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SARS-CoV-2-specific B- and T-cell immunity in a population-based study of young Swedish adults.
Björkander, S, Du, L, Zuo, F, Ekström, S, Wang, Y, Wan, H, Sherina, N, Schoutens, L, Andréll, J, Andersson, N, et al
The Journal of allergy and clinical immunology. 2022;(1):65-75.e8
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Abstract
BACKGROUND Young adults are now considered major spreaders of coronavirus disease 2019 (COVID-19) disease. Although most young individuals experience mild to moderate disease, there are concerns of long-term adverse health effects. The impact of COVID-19 disease and to which extent population-level immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists in young adults remain unclear. OBJECTIVE We conducted a population-based study on humoral and cellular immunity to SARS-CoV-2 and explored COVID-19 disease characteristics in young adults. METHODS We invited participants from the Swedish BAMSE (Barn [Children], Allergy Milieu, Stockholm, Epidemiology) birth cohort (age 24-27 years) to take part in a COVID-19 follow-up. From 980 participants (October 2020 to June 2021), we here present data on SARS-CoV-2 receptor-binding domain-specific IgM, IgA, and IgG titers measured by ELISA and on symptoms and epidemiologic factors associated with seropositivity. Further, SARS-CoV-2-specific memory B- and T-cell responses were detected for a subpopulation (n = 108) by ELISpot and FluoroSpot. RESULTS A total of 28.4% of subjects were seropositive, of whom 18.4% were IgM single positive. One in 7 seropositive subjects was asymptomatic. Seropositivity was associated with use of public transport, but not with sex, asthma, rhinitis, IgE sensitization, smoking, or body mass index. In a subset of representative samples, 20.7% and 35.0% had detectable SARS-CoV-2 specific B- and T-cell responses, respectively. B- and T-cell memory responses were clearly associated with seropositivity, but T-cell responses were also detected in 17.2% of seronegative subjects. CONCLUSIONS Assessment of IgM and T-cell responses may improve population-based estimations of SARS-CoV-2 infection. The pronounced surge of both symptomatic and asymptomatic infections among young adults indicates that the large-scale vaccination campaign should be continued.
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T Cell Response Toward Tissue-and Epidermal-Transglutaminases in Coeliac Disease Patients Developing Dermatitis Herpetiformis.
Caproni, M, Capone, M, Rossi, MC, Santarlasci, V, Maggi, L, Mazzoni, A, Rossettini, B, Renzi, D, Quintarelli, L, Bianchi, B, et al
Frontiers in immunology. 2021;:645143
Abstract
The reason why only few coeliac patients develop the cutaneous manifestation of the disease, named dermatitis herpetiformis (DH), is still unknown. Epidermal transglutaminase (TG3) has been described as the main autoantigen of humoral immunity in DH but the mechanisms leading to this autoimmune response remain obscure. Here we characterized T cells from skin, gut and peripheral blood of DH and coeliac disease (CD) patients, evaluated the impact of the gluten-free diet on circulating T lymphocytes' phenotype and investigated antigen specific T cell response toward epidermal and tissue transglutaminase (TG2). DH patients showed an increased frequency of skin-derived T cells producing TNFα when compared to CD patients. Moreover, circulating T cells producing TNFα and IL-17A positively correlated with clinical score of skin disease activity and decreased after gluten-free diet. Finally, TG2 and TG3-specific T cells resulted more reactive to antigens stimulation in DH patients and showed cross reactivity toward the two autoantigens in both the group of patients. Our data suggest a role of TNFα and IL-17A producing cells in the development of DH and, for the first time, show the existence of a crossed T cell response toward the two transglutaminases isoforms, thus suggesting new insights on T cells role in skin damage.
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Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma.
Da Vià, MC, Dietrich, O, Truger, M, Arampatzi, P, Duell, J, Heidemeier, A, Zhou, X, Danhof, S, Kraus, S, Chatterjee, M, et al
Nature medicine. 2021;(4):616-619
Abstract
B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial ( NCT03361748 ) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.
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mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer.
Cafri, G, Gartner, JJ, Zaks, T, Hopson, K, Levin, N, Paria, BC, Parkhurst, MR, Yossef, R, Lowery, FJ, Jafferji, MS, et al
The Journal of clinical investigation. 2020;(11):5976-5988
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Abstract
BACKGROUNDTherapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODSWe recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTSThe vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSIONThis vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATIONPhase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDINGCenter for Clinical Research, NCI, NIH.
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Rapid Generation of Sustainable HER2-specific T-cell Immunity in Patients with HER2 Breast Cancer using a Degenerate HLA Class II Epitope Vaccine.
