246 results on '"Kupper TS"'
Search Results
2. Skin CD4+ memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation
- Author
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Collins, N, Jiang, X, Zaid, A, Macleod, BL, Li, J, Park, CO, Haque, A, Bedoui, S, Heath, WR, Mueller, SN, Kupper, TS, Gebhardt, T, Carbone, FR, Collins, N, Jiang, X, Zaid, A, Macleod, BL, Li, J, Park, CO, Haque, A, Bedoui, S, Heath, WR, Mueller, SN, Kupper, TS, Gebhardt, T, and Carbone, FR
- Abstract
Although memory T cells within barrier tissues can persist as permanent residents, at least some exchange with blood. The extent to which this occurs is unclear. Here we show that memory CD4(+) T cells in mouse skin are in equilibrium with the circulation at steady state. These cells are dispersed throughout the inter-follicular regions of the dermis and form clusters with antigen presenting cells around hair follicles. After infection or administration of a contact sensitizing agent, there is a sustained increase in skin CD4(+) T-cell content, which is confined to the clusters, with a concomitant CCL5-dependent increase in CD4(+) T-cell recruitment. Skin CCL5 is derived from CD11b(+) cells and CD8(+) T cells, with the elimination of the latter decreasing CD4(+) T-cell numbers. These results reveal a complex pattern of tissue-retention and equilibration for CD4(+) memory T cells in skin, which is altered by infection and inflammation history.
- Published
- 2016
3. Oral epithelial overexpression of IL-1alpha causes periodontal disease.
- Author
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Dayan S, Stashenko P, Niederman R, Kupper TS, Dayan, S, Stashenko, P, Niederman, R, and Kupper, T S
- Abstract
Periodontal disease is a bacterial infection that results in inflammatory destruction of tissues that support the teeth, including connective tissue and bone. In this study, we report that transgenic mice that overexpress the 17-kDa form of IL-1alpha in the basal layer of oral mucosal epithelium develop a syndrome that possesses all of the cardinal features of periodontal disease, including epithelial proliferation and apical migration, loss of attachment, and destruction of cementum and alveolar bone. In this model, bacterial colonization and infection were not required, since levels of periodontal bacteria were equivalent in transgenic and wild-type mice, and continuous treatment with antibiotics from birth did not ameliorate the disease. Our findings therefore indicate that elevated levels of IL-1alpha in the oral micro-environment can mediate all of the clinical features of periodontal disease. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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4. IL-32 supports the survival of malignant T cells in cutaneous T cell lymphoma
- Author
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Yu, KK, primary, Smith, NP, additional, Essien, SV, additional, Teague, JE, additional, Vieyra-Garcia, P, additional, Gehad, A, additional, Zhan, Q, additional, Crouch, JD, additional, Gerard, N, additional, Larocca, C, additional, Wolf, P, additional, LeBoeuf, NR, additional, Tawa, M, additional, Kupper, TS, additional, Villani, A, additional, and Clark, RA, additional
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5. Etanercept for Crohn's disease.
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Travers SB and Kupper TS
- Published
- 2004
6. BioIns-O-15 - CCR8 is a new therapeutic target in cutaneous T-cell lymphomas.
- Author
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de Masson, A, Bensussan, A, Dobos, G, Moins-Teisserenc, H, Eustaquio, T, Battistella, M, Ortonne, N, Ram-Wolff, C, Bouaziz, JD, Marie-Cardine, A, Mourah, S, Bagot, M, Kupper, TS, Clark, RA, and Giustiniani, J
- Subjects
- *
CELL receptors , *CONFERENCES & conventions , *CUTANEOUS T-cell lymphoma - Published
- 2022
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7. Integrative epidemiology and immuno-transcriptomics uncover a risk and potential mechanism for cutaneous lymphoma unmasking or progression with dupilumab therapy.
