IL-2/IL-2 antibody immune complex regulates HSV-induced inflammation through induction of IL-2 receptor alpha, beta, and gamma in a mouse model

IL-2/IL-2 antibody immune complex regulates HSV-induced inflammation through induction of IL-2 receptor alpha, beta, and gamma in a mouse model

Patients with recurrent herpes labialis and genitalis as well as normal controls were tested for the in vitro responsiveness of their lymphocytes to mitogens, to several herpes antigens and to carrier medium alone (containing chorioallantois membrane antigens). Such is the case when it comes to humans versus herpes simplex virus type-1 (HSV-1), a highly contagious virus that is virtually impossible to get rid of once it becomes established. Exposure of varicella-immune persons to VZV may boost the host’s immune response, resulting in a protective effect against HZ. Immunodeficient B6 (IL-7R-/-Kitw41/w41) mice lacking adaptive cells (B6-E mice) transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control non-transplanted B6-E mice. 1965;58:9-20), that cell-mediated protection against HZ increases after each episode of exposure to VZV. The transfer of CD8+T cells increased survival in the acute infection, but their engraftment seemed less needed for latency than that of CD4+T cells. The change of expression in IL-2R was accompanied by the increase of CD8+CD44+ memory T cells, CD3-NK1.1+CD11b+CD27+ natural killer cells, and improvement of symptoms.

In this study, we elucidated the role of IL-2R subunits on BD, a finding that can be connected to therapeutic strategy for patients based on the results from the treatment of BD mice. hepaticus-infected mice and noninfected mice were measured in separate experiments. Several papers reported that serum levels of IL-2 were significantly higher in BD patients than in healthy controls (Ahn et al., 2006, Akdeniz et al., 2004 and Alpsoy et al., 1998), whereas other papers have reported that IL-2 levels are not much different between BD patients and healthy controls (Aktas Cetin et al., 2013 and Pekiner et al., 2012). According to Sugi-Ikai et al. (1998) the frequencies of IL-2 producing CD4+ and CD8+ cells in active patients are significantly higher than those in inactive patients (Sugi-Ikai et al., 1998). Ex vivo analysis of immune cells following treatment showed increased inflammatory cytokine production and the presence of mature dendritic cells for the OSVP, OSV, and OS viruses. (1986) suggested that the impairment of IL-2 responsiveness in concanavalin-A activated lymphoblasts was due to a decrease in the density of IL-2 receptors on T cells and this may thus contribute to the immunologic aberrations in BD.

For the signaling of IL-2, IL-2 and IL-2 receptor (IL-2R) interaction is important (Gaffen, 2001). From previous reports, the serum IL-2 levels were not consistent and there were no reports related to the frequencies of IL-2 receptor-expressing leukocytes in BD patients. In spite of the success of many vaccines in protecting against some infectious pathogens, there remain numerous other pathogens such as malaria, HIV, influenza, hepatitis C, for which no effective vaccine exists and is the cause of tens of millions deaths each year [4]. Therefore, this study focused on the expression and regulation of IL-2R on peripheral blood mononuclear cells (PBMC) in a BD mouse model and BD patients. BD mice were produced by herpes simplex virus (HSV) inoculation on the scratched earlobe and they showed BD-like symptoms, including major symptoms such as oral, genital, eye inflammation, and minor symptoms such as arthritis and intestinal involvement (Sohn et al., 1998). The structural studies also shed light on previous findings regarding the effects of mutations in gE on its ability to bind IgG and on cell-to-cell spread of HSV-1. IL-2Rα, CD25, is a well-known marker of regulatory T cells, as CD4+CD25+ cells (Turka and Walsh, 2008).
IL-2/IL-2 antibody immune complex regulates HSV-induced inflammation through induction of IL-2 receptor alpha, beta, and gamma in a mouse model