Knutson, KL, Block, MS, Norton, N, Erskine, CL, Hobday, TJ, Dietz, AB, Padley, D, Gustafson, MP, Puglisi-Knutson, D, Mangskau, TK, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;(5):1045-1053
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Abstract
PURPOSE Patients with HER2+ breast cancer benefit from trastuzumab-containing regimens with improved survival. Adaptive immunity, including cytotoxic T-cell and antibody immunity, is critical to clinical efficacy of trastuzumab. Because Th cells are central to the activation of these antitumor effectors, we reason that HER2 patients treated with trastuzumab may benefit by administering vaccines that are designed to stimulate Th-cell immunity. PATIENTS AND METHODS We developed a degenerate HER2 epitope-based vaccine consisting of four HLA class II-restricted epitopes mixed with GM-CSF that should immunize most (≥84%) patients. The vaccine was tested in a phase I trial. Eligible women had resectable HER2+ breast cancer and had completed standard treatment prior to enrollment and were disease free. Patients were vaccinated monthly for six doses and monitored for safety and immunogenicity. RESULTS Twenty-two subjects were enrolled and 20 completed all six vaccines. The vaccine was well tolerated. All patients were alive at analysis with a median follow-up of 2.3 years and only two experienced disease recurrence. The percent of patients that responded with augmented T-cell immunity was high for each peptide ranging from 68% to 88%, which led to 90% of the patients generating T cells that recognized naturally processed HER2 antigen. The vaccine also augmented HER2-specific antibody. Immunity was sustained in patients with little sign of diminishing at 2 years following the vaccination. CONCLUSIONS Degenerate HLA-DR-based HER2 vaccines induce sustainable HER2-specific T cells and antibodies. Future studies, could evaluate whether vaccination during adjuvant treatment with trastuzumab-containing regimens improves patient outcomes.
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Vitamin D status and the immune assessment in 22q11.2 deletion syndrome.
Legitimo, A, Bertini, V, Costagliola, G, Baroncelli, GI, Morganti, R, Valetto, A, Consolini, R
Clinical and experimental immunology. 2020;(3):272-286
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Abstract
22q11.2 deletion syndrome (22q11.2DS) is characterized by a heterogeneous phenotype, including alterations in phospho-calcium metabolism and immunodeficiency. We analyzed vitamin D status and the immune assessment, focusing on T cell subpopulations and dendritic cells (DCs) in a cohort of 17 pediatric 22q11.2DS patients and 17 age-matched healthy subjects. As antigen-presenting cells, DCs are the main target of vitamin D, promoting a tolerogenic T cell response. Patients were subdivided into three groups according to the parameters of phospho-calcium metabolism and serum levels of 25OHD: normal values, vitamin D deficiency and hypoparathyroidism. Different degrees of T cell deficiency, ranging from normal to partial T cell numbers, were observed in the cohort of patients. The group with vitamin D deficiency showed a significant reduction of naive T cells and a significant increase of central memory T cells compared to controls. In this group the number of circulating DCs was significantly reduced. DC decrease affected both myeloid and plasmacytoid DC subsets (mDCs and pDCs), with the most relevant reduction involving pDCs. A direct correlation between 25OHD levels and recent thymic emigrant (RTE) and DC number was identified. Despite the limited cohort analyzed, our results show that deficiency of the pDC subset in patients with 22q11.2DS may be included among the causative factors of the progressive increase of risk of autoimmune diseases in these patients. As most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, we suggest a potential role of vitamin D supplementation in preventing autoimmune or proinflammatory diseases in 22q11.2DS.
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Dynamics of virus-specific T cell immunity in pediatric liver transplant recipients.
Arasaratnam, RJ, Tzannou, I, Gray, T, Aguayo-Hiraldo, PI, Kuvalekar, M, Naik, S, Gaikwad, A, Liu, H, Miloh, T, Vera, JF, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018;(9):2238-2249
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Abstract
Immunosuppression following solid organ transplantation (SOT) has a deleterious effect on cellular immunity leading to frequent and prolonged viral infections. To better understand the relationship between posttransplant immunosuppression and circulating virus-specific T cells, we prospectively monitored the frequency and function of T cells directed to a range of latent (CMV, EBV, HHV6, BK) and lytic (AdV) viruses in 16 children undergoing liver transplantation for up to 1 year posttransplant. Following transplant, there was an immediate decline in circulating virus-specific T cells, which recovered posttransplant, coincident with the introduction and subsequent routine tapering of immunosuppression. Furthermore, 12 of 14 infections/reactivations that occurred posttransplant were successfully controlled with immunosuppression reduction (and/or antiviral use) and in all cases we detected a temporal increase in the circulating frequency of virus-specific T cells directed against the infecting virus, which was absent in 2 cases where infections remained uncontrolled by the end of follow-up. Our study illustrates the dynamic changes in virus-specific T cells that occur in children following liver transplantation, driven both by active viral replication and modulation of immunosuppression.
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A pilot study of peripheral blood BDCA-1 (CD1c) positive dendritic cells pulsed with NY-ESO-1 ISCOMATRIX™ adjuvant.