- Author
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Cabrera-Perez JS, Carey VJ, Odejide OO, Singh S, Kupper TS, Pillai SS, Weiss ST, and Akenroye A
- Abstract
Background: There have been multiple reports of the anti-IL4Rα agent, dupilumab, as associated with the onset and/or progression of cutaneous T-cell lymphoma (CTCL)., Objective: We sought to evaluate safety signals associated with dupilumab, with a focus on CTCL, and to evaluate possible underlying mechanism(s) for the potential association., Methods: First, we used the FDA pharmacovigilance database, FAERS, to evaluate if dupilumab was associated with CTCL including both positive controls (conjunctivitis, eosinophilia, and arthralgia) and exposure controls (other medications with similar indications including JAK-inhibitors and the anti-IL13, tralokinumab,) to reduce and evaluate confounding bias. Thereafter, we used publicly available bulk and single cell-RNA seq datasets to probe possible underlying mechanisms through which dupilumab might be associated with CTCL., Results: Between January 2019 and Q2 of 2023, there were 181,575 unique reports of dupilumab related adverse events (AE) in FAERS with 606 of these being for a neoplasm. Dupilumab had 30.0 times the proportional reporting ratio (PRR) (95% CI: 25.0 - 35.9) for CTCL compared to all other medications in FAERS. The risk was highest in males aged 45-65. The PRR for conjunctivitis, eosinophilia, and arthralgia, known side effects of dupilumab, were 35.6 (34.4 - 36.8), 2.15 (2.00 - 2.31), and 2.14 (2.07 - 2.18) respectively. Using the log-count normalized PRR (AE score) to account for PRR inflation when reports were small, the top safety signals included conjunctivitis (AEscore 8.3) and CTCL (AEscore 4.9). Bulk RNA sequencing data showed changes in IL4RA and IL13RA1 expression in CTCL and in epidermal layers of atopic dermatitis (AD) biopsies. Single-cell transcriptomic studies revealed that this change was similar in AD and CTCL, and that keratinocytes seemed to be the most divergent cell type with regards to IL4R and IL13RA1. An effect on keratinocyte specific gene expression was also independently observed in available bulk RNA sequencing data., Conclusion: These data suggest that dupilumab might be causing an unmasking or progression of CTCL via the same mechanism through which it improves atopic dermatitis: IL13 receptor blockade, which leads to increased IL13 in the local milieu, driving CTCL stimulation and progression. However, these associations need further evaluation given the inherent limitations of the FAERS database and our non-experimental approach., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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8. Primary cutaneous EBV+ extranodal NK/T-cell lymphoma of gamma/delta T-cell lineage in the posttransplantation setting.
- Author
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Williams JF, Lucas FM, Carrasco RD, Lovitch SB, Fisher DC, Kupper TS, and Sadigh S
- Subjects
- Humans, Aged, Male, Herpesvirus 4, Human isolation & purification, Cell Lineage, Lymphoma, T-Cell, Cutaneous pathology, Lymphoma, T-Cell, Cutaneous virology, Skin Neoplasms pathology, Skin Neoplasms virology, Epstein-Barr Virus Infections pathology, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections virology, Liver Transplantation adverse effects, Lymphoma, Extranodal NK-T-Cell pathology, Lymphoma, Extranodal NK-T-Cell virology
- Abstract
Posttransplantation primary cutaneous T-cell lymphomas (PT-CTCL) are a rare complication of sustained immunosuppression in the posttransplant setting. When present, PT-CTCLs are typically EBV- and exhibit features of mycosis fungoides/Sézary syndrome or CD30+ lymphoproliferative disorders. We present a case of a 75-year-old individual who developed skin lesions 30 years after liver transplantation. Pathologic evaluation of the skin biopsy revealed involvement by a clonal, EBV+ T-cell population of gamma/delta lineage with no evidence of systemic disease. Comprehensive genomic profiling was performed, confirming focal one-copy loss of 6q23.3, altogether consistent with the extremely rare and unusual diagnosis of primary cutaneous EBV+ extranodal NK/T-cell lymphoma of gamma/delta T-cell lineage in the posttransplantation setting., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2024
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9. Racial Disparities in Mycosis Fungoides/Sézary Syndrome-A Single-Center Observational Study of 292 Patients.
