elizabeth Motunrayo Kolawole, et al. "Lactic acid inhibits IL-33-mediated mast cell inflammatory responses via HIF-1α suppressing miR-155 expression." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 202.8. http://dx.doi.org/10.4049/jimmunol.196.supp.202.8.
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Abstract Lactic acid (LA) is elevated in tumors, asthma, and wound healing, environments that also include mast cells and IL-33. However, how LA affects mast cell function is unknown. Therefore we evaluated how LA modifies the IL-33-mediated mast cell response. When bone marrow derived mast cells were cultured with LA, we noted reduced IL-33-mediated cytokine production, an effect that was both monocarboxylate transporter (MCT)1- and pH-dependent. LA selectively decreased IL-33-induced TAK1, JNK, ERK, and NFkB phosphorylation, but not p38 activation. Additionally, LA increased HIF-1α expression. Since HIF-1α has been shown to regulate the pro-inflammatory microRNA miR-155, we examined miR-155 expression. miR-155-5p was reduced by LA, an effect that was reversed by HIF-1α antagonism. More importantly, miR-155-5p overexpression abolished the suppressive effects of LA. Additionally, the negative regulator SOCS1, a known miR-155 target, was elevated by LA addition. This suggests that LA employs HIF-1a to suppress miR-155, indirectly increasing SOCS-1 and limiting cytokine production. These data were recapitulated in vivo, since C57BL/6 mice injected with LA showed less IL-33-induced plasma cytokine levels than control mice. Lastly, LA suppressed IL-33-mediated human skin mast cell activation, an effect that was also MCT1-dependent. Our data demonstrate that lactic acid, present in inflammatory and malignant microenvironments, alters mast cell function to suppress inflammation.
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Lei, Ziying, Zhishuo Mo, Jianyun Zhu, Xiuqing Pang, Xingrong Zheng, Zhebin Wu, Ke Wang, Xinhua Li, Dongying Xie, and Zhiliang Gao. "Soluble ST2 Plasma Concentrations Predict Mortality in HBV-Related Acute-on-Chronic Liver Failure." Mediators of Inflammation 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/535938.
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Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a rapidly progressing and frequently fatal condition. The aim of this study was to determine whether interleukin- (IL-) 33 and soluble ST2 (sST2) were associated with disease severity and mortality in HBV-ACLF. We found that plasma levels of sST2 but not IL-33 were higher in HBV-ACLF patients compared with chronic hepatitis B (CHB) patients and healthy controls. However, plasma levels of IL-33, TNF-α, IFN-γ, and IL-10 did not correlate with sST2 levels. Similarly, immunohistochemistry revealed low IL-33 expression and high ST2 expression in liver sections of patients with HBV-ACLF. Evaluation of dynamic changes of sST2 in HBV-ACLF showed that plasma sST2 levels increased over time in patients who died during the 180-day follow-up but decreased in those who survived. In addition, plasma sST2 level after week 1 correlated with disease severity, as assessed by total bilirubin, prothrombin time, and model for end-stage liver disease score. Results of Kaplan-Meier survival analysis showed that higher sST2 concentration (≥87 ng/mL) at week 3 was associated with poor survival. These findings indicate the potential usefulness of sST2 as a predictor of disease severity and in making treatment decisions for patients with HBV-ACLF.
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Usman, S. O., O. M. Ajayi, O. Ebiekura, N. Egbonrelu, G. Ebhojie, and A. O. Ariyo. "Evidence of virological failure in patients on second-line anti-retroviral therapy in Southwestern Nigeria: An indication for HIV drug resistance testing." African Journal of Clinical and Experimental Microbiology 22, no. 3 (July 2, 2021): 415–19. http://dx.doi.org/10.4314/ajcem.v22i3.13.
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Background: In sub-Saharan Africa where genotypic anti-retroviral (ARV) drug resistance testing is rarely performed and poor adherence is blamed for the inability to achieve viral suppression and treatment failure, programmatic approaches to preventing and handling these are essential. This study was aimed at assessing the virological outcomes among HIV patients receiving second-line anti-retroviral therapy (ART) in Southwestern Nigeria.Methodology: This was a 5-year observational retrospective study of randomly selected people living with HIV (PLWHIV) who have been switched to second-line ART for at least six months before the commencement of the study in multiple comprehensive ART sites across the three levels of care, in Ondo and Ekiti States, Southwestern Nigeria, from January 2015 to December 2019. Quantitative viral load analysis was done using polymerase chain reaction (PCR) assay. Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 24.0.Results: A total of 249 (71 males and 178 females) subjects eligible for the study were recruited using simple random sampling technique. The mean age (± SD) of the subjects was 44.21 ± 11.45 years. The mean number of years the patients have been on ART regimen was 7.92 ± 2.68 years. The mean number of years the patients were on first line ART regimen before being switched to second line was 4.27 ± 2.63 years. Patients with viral load <1000 RNA copies/ml (suppressed viral load) were 216 (86.7%) out of which 113 (45.4%) had viral load <20 RNA copies/ml while 33 (13.3%) had viral load >1000 RNA copies/ml (unsuppressed viral load or virological failure).Conclusion: About 13% of the patients on second line ART had unsuppressed viral load of more than 1000 RNA copies/ml indicating virological failure. Thus, critical factors such as poor adherence to ART and drug resistance chiefly contributing to virological failure have to be routinely checked.