Davis, ID, Quirk, J, Morris, L, Seddon, L, Tai, TY, Whitty, G, Cavicchiolo, T, Ebert, L, Jackson, H, Browning, J, et al
Immunotherapy. 2017;(3):249-259
Abstract
AIM: Pilot clinical trial of NY-ESO-1 (ESO) protein in ISCOMATRIX™ adjuvant pulsed onto peripheral blood dendritic cells (PBDC), to ascertain feasibility, evaluate toxicity and assess induction of ESO-specific immune responses. PATIENTS & METHODS Eligible participants had resected cancers expressing ESO or LAGE-1 and were at high risk of relapse. PBDC were produced using CliniMACS®plus, with initial depletion of CD1c+ B cells followed by positive selection of CD1c+ PBDC. Patients received three intradermal vaccinations of ESO/IMX-pulsed PBDC at 4-week intervals. RESULTS The process was feasible and safe. No vaccine-induced immune responses were detected. Assays of immunomodulatory cells did not correlate with outcomes. One patient had a long lasting complete remission. CONCLUSION This method was feasible and safe but was minimally immunogenic.
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The Effect of Treatment of Denture-related Stomatitis on Peripheral T Cells and Monocytes.
Maciąg, J, Mikołajczyk, T, Matusik, P, Nowakowski, D, Robertson, D, Maciąg, A, Osmenda, G, Cześnikiewicz-Guzik, M
Oral health & preventive dentistry. 2017;(3):259-268
Abstract
PURPOSE Systemic immune activation has been recently linked to chronic inflammatory disorders of the oral cavity, particularly to periodontitis. The purpose of this study was to determine whether treatment of a fungus-induced oral inflammation, namely denture-related stomatitis (DRS), can affect the activation of the systemic immune response. MATERIALS AND METHODS Peripheral blood from patients with denture-related stomatitis caused by Candida albicans infection (n = 15) was collected at three time points: before treatment with nystatin, at the end of therapy and 2 months after finishing therapy. Activation of T cells and monocytes was assessed by flow cytometry. RESULTS The percentages of peripheral lymphocytes, T cells and their subpopulations, as well as monocytes were similar before, immediately following and two months after nystatin treatment. Cells expressing early activation marker CD69 and RANTES C-C chemokine receptor type 5 significantly increased immediately after treatment and returned to baseline levels after two months. Th17 cells, which have been implicated in the pathogenesis of DRS, remained unchanged. Central memory CD4+ subset and intermediate subset of monocytes were lower after therapy and this effect was sustained for two months. CONCLUSION Treatment of denture-related stomatitis does not seem to affect the general state of the cellular components of the immune system. The results suggest a potential proinflammatory effect of the antifungal agent, nystatin. Although transient and not intense, this effect might be of particular clinical importance, because of relationships between inflammation and certain diseases. Further studies are required to clarify this aspect.
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Immune Response of Healthy Adults to the Ingested Probiotic Lactobacillus casei Shirota.
Harbige, LS, Pinto, E, Allgrove, J, Thomas, LV
Scandinavian journal of immunology. 2016;(6):353-364
Abstract
Daily ingestion of a probiotic drink containing Lactobacillus casei Shirota (LcS; 1.3 × 1010 live cells) by healthy adults for (1) 4-week LcS, (2) 6-week discontinuation of LcS and (3) a final 4 weeks of LcS was investigated. There was a significant increase in expression of the T cell activation marker CD3+ CD69+ in ex vivo unstimulated blood cells at weeks 10 and 14, and there was a significant increase in the NK cell marker CD3+ CD16/56+ in ex vivo unstimulated blood cells at weeks 4, 10 and 14. Expression of the NK cell activation marker CD16/56+ CD69+ in ex vivo unstimulated blood cells was 62% higher at week 10 and 74% higher at week 14. Intracellular staining of IL-4 in ex vivo unstimulated and PMA-/ionomycin-stimulated CD3+ β7+ integrin blood cells was significantly lower at weeks 10 and 14. Intracellular staining of IL-12 in ex vivo unstimulated and LPS-stimulated CD14+ blood cells was significantly lower at weeks 4, 10 and 14. Intracellular staining of TNF-α in LPS-stimulated CD14+ blood cells was significantly lower at weeks 4, 10 and 14. Mucosal salivary IFN-γ, IgA1 and IgA2 concentrations were significantly higher at week 14, but LcS did not affect systemic circulating influenza A-specific IgA or IgG and tetanus-specific IgG antibody levels. In addition to the decrease in CD3+ β7+ integrin cell IL-4 and a reduced CD14+ cell pro-inflammatory cytokine profile, at week 14 increased expression of activation markers on circulating T cells and NK cells and higher mucosal salivary IgA1 and IgA2 concentration indicated a secondary boosting effect of LcS.