- Author
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Gandham AR, Geller S, Dusza SW, Kupper TS, and Myskowski PL
- Subjects
- Aged, Female, Humans, Male, Case-Control Studies, Medicare, Retrospective Studies, United States epidemiology, Lymphoma, T-Cell, Cutaneous pathology, Mycosis Fungoides diagnosis, Sezary Syndrome, Skin Neoplasms diagnosis
- Abstract
Background: Clinical presentation of Mycosis fungoides/Sézary syndrome (MF/SS) in Black and African American (AA) patients can be heterogeneous with poor survival reported in AA/black patients. In this study, we aim to characterize differences between AA/black and white patients with MF/SS., Patients and Methods: A retrospective single-center hospital-based case-control study including 292 MF/SS patients (146 AA/black matched with 146 white patients). We analyzed demographic, clinical and survival differences., Results: AA/black patients were diagnosed at an earlier age (9 years younger), were predominantly females, had higher rates of Medicaid/Medicare insurance and lower income compared to matched white patients (P <.001). Adjusting for age, sex, insurance type, and income bracket, AA/black patients had significantly worse overall survival (hazard ratio [HR] 2.88, 95%CI 1.21-6.85, P = .017). Association of clinical MF phenotype with survival showed that hypopigmentation was associated with survival in AA/black patients but not in white patients. Erythroderma and ulceration were associated with worse survival risk in AA/black patients., Conclusions: AA/black patients with MF/SS have a significant worse survival outcome compared to white patients. The association between clinical phenotypes and survival differed between these groups. Further studies are required to investigate whether race-specific pathogenesis or genetic factors may explain these differences., Competing Interests: Disclosure Geller has received speakers’ honoraria from Rafa and Takeda. All other authors have no conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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10. Phototherapy Restores Deficient Type I IFN Production and Enhances Antitumor Responses in Mycosis Fungoides.
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Yu Z, Vieyra-Garcia P, Benezeder T, Crouch JD, Kim IR, O'Malley JT, Devlin PM, Gehad A, Zhan Q, Gudjonsson JE, Sarkar MK, Kahlenberg JM, Gerard N, Teague JE, Kupper TS, LeBoeuf NR, Larocca C, Tawa M, Pomahac B, Talbot SG, Orgill DP, Wolf P, and Clark RA
- Subjects
- Humans, CD8-Positive T-Lymphocytes pathology, Phototherapy, Gene Expression, Skin Neoplasms therapy, Skin Neoplasms drug therapy, Mycosis Fungoides therapy, Mycosis Fungoides drug therapy, Furocoumarins therapeutic use
- Abstract
Transcriptional profiling demonstrated markedly reduced type I IFN gene expression in untreated mycosis fungoides (MF) skin lesions compared with that in healthy skin. Type I IFN expression in MF correlated with antigen-presenting cell-associated IRF5 before psoralen plus UVA therapy and epithelial ULBP2 after therapy, suggesting an enhancement of epithelial type I IFN. Immunostains confirmed reduced baseline type I IFN production in MF and increased levels after psoralen plus UVA treatment in responding patients. Effective tumor clearance was associated with increased type I IFN expression, enhanced recruitment of CD8
+ T cells into skin lesions, and expression of genes associated with antigen-specific T-cell activation. IFNk, a keratinocyte-derived inducer of type I IFNs, was increased by psoralen plus UVA therapy and expression correlated with upregulation of other type I IFNs. In vitro, deletion of keratinocyte IFNk decreased baseline and UVA-induced expression of type I IFN and IFN response genes. In summary, we find a baseline deficit in type I IFN production in MF that is restored by psoralen plus UVA therapy and correlates with enhanced antitumor responses. This may explain why MF generally develops in sun-protected skin and suggests that drugs that increase epithelial type I IFNs, including topical MEK and EGFR inhibitors, may be effective therapies for MF., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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11. Prevalence and implications of mogamulizumab-induced immune-related adverse events in mycosis fungoides/Sézary syndrome; a single-center experience.