Keywords: suppression, ART, resistance, virological, failure, Nigeria
French title: Preuve d'échec virologique chez les patients sous traitement antirétroviral de deuxième intention dans le sud-ouest du Nigeria: une indication pour le test de résistance aux médicaments contre le VIH
Contexte: En Afrique subsaharienne, où les tests génotypiques de résistance aux antirétroviraux (ARV) sont rarement effectués et où une mauvaise observance est imputée à l'incapacité d'obtenir la suppression virale et l'échec du traitement, des approches programmatiques pour les prévenir et les gérer sont essentielles. Cette étude visait à évaluer les résultats virologiques chez les patients VIH recevant un traitement antirétroviral (TAR) de deuxième intention dans le sud-ouest du Nigeria.
Méthodologie: Il s'agissait d'une étude rétrospective d'observation de 5 ans portant sur des personnes vivant avec le VIH (PVVIH) sélectionnées au hasard et passées à un TAR de deuxième intention pendant au moins six mois avant le début de l'étude dans plusieurs sites de TAR complets aux trois niveaux. de soins, dans les États d'Ondo et d'Ekiti, dans le sud-ouest du Nigéria, de janvier 2015 à décembre 2019. L'analyse quantitative de la charge virale a été effectuée à l'aide d'un test de réaction en chaîne par polymérase (PCR). Les données ont été analysées à l'aide du logiciel Paquet statistique pour les sciences sociales (SPSS) version 24.0.
Résultats: Un total de 249 (71 hommes et 178 femmes) sujets éligibles à l'étude ont été recrutés à l'aide d'une technique d'échantillonnage aléatoire simple. L'âge moyen (± ET) des sujets était de 44,21±11,45 ans. Le nombre moyen d'années pendant lesquelles les patients ont été sous traitement antirétroviral était de 7,92±2,68 ans. Le nombre moyen d'années pendant lesquelles les patients étaient sous traitement antirétroviral de première ligne avant de passer en deuxième ligne était de 4,27 ± 2,63 ans. Les patients avec une charge virale <1000 copies d'ARN/ml (charge virale supprimée) étaient 216 (86,7%) dont 113 (45,4%) avaient une charge virale <20 copies d'ARN/ml tandis que 33 (13,3%) avaient une charge virale >1000 ARN copies/ml (charge virale non supprimée ou échec virologique).
Conclusion: Environ 13 % des patients sous TAR de deuxième ligne avaient une charge virale non supprimée de plus de 1000 copies d'ARN/ml indiquant un échec virologique. Ainsi, les facteurs critiques tels qu'une mauvaise adhésion au TARV et la résistance aux médicaments contribuant principalement à l'échec virologique doivent être systématiquement vérifiés.
Mots clés: suppression, TAR, résistance, virologique, échec, Nigeria
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Weisberg, Stuart P., Mark Chang, Pawel Muranski, and Donna Farber. "Efficient Expansion of Polyfunctional Virus-Specific T Cells from Human Lymph Nodes: Implications for Cellular Therapies." Blood 132, Supplement 1 (November 29, 2018): 3715. http://dx.doi.org/10.1182/blood-2018-99-116507.
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Abstract BACKGROUND: Adoptive transfer of in vitro expanded autologous and allogeneic virus specific T (VST) cells has been successfully used to prevent and treat EBV viral reactivation in transplant patients and aggressive EBV-driven cancers such as post-transplant lymphoproliferative disease (PTLD), nasopharyngeal carcinoma, and extranodal NK/T-cell lymphoma. Due to the easy accessibility of peripheral blood, VST cell products are universally generated from circulating T cells. However, the T cells in circulation represent only a minor fraction of T cells in the body with most residing in tissue sites, particularly lymph nodes. Recent animal data suggest that unique T cell populations that sustain memory responses to chronic viral infections exclusively reside in lymph nodes. The efficacy of using lymph node-derived T cells for adoptive cellular therapy has not been reported. AIMS: To assess the feasibility of generating VST cells from human lymph nodes using our clinically-compatible strategy and to test the ability of T cells derived from peripheral lymph nodes to expand in response to EBV-derived viral antigens and display functionality compared to T cells derived from blood. METHODS: Human blood and lymphoid tissues were obtained from brain dead organ donors at the time of organ procurement for transplantation through an approved protocol with LiveOnNY. Human blood was also obtained from healthy volunteers through an IRB approved protocol. Donors were cancer free, EBV seropositive, and negative for hepatitis B, C and HIV. Lymph nodes were isolated in sterile fashion, enzymatically and mechanically digested to a single cell suspension. Overlapping 15 mer peptide pools (pepmixes) of EBV latency viral antigens EBNA1 and LMP1 (JPT, Berlin, Germany) were used for expansion and restimulation. T cells were isolated by fluorescence activated cell sorting and stimulated with peptide pulsed irradiated mononuclear cells from blood (healthy donors) or spleen (organ donors), followed by 14-day culture in IL-7 and 15 (10 ng/mL) with addition of IL-2 (20 IU/mL) starting on day +3. Expanded T cells were