Delayed differentiation of potent effector CD8⁺ T cells reducing viremia and reservoir seeding in acute HIV infection

Takata, Hiroshi,Buranapraditkun, Supranee,Kessing, Cari,Fletcher, James L. K.,Muir, Roshell,Tardif, Virginie,Cartwright, Pearline,Vandergeeten, Claire,Bakeman, Wendy,Nichols, Carmen N.,Pinyakorn, Sute American Association for the Advancement of Scienc 2017 Science Translational Medicine Vol.9 No.377

<P>CD8(+) T cells play a critical role in controlling HIV viremia and could be important in reducing HIV-infected cells in approaches to eradicate HIV. The simian immunodeficiency virus model provided the proof of concept for a CD8(+) T cell-mediated reservoir clearance but showed conflicting evidence on the role of these cells to eliminate HIV-infected cells. In humans, HIV-specific CD8(+) T cell responses have not been associated with a reduction of the HIV-infected cell pool in vivo. We studied HIV-specific CD8(+) T cells in the RV254 cohort of individuals initiating ART in the earliest stages of acute HIV infection (AHI). We showed that the HIV-specific CD8(+) T cells generated as early as AHI stages 1 and 2 before peak viremia are delayed in expanding and acquiring effector functions but are endowed with higher memory potential. In contrast, the fully differentiated HIV-specific CD8(+) T cells at peak viremia in AHI stage 3 were more prone to apoptosis but were associated with a steeper viral load decrease after ART initiation. Their capacity to persist in vivo after ART initiation correlated with a lower HIV DNA reservoir. These findings demonstrate that HIV-specific CD8(+) T cell magnitude and differentiation are delayed in the earliest stages of infection. These results also demonstrate that potent HIV-specific CD8(+) T cells contribute to the reduction of the pool of HIV-producing cells and the HIV reservoir seeding in vivo and provide the rationale to design interventions aiming at inducing these potent responses to cure HIV infection.</P>

The Role of In Vitro Detection of Drug- Specific Mediator-Releasing Cells to Diagnose Different Phenotypes of Severe Cutaneous Adverse Reactions

Klaewsongkram Jettanong,Buranapraditkun Supranee,Thantiworasit Pattarawat,Rerknimitr Pawinee,Tuchinda Papapit,Chularojanamontri Leena,Rerkpattanapipat Ticha,Chanprapaph Kumutnart,Disphanurat Wareeporn 대한천식알레르기학회 2021 Allergy, Asthma & Immunology Research Vol.13 No.6

Propose: The purpose of this study was to investigate panels of enzyme-linked immunospot assays (ELISpot) to detect drug-specific mediator releasing cells for confirming culprit drugs in severe cutaneous adverse reactions (SCARs). Methods: Frequencies of drug-induced interleukin-22 (IL-22)-, interferon-gamma (IFN-γ)-, and granzyme-B (GrB)-releasing cells were measured by incubating peripheral blood mononuclear cells (PBMCs) from SCAR patients with the culprit drugs. Potential immunoadjuvants were supplemented to enhance drug-induced mediator responses. Results: Twenty-seven patients, including 9 acute generalized exanthematous pustulosis (AGEP), 10 drug reactions with eosinophilia and systemic symptoms, and 8 Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) were recruited. The average frequencies of drug-induced IL-22-, IFN-γ-, and GrB-releasing cells were 35.5±16.3, 33.0±7.1, and 164.8±43.1 cells/million PBMCs, respectively. The sensitivity of combined IFN-γ/IL-22/GrB ELISpot was higher than that of IFN-γ ELISpot alone for culprit drug detection in all SCAR subjects (77.8% vs 51.9%, P < 0.01). The measurement of drug-induced IL-22- and IFN-γ releasing cells confirmed the culprit drugs in 77.8% of AGEP. The measurement of druginduced IFN-γ- and GrB-releasing cells confirmed the culprit drugs in 62.5% of SJS/TEN. Alpha-galactosylceramide supplementation significantly increased the frequencies of druginduced IFN-γ releasing cells. Conclusion: The measurement of drug-induced IFN-γ-releasing cells is the key for identifying culprit drugs. The additional measurement of drug-induced IL-22-releasing cells enhances ELISpot sensitivity to identify drug-induced AGEP, while the measurement of drug-induced GrB-releasing cells could have a role in SJS/TEN. ELISpot sensitivity might be improved by supplementary alpha-galactosylceramide.

Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions

Klaewsongkram Jettanong,Buranapraditkun Supranee,Mongkolpathumrat Pungjai,Palapinyo Sirinoot,Chantaphakul Hiroshi 대한천식알레르기학회 2021 Allergy, Asthma & Immunology Research Vol.13 No.2

Purpose: Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes. Methods: The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization. Results: More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects. Conclusions: NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.

Randomized, Double-Blind, Placebo-Controlled Trial of Vitamin D Supplementation in the Build-up Phase of House Dust Mite-Specific Immunotherapy

Chiewchalermsri Chirawat,Sangkanjanavanich Sasipa,Pradubpongsa Panitan,Mitthamsiri Wat,Jaisupa Nattapon,Jindarat Sarawut,Buranapraditkun Supranee,Jacquet Alain,Sangasapaviliya Atik,Boonpiyathad Tadech 대한천식알레르기학회 2023 Allergy, Asthma & Immunology Research Vol.15 No.3

Purpose: Vitamin D (VitD) is an immunomodulatory molecule capable of alleviating allergic symptoms. However, the effectiveness of allergen-specific immunotherapy (AIT) is not commonly evidenced in the early build-up phase. The aim of the study was to determine the potential of VitD supplementation in this treatment phase. Methods: Thirty-four house dust mite (HDM)-allergic adult patients treated with subcutaneous AIT were randomized to receive VitD2 60,000 IU/week or placebo for 10 weeks and followed up for 10 weeks. The primary endpoints were the symptom-medication score (SMS) and the treatment response rate. The secondary endpoints were eosinophil count and levels of plasma IL-10, Der p 2-specific IgG4, and dysfunctional regulatory T (CRTH2+ Treg) cells. Results: Of 34 patients, 15 in each group completed the study. Patients with VitD deficiency receiving a VitD supplement showed significantly lower mean change SMS than the placebo group in weeks 10 (mean difference −54.54%, P = 0.007) and 20 (mean difference −42.69%, P = 0.04). The percentage of treatment responders reached 78% and 50% in the VitD and placebo groups, respectively, and the effect remained in week 20 (89% and 60%). No significant difference was observed for the tested immunological read-outs, with the exception of the frequency of CRTH2+ Treg cells, which was remarkably reduced in the VitD-treated patients. Moreover, improvement in SMS was correlated to the number of CRTH2+ Treg cells. Our in vitro experiment indicated that VitD downregulated activation markers, whereas it improved the function of CRTH2+ Treg cells. Conclusions: VitD supplementation in the build-up phase of AIT could relieve symptoms and decrease Treg cell dysfunction, especially in patients with VitD deficiency.