- Author
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Jfri A, Virgen CA, Tawa M, Giobbie-Hurder A, Kupper TS, Fisher DC, LeBoeuf NR, and Larocca C
- Abstract
Competing Interests: Conflicts of interest T.S.K. is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers R01 AR065807 and T32 AR007098) and the National Institute of Allergy and Infectious Diseases (grant number R01 AI127654). He is a scientific advisor for Pellis Therapeutics. N.R.L. is a consultant and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback and Synox Therapeutics outside the submitted work. C.L. is supported by the National Cancer Institute (grant number R37 CA252312). She has served on a medical advisory board for Kyowa Kirin. The other authors declare no conflicts of interest with respect to the research, authorship and/or publication of this article.
- Published
- 2023
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12. Resident memory T cell development is associated with AP-1 transcription factor upregulation across anatomical niches.
- Author
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Smith NP, Yan Y, Pan Y, Williams JB, Manakongtreecheep K, Pant S, Zhao J, Tian T, Pan T, Stingley C, Wu K, Zhang J, Kley AL, Sorger PK, Villani AC, and Kupper TS
- Abstract
Tissue-resident memory T (T
RM ) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive TRM differentiation and priming for their recall effector function remains unclear. In this study, we leveraged both newly generated and publicly available single-cell RNA-sequencing (scRNAseq) data generated across 10 developmental time points to define features of CD8 TRM across both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture temporally-associated gene programs that increase their expression levels in T cell subsets transitioning from an effector to a memory T cell state. In addition to capturing tissue-specific gene programs, we defined a consensus TRM signature of 60 genes across skin and siIEL that can effectively distinguish TRM from circulating T cell populations, providing a more specific TRM signature than what was previously generated by comparing bulk TRM to naïve or non-tissue resident memory populations. This updated TRM signature included the AP-1 transcription factor family members Fos, Fosb and Fosl2 . Moreover, ATACseq analysis detected an enrichment of AP-1-specific motifs at open chromatin sites in mature TRM . CyCIF tissue imaging detected nuclear co-localization of AP-1 members Fosb and Junb in resting CD8 TRM >100 days post-infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in TRM biology and suggests a novel mechanism for rapid reactivation of resting TRM in tissue upon antigen encounter.- Published
- 2023
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13. Assessing the generation of tissue resident memory T cells by vaccines.
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Rotrosen E and Kupper TS
- Subjects
- Humans, Memory T Cells, SARS-CoV-2, Vaccination, Antibodies, Neutralizing, COVID-19, Vaccines
- Abstract
Vaccines have been a hugely successful public health intervention, virtually eliminating many once common diseases of childhood. However, they have had less success in controlling endemic pathogens including Mycobacterium tuberculosis, herpesviruses and HIV. A focus on vaccine-mediated generation of neutralizing antibodies, which has been a successful approach for some pathogens, has been complicated by the emergence of escape variants, which has been seen for pathogens such as influenza viruses and SARS-CoV-2, as well as for HIV-1. We discuss how vaccination strategies aimed at generating a broad and robust T cell response may offer superior protection against pathogens, particularly those that have been observed to mutate rapidly. In particular, we consider here how a focus on generating resident memory T cells may be uniquely effective for providing immunity to pathogens that typically infect (or become reactivated in) the skin, respiratory mucosa or other barrier tissues., (© 2023. Springer Nature Limited.)
- Published
- 2023
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14. Mogamulizumab-Associated Myositis With and Without Myasthenia Gravis and/or Myocarditis in Patients With T-Cell Lymphoma.