IL-2Rβ, CD122, is the common receptor for IL-15 receptor beta (Pillet et al., 2009). IL-2Rγ, CD132, is the common gamma chain of receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 (Vosshenrich et al., 2005). Recently, the IL-2/anti-IL-2 monoclonal antibody complex was found to display an extended lifespan, beyond that of IL-2 alone in vivo, and to have the biological activity for proliferation of memory CD8+ T cells ( Boyman et al., 2010 and Mostbock et al., 2008) and expansion of CD4+CD25+ regulatory T cells (Polhill et al., 2012). In HSV-induced BD mice, up-regulation of memory CD8+ T cells and CD4+CD25+ regulatory T cells were correlated to the improvement of symptoms ( Choi et al., 2013a and Shim et al., 2011). In this study, the expression of IL-2R α, β, and γ was analyzed in BD mice and the regulation of the receptor subunits through IL-2/anti-IL-2Ab complex was applied to BD mice for the resolution of inflammation by expansion of regulatory T cells, or memory T cells, or the regulation of natural killer (NK) cell maturation. hepaticus-specific secretory IgA antibodies are persistently detected in the feces of mice.40 How these immune responses in H. Virus inoculation was conducted twice with a 10 day interval in between, and after the second HSV inoculation, mice were observed from 4 weeks to 32 weeks.

Animals were handled in accordance with a protocol approved by the animal care committee of Ajou University School of Medicine (AMC-102). BD manifestations were shown as several different symptoms in mice. Of the total HSV-infected mice, 15% developed BD-like symptoms. Symptoms included oral ulcerations, genital ulcerations, erythema, skin pustules, skin ulcerations, joint-arthritis, diarrhoea, red eye (right, left), reduced vision (right, left), loss of balance, discoloration, and swelling of the face. Oral, genital and other skin ulcers and eye symptoms were classified as major symptoms. Arthritis, intestinal ulcers, and neurological involvement were identified as minor symptoms. The dose for each ligand was arrived at after careful dose–response studies (Fig.

The score of each symptom was one, and the sum of the symptoms was used to determine the severity of BD. The disappearance of symptoms or 20% or greater decrease in the lesion size were classified as improvements. The calculation of severity of BD was followed by that of the BD activity index, as outlined in the BD Activity Form (www.behcet.ws/pdf/BehcetsDiseaseActivityForm.pdf). The control group was inoculated with HSV, but asymptomatic healthy mice were used as a BD normal (BDN) control, as previously described. The patient population consisted of 32 patients with BD, who presented for the first time or were monitored at the Department of Dermatology, Ajou University Hospital and Yonsei University Severance Hospital. Clinical characteristics and therapeutic histories of these patients are shown in Table 1 and Table 2. According to the International Study Group for BD criteria, the presence of any two of the following symptoms in addition to recurrent oral ulcerations is considered to be sufficient for a BD diagnosis recurrent genital ulceration, uveitis, large-vessel vasculitis, cutaneous erythema nodosum, and a positive pathergy test.

The active patients group (n = 21 (male 7, female 14), 41.5 ± 8.2 years) had at least one of the BD symptoms despite treatment, and the inactive patients group (n = 11 (male 5, female 6), 43.5 ± 7.8 years) had their BD under control through the use of anti-inflammatory medication. At the time point of collecting PBMC, inactive patients had no symptoms. All of the mice were maintained in a specific-pathogen-free environment and were confirmed to be serologically negative for mouse hepatitis virus, minute virus of mice, mouse parvovirus, mouse norovirus, Sendai virus, Mycoplasma pulmonis, Theiler murine encephalomyelitis virus, mouse rotavirus, pneumonia virus of mice, reovirus 3, lymphocytic choriomeningitis virus, and ectromelia virus at the conclusion of the experiments. The healthy control group (n = 14, 31.9 ± 3.7 years) consisted of 8 male and 6 female subjects. This study was approved by the Institutional Review Board (IRB no.: AJIRB-GN3-07-098 and 4-2012-0779). Statistical analysis of patients’ data was performed using the Kruskal–Wallis Test and Bonferroni correction.

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