then rested overnight and restimulated with individual pepmixes for 6 hours followed by surface marker and intracellular cytokine staining to evaluate differentiation state and function. RESULTS: T cells from lymph node, blood and spleen displayed comparable levels of in vitro expansion (Fig. 1A). Compared to blood, there was increased EBNA1 reactive cell frequency (TNF-α/IFN-ꝩ positive) in the lymph node derived T cell cultures (Fig. 1B). VST cells were predominately CD8 from blood (56 ± 15%) and lymph node (86 ± 3.8%) but not spleen (24 ± 6.4%). One donor in this cohort displayed significant reactivity for LMP1. Both blood and lymph node derived VST cells were uniformly positive for granzyme B and the degranulation marker CD107a (Fig. 1C). Remarkably, the lymph node derived VST cells displayed markedly enhanced polyfunctionality with robust secretion of IL-2, as well as increased surface expression of the co-stimulatory molecule CD28 with 33±3.6% displaying strong co-expression of both molecules compared to 8.1±2.7% of those derived from blood (Fig. 1D). CONCLUSION: These results suggest that it is feasible to generate highly-reactive EBV-specific T cells from human lymph node tissue using the methodology compatible with good manufacturing practice (GMP). In contrast to VST cells derived from peripheral blood, increased expression of CD28 and IL-2 on lymph node derived EBV reactive cells may indicate a superior capacity to survive, expand in vivo and eradicate EBV-driven disease upon adoptive transfer. Figure 1. Characterization of lymph node derived EBV reactive T cells. A) Expanded T cells from Blood (BL), iliac lymph node (iLN), mesenteric lymph node (MLN), and spleen (Spl), were restimulated with EBNA1 or LMP1 peptides for 6 hours, followed by surface and intracellular cytokine stain and flow cytometry. (A) Shown are the live cell counts in each culture per 100,000 cells plated; (B) the frequencies of VST cells (TNF-α/IFN-ꝩ positive) in each culture and (C) the frequency of cytotoxic CD107a / Granzyme B (GZMB) positive cells within the VST cell population. (D) Representative flow cytometry data from matched samples of an organ donor is shown to the left of compiled data showing subsets of the EBNA1 reactive cells defined by CD28 and IL-2 expression. (mean ± SEM, n = 2-4). *P < 0.05 t-test with comparison to blood. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Olaniyan, Mathew F., and Alade Ogunlade. "Possible Alterations in the Plasma Levels of Pro (TNF-alpha) and Anti-inflammatory (IL-10) Cytokines in Long-Term Insomnia." Recent Advances in Biology and Medicine 5 (2019): 1. http://dx.doi.org/10.18639/rabm.2019.770620.
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Long-term/chronic insomnia occurs in patients for over one month; it can affect the functions of the immune system and responses, which may involve cytokines. The aim was to determine alterations of Tumor necrosis factor alpha (TNF-alpha) and IL-10 cytokines in long-term insomnia. Thirty-three long-term/chronic insomnia patients (male, 22; female, 11) aged 47-61 years were initially recruited. Seven of them who were infected with microbial agents were excluded from the study. Of the 26 free of infectious agents only 21 (female, 5; male, 16) were successfully monitored. Age-matched apparently healthy non-insomnia subjects (male, 25; female, 25) free of the infectious agents were recruited as control. Plasma TNF-alpha, IL-10, HBsAg, anti-HCV, and HIVp24 antigen were assayed by ELISA method while determination of Mycobacterium tuberculosis was by Ziehl–Neelsen staining of sputum and Plasmodium spp. by thick blood Giemsa staining. Of the 33 insomnia patients initially recruited, 21.2% (7) were infected with microbial agents (Plasmodium spp., 6.1% (2); HCV, 3.0% (1); HBV, 6.1% (2); Mycobacterium tuberculosis, 3.0% (1); Plasmodium spp. + HBV, 3.0% (1); and HIVp24, 0). Twenty-one chronic insomnia patients were finally investigated on cytokines. There were significantly higher mean plasma values of TNF-alpha and IL-10 cytokines in chronic insomnia patients before treatment than the values obtained in the control subjects (p < 0.05). The results also showed a significantly lower mean plasma value of TNF-alpha cytokine in chronic insomnia patients after treatment than the values obtained in the patients before treatment. There were no significant differences in the mean plasma values of IL-10 cytokines in chronic insomnia patients before and after treatment (p > 0.05). There was a significant increase in plasma TNF-alpha and IL-10 cytokines in long-term insomnia patients before treatment while plasma TNF-alpha significantly decreased after treatment, and no significant difference was obtained in the plasma IL-10 before and after treatment. TNF-alpha could be a good investigative index of insomnia.
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Neurath, A. R., N. Strick, and Y. Y. Li. "Cells transfected with human interleukin 6 cDNA acquire binding sites for the hepatitis B virus envelope protein." Journal of Experimental Medicine 176, no. 6 (December 1, 1992): 1561–69. http://dx.doi.org/10.1084/jem.176.6.1561.