- Author
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Virgen CA, Sparks JA, Nohria A, O'Hare MJ, Goyal A, Said JT, Tawa M, LeBoeuf NR, Kupper TS, Fisher DC, and Larocca C
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- Humans, Retrospective Studies, Myocarditis chemically induced, Lymphoma, T-Cell, Lymphoma, T-Cell, Peripheral drug therapy, Myositis chemically induced, Myasthenia Gravis chemically induced, Myasthenia Gravis drug therapy
- Abstract
Mogamulizumab is being increasingly prescribed for the treatment of T-cell lymphomas (MF/SS/ATLL). We conducted a retrospective cohort study to identify muscular immune-related adverse events (irAEs) associated with mogamulizumab in patients with T-cell lymphoma followed at Dana-Farber Cancer Institute from January 2015 to June 2022. We identified 5 cases of mogamulizumab-associated myositis and/or myocarditis (MAM/Mc), 2 additionally affected by myasthenia gravis, among 42 patients with T-cell lymphoma. Three cases experienced -mogamulizumab-associated rash (MAR) prior to developing MAM/Mc. The incidence (n = 5/42, 11.9%) of muscular mogamulizumab-associated irAEs may be higher than has been previously reported in clinical trials and may be of late onset (a median of 5 cycles and as late as 100 days from the last infusion). We highlight the utility of IVIG, together with systemic corticosteroids, for the treatment of these potentially fatal side effects associated with mogamulizumab therapy., (© The Author(s) 2023. Published by Oxford University Press.)
- Published
- 2023
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15. Clinical features and treatment outcomes for primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder: a retrospective cohort study from the Dana-Farber Cancer Institute and updated literature review.
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Plumptre IR, Said JT, Sun T, Larocca C, Virgen CA, Kupper TS, Fisher DC, Devlin PM, Elco CP, Song JS, and LeBoeuf NR
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- Humans, Middle Aged, Retrospective Studies, CD4-Positive T-Lymphocytes pathology, Treatment Outcome, Lymphoma, T-Cell, Cutaneous pathology, Skin Neoplasms diagnosis, Skin Neoplasms therapy, Skin Neoplasms pathology, Skin Diseases pathology, Lymphoproliferative Disorders therapy
- Abstract
Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-TCLPD) was reclassified in 2016 as a rare benign entity with an excellent prognosis, yet its clinical features and best treatments remain poorly defined. We collected clinical data, treatments, and treatment-responses from our institution's patients with PCSM-TCLPD through September 2018 and an identical PubMed review through June 2021. Among 36 cases (median-age 54 years; 58.3% head/neck), diagnostic biopsy resulted in sustained complete remission (CR) in 13/33 punch/shave biopsies and 3/3 excisional biopsies. The remaining 20 patients further required topical corticosteroids ( n = 5); intralesional corticosteroids ( n = 1); surgical-excision ( n = 5); electron-beam-radiation ( n = 6); or brachytherapy ( n = 3). All patients ultimately achieved CR, excluding one patient continuing treatment at end-of-study. 57/59 (96.6%) of institutional and literature-reported radiation-treated patients experienced CR. No institutional cases progressed beyond skin; 5/209 (2.4%) literature-reported cases progressed to systemic/extracutaneous involvement, all pre-reclassification. PCSM-TCLPD responds well to local-directed therapy including radiation, and only rarely if ever progresses.
- Published
- 2022
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16. Inhibition of Melanoma Cell-Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis.
- Author
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Schatton T, Itoh Y, Martins C, Rasbach E, Singh P, Silva M, Mucciarone K, Heppt MV, Geddes-Sweeney J, Stewart K, Brandenburg A, Liang J, Dimitroff CJ, Mihm MC, Landsberg J, Schlapbach C, Lian CG, Murphy GF, Kupper TS, Ramsey MR, and Barthel SR
- Subjects
- Animals, Carcinogenesis, Cell Transformation, Neoplastic, Humans, Immunoglobulins, Mice, Mice, Inbred C57BL, Mucins, Hepatitis A Virus Cellular Receptor 2, Melanoma pathology
- Abstract
T-cell immunoglobulin mucin family member 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify an additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Ab-mediated Tim-3 blockade inhibited growth of immunogenic murine melanomas in T-cell-competent hosts, consistent with established antitumor effects of T-cell-Tim-3 inhibition. In contrast, Tim-3 Ab administration stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream MAPK signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and enhanced desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition., Significance: Tim-3 is a growth-suppressive receptor intrinsic to melanoma cells, the blockade of which promotes MAPK-dependent tumorigenesis and thus counteracts antitumor activity of T-cell-directed Tim-3 inhibition., (©2022 American Association for Cancer Research.)
