Indoleamine 2,3-Dioxygenase in Hematopoietic Stem Cell-Derived Cells Suppresses Rhinovirus-Induced Neutrophilic Airway Inflammation by Regulating Th1- and Th17-Type Responses

Asthma exacerbations are a major cause of intractable morbidity, increases in health care costs, and a greater progressive loss of lung function. Asthma exacerbations are most commonly triggered by respiratory viral infections, particularly with human rhinovirus (hRV). Respiratory viral infections are believed to affect the expression of indoleamine 2,3-dioxygenase (IDO), a limiting enzyme in tryptophan catabolism, which is presumed to alter asthmatic airway inflammation. Here, we explored the detailed role of IDO in the progression of asthma exacerbations using a mouse model for asthma exacerbation caused by hRV infection. Our results reveal that IDO is required to prevent neutrophilic inflammation in the course of asthma exacerbation caused by an hRV infection, as corroborated by markedly enhanced Th17- and Th1-type neutrophilia in the airways of IDO-deficient mice. This neutrophilia was closely associated with disrupted expression of tight junctions and enhanced expression of inflammasomerelated molecules and mucin-inducing genes. In addition, IDO ablation enhanced allergenspecific Th17- and Th1-biased CD4 + T-cell responses following hRV infection. The role of IDO in attenuating Th17- and Th1-type neutrophilic airway inflammation became more apparent in chronic asthma exacerbations after repeated allergen exposures and hRV infections. Furthermore, IDO enzymatic induction in leukocytes derived from the hematopoietic stem cell (HSC) lineage appeared to play a dominant role in attenuating Th17- and Th1-type neutrophilic inflammation in the airway following hRV infection. Therefore, IDO activity in HSC-derived leukocytes is required to regulate Th17- and Th1-type neutrophilic inflammation in the airway during asthma exacerbations caused by hRV infections.

The Interplay between Host Immunity and Respiratory Viral Infection in Asthma Exacerbation

Asthma is one of the most common and chronic diseases characterized by multidimensional immune responses along with poor prognosis and severity. The heterogeneous nature of asthma may be attributed to a complex interplay between risk factors (either intrinsic or extrinsic) and specific pathogens such as respiratory viruses, and even bacteria. The intrinsic risk factors are highly correlated with asthma exacerbation in host, which may be mediated via genetic polymorphisms, enhanced airway epithelial lysis, apoptosis, and exaggerated viral replication in infected cells, resulting in reduced innate immune response and concomitant reduction of interferon (types I, II, and III) synthesis. The canonical features of allergic asthma include strong Th2-related inflammation, sensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), eosinophilia, enhanced levels of Th2 cytokines, goblet cell hyperplasia, airway hyper-responsiveness, and airway remodeling. However, the NSAID-resistant non-Th2 asthma shows a characteristic neutrophilic influx, Th1/Th17 or even mixed (Th17-Th2) immune response and concurrent cytokine streams. Moreover, inhaled corticosteroid-resistant asthma may be associated with multifactorial innate and adaptive responses. In this review, we will discuss the findings of various in vivo and ex vivo models to establish the critical heterogenic asthmatic etiologies, host-pathogen relationships, humoral and cell-mediated immune responses, and subsequent mechanisms underlying asthma exacerbation triggered by respiratory viral infections.

The Clinical Effect with the Use of Gel Anesthesia within Gingival Sulcus during Scaling / 치위생과학회지

Although scaling is the primary method for improving oral health, it is also associated with dental fear. The objective of this study was to empirically verify whether the use of gel anesthetic within the gingival sulcus during scaling relieves pain and improves other factors. A total of 128 patients scheduled to undergo scaling at a dental clinic of a general hospital located in the Gyeonggi Province, between July 2014 and July 2015, were enrolled in the study. The participants underwent scaling following the application of 20% benzocaine gel or placebo gel anesthetic within the gingival sulcus, and the data was collected using a questionnaire. There was a significant difference in the severity of pain, participant satisfaction, perceived sensitivity, overall discomfort, and fear of scaling between the two groups. The two groups were compared in terms of perceived need for gel anesthesia, willingness to pay for anesthesia costs, and willingness to receive scaling in the future. There were significant differences in all the three parameters depending on whether gel anesthesia was used or not. There were significant differences between the two groups in perceived sensitivity immediately after scaling and one day after scaling, with no difference seen one week after scaling. With regards to overall discomfort over time, there were significant differences between the two groups immediately after scaling. Based on these findings, we expect that application of gel anesthetic within the gingival sulcus during scaling will reduce pain, perceived sensitivity, overall discomfort, and fear of scaling with increased satisfaction.