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Earlier studies revealed that human interleukin 6 (IL-6) contains recognition sites for the hepatitis B virus (HBV) envelope (env) protein, and that IL-6 and anti-IL-6 antibodies, respectively, inhibited the interaction of cells expressing a receptor for HBV with the preS(21-47) segment of the HBV env protein, encompassing the complementary attachment site for IL-6. This suggested that IL-6 mediates HBV-cell interactions. We report that: (a) Chinese hamster ovary cells transfected with human IL-6 cDNA and Spodoptera frugiperda ovarian insect cells infected with recombinant baculovirus carrying human IL-6 cDNA expressed receptors for the preS(21-47) region of the HBV env protein, indicating that expression of IL-6 on the surface of cells is sufficient to endow them with receptors for HBV. (b) Among peptides covering the entire sequence of human IL-6 and the corresponding antipeptide antibodies, the peptide IL-6[35-66] and anti-IL-6[35-66] most effectively inhibited the interaction between human hepatoma HepG2 cells and the preS(21-47) ligand, suggesting that this region of the human IL-6 sequence encompasses a binding site for the HBV env protein. (c) Studies with replacement set peptides from the preS(21-47) sequence indicated that residues 21-25, 28, 31, 33-35, 39, and 43-45 can be replaced by alanine (serine) residues, while all the other residues are essential for maintaining the cell receptor/IL-6 binding activity. Further delineation of complementary sites on IL-6 and on the HBV env protein may contribute to the design of compounds inhibiting HBV replication.
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El-Emshaty, Hoda Mohamed, Wesam Ahmad Nasif, and Ibrahim Eldsoky Mohamed. "Serum Cytokine of IL-10 and IL-12 in Chronic Liver Disease: The Immune and Inflammatory Response." Disease Markers 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/707254.
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The current study was designed to investigate the potential association of serum interleukin-10 and interleukin-12 with HCV infection in chronic liver disease and to evaluate their possible role as new biomarkers in HCC development.Material and Methods. Forty-one patients suffering from chronic liver disease (33 patients harbor HCV infection and 8 are HCV-negative patients) were enrolled in the present study and histopathologically diagnosed into 15 patients with HCC, 16 patients with LC, and 10 patients with liver histology compatible with precirrhotic hepatitis (PCH). Ten patients complaining of cholecystitis were included as nondisease control. Serum levels of IL-10 and IL-12 were measured by enzyme linked immunosorbent assay (ELISA).Results. HCV-infected patients showed elevated expression of IL-10 and IL-12 compared to nondisease controls (P<0.0001) but there is no significant difference with respect to their expression in HCV-negative patients. Serum IL-10 and IL-12 were elevated significantly with disease progression (P<0.0001) and a positive correlation coefficient was detected between IL-10, IL-12 (r=0.785,P<0.0001), and transaminase values suggesting their possible role in chronic inflammation progression leading to HCC.Conclusion. IL-10 and IL-12 might be involved in chronic inflammation progression leading to HCC and their evaluation could be used as new biomarkers to reflect the degree of inflammation in HCC development.
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Lukic, Ruzica, Maja Cupic, Nevena Gajovic, Milena Jurisevic, Zeljko Mijailovic, Bojana Davidovic, Bojan Kujundzic, Bojan Joksimovic, Nebojsa Arsenijevic, and Ivan Jovanovic. "Increased systemic sST2 in patients with end stage renal disease contributes to milder liver damage during HCV infection." Journal of Infection in Developing Countries 14, no. 05 (May 31, 2020): 519–26. http://dx.doi.org/10.3855/jidc.11741.
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Introduction: Hepatitis C Virus (HCV) is the leading cause of chronic liver disease and is a serious global health problem. Hepatitis C infection is highly prevalent in patients with end stage renal disease (ESRD), due to frequent exposure to blood and blood products, nosocomial transmission of HCV, and prolong hemodialysis duration. The aim of the study was to evaluate the influence of IL-33/ST2 signaling pathway on severity of the liver disease in ESRD HCV+ patients.
Methodology: Blood samples from patients with end stage renal disease (ESRD) and hepatitis C infection (HCV), 20 patients with HCV infection, 20 patients with ESRD and 20 healthy control donor patients were taken for the examination of biochemical parameters, for the determination of the serum cytokine concentration, and for the molecular diagnostics of HCV.
Results: Systemic sST2 positively correlated with serum level of urea and creatinine, respectively. Serum sST2 was significantly increased in ESRD HCV+ patients in comparison to HCV+ group. sST2/IL-1, sST2/IL-4 and sST2/IL-23 ratios were significantly increased in serum of ESRD HCV+ patients in comparison to HCV+ patients. Significantly higher systemic level of sST2 and sST2/IL-1 and sST2/IL-4 ratios were measured in ESRD patients compared to non-ESRD patients.
Conclusion: These results suggested that elevated level sST2, as the consequence of renal failure, causes less destruction of liver in HCV infection.
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Zhao, Ping-Wei, Xu Shi, Cong Li, Desalegn Admassu Ayana, Jun-Qi Niu, Jun-Yan Feng, Juan Wang, and Yan-Fang Jiang. "IL-33 Enhances Humoral Immunity Against Chronic HBV Infection Through Activating CD4+CXCR5+ TFH Cells." Journal of Interferon & Cytokine Research 35, no. 6 (June 2015): 454–63. http://dx.doi.org/10.1089/jir.2013.0122.
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Yu, Xueping, Ruyi Guo, Desong Ming, Yong Deng, Milong Su, Chengzu Lin, Julan Li, Zhenzhong Lin, and Zhijun Su. "The Transforming Growth Factor β1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival." Clinical and Vaccine Immunology 22, no. 5 (February 25, 2015): 484–92. http://dx.doi.org/10.1128/cvi.00649-14.
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ABSTRACTThe transforming growth factor β1/interleukin-31 (TGF-β1/IL-31) pathway plays an important role in the process of cell injury and inflammation. The purpose of this work was to explore the role of the TGF-β1/IL-31 pathway in the cytopathic process of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). The quantitative serum levels of TGF-β1, IL-9, IL-10, IL-17, IL-22, IL-23, IL-31, IL-33, and IL-35 were analyzed among chronic hepatitis B (CHB) patients (n= 17), ACLF patients (n= 18), and normal control (NC) subjects (n= 18). Disease severity in patients with ACLF was assessed using the model for end-stage liver disease (MELD) and Child-Pugh scores. Serum TGF-β1 levels were strongly positively correlated with IL-31 in all subjects, and both of them were positively correlated with IL-17, IL-22, and IL-33. In CHB and ACLF patients, serum levels of TGF-β1 and IL-31 were both increased significantly compared with those in NC subjects and positively correlated with total bilirubin (TBil) and alpha-fetoprotein (AFP) levels. ACLF patients showed the highest levels of TGF-β1 and IL-31, which were positively correlated with Child-Pugh scores. Furthermore, the recovery from the liver injury in CHB was accompanied by decreased TGF-β1 and IL-31 levels. More importantly, serum levels of TGF-β1 and IL-31 were markedly upregulated in ACLF nonsurvivors, and IL-31 displayed the highest sensitivity and specificity (85.7% and 100.0%, respectively) in predicting nonsurvival of ACLF patients. Increasing activity of the TGF-β1/IL-31 pathway is well correlated with the extent of liver injury, disease severity, and nonsurvival of ACLF patients, while reducing activity is detected along the recovery from liver injury in CHB, suggesting its potential role in the pathogenesis of liver injury during chronic HBV infection.
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Logan, Aaron C., Robert Su, Tracy I. George, Holbrook E. Kohrt, Bruno C. Medeiros, and Ash A. Alizadeh. "High Risk of Early Mortality in Adult Patients with Acquired Hemophagocytic Lymphohistiocytosis." Blood 114, no. 22 (November 20, 2009): 1359. http://dx.doi.org/10.1182/blood.v114.22.1359.1359.
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Abstract Abstract 1359 Poster Board I-381 Background Hemophagocytic lymphohistiocytosis (HLH) is a rare condition in which dysregulation of innate immune effectors including natural killer (NK) cells and macrophages leads to destruction of hematopoietic elements. HLH is most frequently reported in association with malignancies or viral infections, with heritable deficiencies in cytotoxicity pathways predisposing children (and rarely adults) to HLH. Criteria for diagnosing HLH include: histological evidence of hemophagocytosis, two or more cytopenias, hyperferritinemia, hypofibrinogenemia or hypertriglyceridemia, elevated soluble IL-2R, decreased in vitro NK cell function, fever, and splenomegaly. Patients meeting >=5 of these criteria are diagnosed with HLH. Source: We identified 19 consecutive adult patients (53% male; median age 43y, range 16-83) admitted to Stanford Hospital with clinical suspicion for HLH and histological evidence of hemophagocytosis between 1997 and 2009; 2 patients were excluded from analysis due to incomplete data. Of the remaining 17 patients, 11 (65%) met criteria for a diagnosis of HLH. Results At presentation, all patients were anemic with a median Hgb concentration of 8.6 g/dL. Leukopenia was present in 8/11 (73%) with a median WBC count of 2 K/uL. Thrombocytopenia was present in 10/11 (91%) patients with a median Plt count of 30 K/uL. In 6 patients not meeting HLH criteria, median hematologic findings were Hgb 8.6 g/dL, WBC 2.6 K/uL, and Plts 126 K/uL. All patients demonstrated marked elevations of ferritin, median 3915 ng/dL (range 1039 – 29,700). Triglycerides were elevated in 7/10 (70%) for whom data were available, median 296 mg/dL (range 204 – 1,506). Fibrinogen was decreased in 3/13 (23%). Soluble IL-2 receptor level was above normal limits in all patients in whom it was measured (range 796 – 17,378 U/mL), but met the >2,400 U/mL criteria in only 3/6 (50%). In vitro NK function was diminished in 2/5 (40%) patients tested. Fever and splenomegaly were found in 94% and 59% of