In vivo CTL Activity Induced by Prime-boost Vaccination using Recombinant Vaccinia Virus and DNA Vaccine Expressing Epitope Specific for CD8+ T Cells

DNA vaccine approaches have been applied to generate the protective immunity against various pathogens. However, the strength of immune responses induced by DNA vaccine is weak compared with conventional vaccines. The primeboost vaccination using DNA vaccine and other viral vector has been suggested as one way to circumvent this limitation. In the present study, we used in vivo CTL activity assay to determine CD8+ T cell-mediated immunity induced by prime-boost vaccination with a DNA vaccine (gB498-505 DNA) and recombinant vaccinia virus (VVgB498-505) expressing gB498-505 epitope peptide (SSIEFARL) of herpes simplex virus type 1 (HSV-1) glycoprotein B (gB). The most potent in vivo CTL activity was induced in mice received VVgB498-505 when both gB498-505 and VVgB498-505 were used at priming step and boosted with the alternative vaccine vector expressing whole antigen protein (gBw). Priming with vaccine vector expressing gBw followed by the use of VVgB498-505 at boosting step also induced strong in vivo CTL activity. We also examined in vivo CTL activity after immunization of mice with epitope-expressing vaccine vector at both priming and boosting step. Curiously, in vivo CTL activity mediated by CD8+ T cells was strongly elicited at memory stage when animals were primed with VVgB498-505 and subsequently boosted with gB498-505 DNA. Because the use of VVgB498-505 at priming followed by boosting with gB498-505 DNA induced most optimal immunity, these results suggest that the order of vaccine type should be carefully considered when used vaccine type expressing only epitope for prime-boost vaccination.

The Kinetics of Secondary Response of Antigen-Specific CD4+ T Cells Primed in vitro with Antigen

BACKGROUND: Memory T lymphocytes of the immune system provide long-term protection in response to bacterial or viral infections/immunization. Ag concentration has also been postulated to be important in determining whether T cell differentiation favors effector versus memory cell development. In the present study we hypothesized that na?ve Ag-specific CD4+ T cells briefly stimulated with different Ag doses at the primary exposure could affect establishment of memory cell pool after secondary immunization. METHODS: To assess this hypothesis, the response kinetics of DO11.10 TCR CD4+ T cells primed with different Ag doses in vitro was measured after adoptive transfer to naive BALB/c mice. RESULTS: Maximum expansion was shown in cells primarily stimulated with high doses of ovalbumin peptide (OVA323-339), whereas cells in vitro stimulated with low dose were expanded slightly after in vivo secondary exposure. However, the cells primed with low OVA323-339 peptide dose showed least contraction and established higher number of memory cells than other treated groups. When the cell division was analyzed after adoptive transfer, the high dose Ag-stimulated donor cells have undergone seven rounds of cell division at 3 days post-adoptive transfer. However, there was very few division in naive and low dose of peptide-treated group. CONCLUSION: These results suggest that primary stimulation with a low dose of Ag leads to better memory CD4+ T cell generation after secondary immunization. Therefore, these facts imply that optimally primed CD4+ T cells is necessary to support effective memory pool following administration of booster dose in prime-boost vaccination.

CD8+ T Cell-mediated Immunity Induced by Heterologous Prime-boost Vaccination Based on DNA Vaccine and Recombinant Vaccinia Virus Expressing Epitope

BACKGROUND: DNA vaccination represents an anticipated approach for the control of numerous infectious diseases. Used alone, however, DNA vaccine is weak immunogen inferior to viral vectors. In recent, heterologous prime-boost vaccination leads DNA vaccines to practical reality. METHODS: We assessed prime-boost immunization strategies with a DNA vaccine (minigene, gB498-505 DNA) and recombinant vaccinia virus (vvgB498- 505) expressing epitope gB498-505 (SSIEFARL) of CD8+ T cells specific for glycoprotein B (gB) of herpes simplex virus (HSV). Animals were immunized primarily with gB498-505 epitope-expressing DNA vaccine/recombinant vaccinia virus and boosted with alternative vaccine type expressing entire Ag. RESULTS: In prime-boost protocols using vvgBw (recombinant vaccinia virus expressing entire Ag) and vvgB498-505, CD8+ T cell-mediated immunity was induced maximally at both acute and memory stages if primed with vvgBw and boosted with vvgB498-505 as evaluated by CTL activity, intracellular IFN-staining, and MHC class I tetramer staining. Similarly gB498-505 DNA prime-gBw DNA (DNA vaccine expressing entire Ag) boost immunization elicited the strongest CD8+ T cell responses in protocols based on DNA vaccine. However, the level of CD8+ T cell-mediated immunity induced with prime-boost vaccination using DNA vaccine expressing epitope or entire Ag was inferior to those based on vvgBw and vvgB498-505. Of particular interest CD8+ T cell-mediated immunity was optimally induced when vvgB498-505 was used to prime and gB DNA was used as alternative boost. Especially CD8+ T cell responses induced by such protocol was longer lasted than other protocols. CONCLUSION: These facts direct to search for the effective strategy to induce optimal CD8+ T cell-mediated immunity against cancer and viral infection.