patients, respectively. Of 11 patients meeting HLH criteria, 5 had associated malignancies (DLBCL, NK cell leukemia, T cell lymphoma, AML, and Kaposi sarcoma) and 4 had concomitant viral infections (2 EBV, 1 EBV/B19, and 1 HIV-1/HHV-8). Three patients had isolated viral infections (all EBV), while 3 had idiopathic HLH. Amongst 6 patients not meeting HLH diagnostic criteria, 2 (33%) had an associated malignancy (SLL and NK cell lymphoma), 1 had an isolated EBV infection, and 3 had idiopathic disease. At a median follow-up of 16 months for surviving patients, the case fatality rate amongst those with established HLH diagnoses was 55%, with all deaths occurring within 2 months from diagnosis. Five patients were treated according the HLH-94/04 protocol combining dexamethasone, cyclosporine and etoposide. Two patients died within 2 months of initiating treatment, and 3 remain alive (survival to date ranges 4-31 months). The longest surviving patient underwent allogeneic HCT. A patient who presented with AML-associated HLH underwent induction chemotherapy then proceeded to allogeneic HCT and remains alive 9 months after diagnosis. Amongst 6 patients not meeting HLH criteria, the case fatality rate was 67% with a median survival of 2.3 months. None of these patients were treated with the HLH-94/04 protocol; however, 2 were treated with cyclosporine and remain alive 16 and 24 months after diagnosis. Conclusions Of the HLH diagnostic criteria, multiple cytopenias, hyperferritinemia, and hypertriglyceridemia were sensitive measures, whereas hypofibrinogenemia, markedly elevated sIL-2R, and decreased in vitro NK cell function were found in fewer than half of patients. At our institution, EBV-associated HLH predominates (7/17 cases, 41%). Most of the malignancy-associated HLH we have seen also occurred in the context of EBV infection. The case fatality rate amongst all patients with histologic evidence of hemophagocytosis, including those not meeting HLH criteria, is high. In most patients, treatment according to HLH-94/04 may be appropriate and likely improves survival. In our experience with the HLH-94/04 protocol, 60% of patients remain alive. Until sufficient evidence emerges that this treatment strategy leads to durable remissions in the majority of patients, allogeneic HCT should remain a consideration for most patients. Disclosures No relevant conflicts of interest to declare.
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Subramanian, Vijay, Anil Seetharam, Venkataswarup Tiriveedhi, Nataraju Angaswamy, Christopher Anderson, Surendra Shenoy, Jeffrey Crippin, William Chapman, and Thalachallour Mohanakumar. "Role of donor liver steatosis on immune responses to Hepatitis C, self antigens and allograft fibrosis following human liver transplantation (169.11)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 169.11. http://dx.doi.org/10.4049/jimmunol.186.supp.169.11.
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Abstract Hepatitis C virus (HCV) recurrence following liver transplantation (OLT) is associated with increased allograft fibrosis. Severe donor graft steatosis results in poor early post-operative outcomes but steatosis resolves within 3 weeks. Goal of this study is to characterize the role of donor liver steatosis on HCV immunity, fibrosis and outcome post OLT. Methods: HCV OLT recipients were enrolled at 1 year. Based on donor steatosis, grafts were divided into: Group 1-No steatosis (0-5% steatosis, n=18), Group 2 - Mild (5-33% steatosis, n=15), Group 3 - moderate (>33% steatosis, n=10). Mononuclear cells were stimulated with HCV antigens, and IL-17 and IL-10 cells were enumerated by ELISpot. Serum antibodies (abs) to Collagen (Col) 3 were measured by ELISA. Results: Patient demographics were similar in all groups. Group 3 OLT had a higher incidence of fibrosis (Batts Ludwig grades 3 or 4) when compared to groups 2 and 1 (93%, 34%, 15%, p<0.05). Group 3 demonstrated higher HCV specific IL17 (10±2.1, 12.2±5.2, 23±3.3 spots per million cells (spm) p<0.05) and IL10 secreting cells (107±23.1, 259.6±30.5, 402.3±37.3 spm, p<0.05). Groups 2 and 3 also had higher abs to Col 3 (11±1.1, 13±1.7, 17±1.5 µg/ml, p=0.05). Patient survival at 2 years was 100%, 95% and 84% among the three groups. Conclusion: Donor graft steatosis significantly influenced immune responses to HCV following OLT leading to increased IL17 and IL10 as well as increased incidence of autoimmunity and poorer outcome.
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Gao, X., X. Chi, X. Wang, H. Xu, R. Wu, D. Li, D. Xu, and J. Niu. "IL-33 Clear Hepatitis B Virus in Hydrodynamic HBV Mouse Model through ST2 Expressed on NK Cell." Journal of Hepatology 64, no. 2 (2016): S604—S605. http://dx.doi.org/10.1016/s0168-8278(16)01117-x.
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Abbas Al-Jawdhari, Ameer J., and Shakir H. Mohammed Al-Alwany. "Association between interleukin-1 receptor polymorphism and human herpesvirus 8 among lymphoma patients." Medical Journal of Babylon 20, no. 4 (2023): 875–81. http://dx.doi.org/10.4103/mjbl.mjbl_649_23.
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Abstract Background: Human herpesvirus 8 (HHV-8) stimulates lymphoproliferation, by activating the signaling pathway of the interleukin-6 receptor, along with several other regulatory mechanisms. The presence of specific genetic variations governing immune responses can impact the promotion or suppression of malignant lymphoma. Polymorphisms in the gene cluster of interleukin-1 (IL-1) have been identified as significant contributors to the regulation of inflammation. Objective: This study aimed to determine the percentage HHV-8 and whether polymorphisms at IL-1 receptor antagonist (IL-1ra) locus modulate the risk of developing malignant lymphoma of a group of Iraqi patients in the Mid-Euphrates Sector, Iraq. Materials and Methods: A case-control study was conducted on 200 specimens obtained from patients with lymphoma and individuals without any apparent health conditions who served as the control group (considered normal individuals). The specimens were collected from various general hospitals and private clinics located in the Middle Euphrates region of Iraq. The study population included individuals aged between 17 and 75 years. Specimen collection took place between October 2022 and February 2023. Conventional polymerase chain reaction (PCR) was chosen for the detection of HHV-8 as well as IL-1ra gene polymorphism by sequencing. Results: According to PCR detection, 31 out of 64 (48.4%) of the specimens revealed PCR detection positivity for HHV-8, whereas 33 out of 64 (51.6%) specimens showed negative detection for HHV-8. The lymphoma which were most HHV-8-infected are related to the age stratum (56–75 years), accounted for 48%, whereas the age strata 15–35 years, and 36–55 years, each accounted for 23% and 29%, respectively. Conclusion: In view of the relatively small numbers included in our study, the present results indicate the possibility that HHV-8 and IL-1ra polymorphism may play a role in the tumor biology of lymphocyte and may contribute to their development.
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Fischer, Janett, Shuang Long, Eleni Koukoulioti, Tobias Müller, Balazs Fueloep, Renate Heyne, Mohammed Eslam, et al. "Association of Common Polymorphisms in the Interleukin-1 Beta Gene with Hepatocellular Carcinoma in Caucasian Patients with Chronic Hepatitis B." Pathogens 12, no. 1 (December 29, 2022): 54. http://dx.doi.org/10.3390/pathogens12010054.
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Interleukin-1 beta (IL-1β) promotes liver disease progression and hepatocarcinogenesis in chronic hepatitis B (CHB). Single nucleotide polymorphisms (SNPs) within the promotor region of the IL-1β gene can affect the progression towards liver cirrhosis and hepatocellular carcinoma (HCC). Aims: We aimed to investigate the association of three common IL-1β SNPs with hepatitis B virus (HBV)-related HCC in Caucasian patients. Method: A Caucasian cohort of 99 patients with HBe antigen (Ag)-positive CHB, 255 patients with HBeAg-negative CHB and 278 inactive carriers (IC) were enrolled. 105 patients were diagnosed with liver cirrhosis, and 64 with HCC and cirrhosis. Genotyping of the IL-1β rs1143623, rs1143627 and rs16944 was performed. Results: The rs1143627 TT and rs16944 CC genotypes were more frequent in patients with HCC compared to patients without liver tumours (48% vs. 33%, p = 0.018 and 47% vs. 31%, p = 0.001, respectively). In multivariate analysis, the rs16944 CC genotype was independently associated with HCC (OR = 6.44 [95% CI 1.50–27.59] p = 0.012). The haplotype, including rs1143623 TT and rs16944 CC, was a risk factor for HCC development (OR = 1.55 [95% CI 1.04–2.32] p = 0.031). Conclusions: We identified an association of common IL-1β SNPs with HBV-related HCC in a Caucasian population. The effect was independent of the phases of chronic HBV infection, which are currently regarded as important HCC risk factors.
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Alani, Muhammad M. "Serum interleukin 1 and interleukin 10 levels in Iraqi leukemic patients with hepatitis G virus infection." Journal of the Faculty of Medicine Baghdad 54, no. 4 (January 2, 2013): 340–43. http://dx.doi.org/10.32007/jfacmedbagdad.544699.
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Background:
Objectives : This prospective study aimed to estimate interleukins 1 and 10 levels in acute hepatitis (G) in Iraqi patients with leukemiaHepatitis G virus and GB virus C (GBV-C) RNA viruses that were independently identified in 1995, and were subsequently found to be two isolates of the same virus. Blood transfusion is the main risk factor for HGV transmission Immune-mediated mechanisms are believed to play an important pathogenic role in hepatitis G virus infection. Interleukin-1 (IL-1) plays an important role in the inflammatory process. implying that IL-1 may play a role in viral clearance and suggesting that IL-1 has direct antiviral activity, so that IL-1 induces novel antiviral pathways within a cell. Interleukin 10 ( IL-10 )is secreted by T helper-2 type cells (Th2) which may down regulate cell-mediated immune effecter mechanisms important in the host defense against intracellular pathogens.
Methods: This cross sectional study was carried out at the national center of hematology , almustansiriya University and department of microbiology in Baghdad medical college in Baghdad, Iraq from January till August 2012. The study involved 33 patients (19 males & 14 females) diagnosed with hepatitis G infection as having a positive IgM antibodies by ELISA technique .Serum IL-1 and IL-10 levels were measured in 33 patients with hepatitis G virus infection and 40 leukemia patients without HGV infections as a control group by ELISA technique .
Results: Twenty three patients (70%) with hepatitis G infection had elevated serum IL-1 alpha levels (the normal detection level is below 5 pg/ml), the patient serum IL 1 alpha range 2-37 pg/ml, with a mean 27.813 and SD 32.765 ). There was also a high significant correlation between serum IL-1 alpha level and hepatitis G infection (p value= ± 0.004) when compared with the control group by the t –test Also serum IL-10 level was below the normal detection limit (5-20 pg/ml) in 20 (60%) patients .The 33 patients had serum IL-10 levels (range 0.6 - 9 pg/ml, with a mean 2.213 & SD± 4.745 ) . There was a significant correlation between serum IL-10 level & hepatitis G infection when compared with the control group (p<0.0386 by t- test),so the viral infection may suppress the T helper 2 cells by the gamma interferon . This elevation in IL1 alpha which is an inflammatory cytokine produced by antigen presenting cells , may suggest that IL-1 is an important interleukin to eradicate hepatitis G virus infection.
Conclusions: This study showed that serum Th2 cytokines are suppressed (IL10 ) while serum inflammatory cytokine (IL 1 alpha ) is elevated in a proportion of patients with hepatitis G virus infection. However, the elevated IL 1 alpha cytokine levels may represent a systemic response and not as a result of increased local production within the liver.
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Rauco, Annamaria, Fabrizio Liberati, Rosanna Capozzi, Maria G. Morandi, Roberta Pace, Vincenzo Capparella, Michele Cianciulli, and Anna M. Liberati. "A Continous Recurrent Course in a Case of Nodular-Sclerosis (NS) Classical Hodgkin’s Lymphoma (cHL) Associated with Castleman’s Disease (CD)." Blood 106, no. 11 (November 16, 2005): 4824. http://dx.doi.org/10.1182/blood.v106.11.4824.4824.
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Abstract Background: CD is a rare entity characterized by unicentric or multicentric clinical presentation. Three histologic variants (hyline vascular, plasmacell and mixed) have been described. Coexistence of CD and non-Hodgkin (NHL) and Hodgkin’s (HL) lymphomas is well documented in literature; however the last type of association is a rare event. When it occurs, the most frequent association is between interfollicular subtype of HL and plasmacell variant of CD, while there is no agreement regarding a more common combination of HL and either the multicentric or the localized form of CD. Methods and Results: On July 2000, a 33-years-old woman HIV-negative was found to be affected by NS grade I of BNLI cHL diagnosed on a supraclavear nodal biopsy. The final stage was IIIA. After 6 cycles of ABVD and mediastinal radiotherapy, the patient obtained a CR (January 2001). One year later (May 2002) she complained asthenia, but not other clinical signs or symptoms. Laboratory tests revelead increased ERS (49 mm/h) and only mild anemia (11,7 mg/dl). Computerized tomography (CT), ultrasonography (US) and positron emission tomography (PET) showed multiple subdiaphgramatic enlarged lymphnodes in celiac tripod region, haepatoduodenal ligament and interaortocaval zone (2–3 cm of diameter). However, the biopsied nodes obtained by laparoscopy reveled a mixed reactive lymphoadenopathy, but not recurrent HL. During the following 13 months of observation, a further reduction in the hemoglobine value (10.9 mg/dl), increased ERS (87 mm/h) and a very slowly progressive increase in the dimension (4–5 cm diameter) of the abdominal enlarged nodes were documented in the absence of others clinical signs or symptoms. A second nodal biopsy (paracaval lymphnode) was performed in October 2003. Histology showed some lymphoid follicles with small germinal centers(GC), which presented prominent hyalinized vessels and politypical plasmacell component in interfollicular areas indicative of CD (mixed hyaline-vascular and plasmacell subtype). Rare Reed-Stenberg and lacunar cells were found in this background. After the second course of chemoterapy (6 cycles of ABVD) a rapid normalization of ERS and anemia were documented. The CT findings showed a reduction of size and numbers, but no disappereance of abdominal lymph nodes (4 residual nodes of 1–2 cm of diameter). A further nodal biopsy was performed, which confirmed the persistence of HL in the background of CD. Only after RT, the patient obtained a second CR as documented by two subsequent negative CT and PET scans. On July 2005, even if laboratory tests were normal, a single ipogastric superficial lymphadenopathy was detected on phisical examination and confirmed by US: so, a new diagnostic work-up, consisting of PET-SCAN and escixional biopsy is ongoing. Conclusion: After cHL sclero-nodular type, the diagnosis of recurrent HL probably arising on a preexisting multifocal CD, both caracterized by a particularly indolent course, was documented. The two pathogenetic mechanisms hypothized for CD and HL association are: secretion of IL-6 by Hodgkin’s RS cells and/or histiocytes or manifestation of an abnormal immune state associated with Hodgkin’s disease.