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- 2022
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17. Tumor Clone Frequency Calculation Using High-Throughput Sequencing of the TCRβ Gene in Patients with Folliculotropic Mycosis Fungoides.
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van Santen S, Zoutman WH, de Masson A, Quint KD, Willemze R, Gerard N, Teague JE, Kupper TS, Clark RA, Tensen CP, and Vermeer MH
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- Clone Cells pathology, High-Throughput Nucleotide Sequencing, Humans, Mycosis Fungoides genetics, Mycosis Fungoides pathology, Skin Neoplasms genetics, Skin Neoplasms pathology
- Published
- 2022
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18. Author Correction: Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis.
- Author
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Deng W, Bai Y, Deng F, Pan Y, Mei S, Zheng Z, Min R, Wu Z, Li W, Miao R, Zhang Z, Kupper TS, Lieberman J, and Liu X
- Published
- 2022
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19. IL-32 Supports the Survival of Malignant T Cells in Cutaneous T-cell Lymphoma.
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Yu KK, Smith NP, Essien SV, Teague JE, Vieyra-Garcia P, Gehad A, Zhan Q, Crouch JD, Gerard N, Larocca C, Wolf P, LeBoeuf NR, Tawa M, Kupper TS, Villani AC, and Clark RA
- Subjects
- Humans, T-Lymphocytes pathology, Lymphoma, T-Cell, Cutaneous pathology, Skin Neoplasms pathology
- Published
- 2022
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20. Topical tofacitinib for the management of lymphocytic-variant hypereosinophilic syndrome with cutaneous involvement.
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Said JT, Elman SA, Tawa M, Fisher DC, Merola JF, and Kupper TS
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- Humans, Piperidines, Pyrimidines, Hypereosinophilic Syndrome diagnosis, Hypereosinophilic Syndrome drug therapy
- Published
- 2022
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21. CCR8 is a new therapeutic target in cutaneous T-cell lymphomas.
- Author
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Giustiniani J, Dobos G, Moins-Teisserenc H, Eustaquio T, Battistella M, Ortonne N, Ram-Wolff C, Bouaziz JD, Marie-Cardine A, Mourah S, Bagot M, Kupper TS, Clark RA, Bensussan A, and de Masson A
- Subjects
- Humans, Receptors, CCR8, Lymphoma, T-Cell, Cutaneous drug therapy, Skin Neoplasms drug therapy
- Published
- 2022
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22. Central memory T cells are the most effective precursors of resident memory T cells in human skin.
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Matos TR, Gehad A, Teague JE, Dyring-Andersen B, Benezeder T, Dowlatshahi M, Crouch J, Watanabe Y, O'Malley JT, Kupper TS, Yang C, Watanabe R, and Clark RA
- Subjects
- Animals, Humans, Memory T Cells, Mice, Skin, T-Lymphocyte Subsets, CD8-Positive T-Lymphocytes, Immunologic Memory
- Abstract
The circulating precursor cells that give rise to human resident memory T cells (T
RM ) are poorly characterized. We used an in vitro differentiation system and human skin-grafted mice to study TRM generation from circulating human memory T cell subsets. In vitro TRM differentiation was associated with functional changes, including enhanced IL-17A production and FOXP3 expression in CD4+ T cells and granzyme B production in CD8+ T cells, changes that mirrored the phenotype of T cells in healthy human skin. Effector memory T cells (TEM ) had the highest conversion rate to TRM in vitro and in vivo, but central memory T cells (TCM ) persisted longer in the circulation, entered the skin in larger numbers, and generated increased numbers of TRM . In summary, TCM are highly efficient precursors of human skin TRM , a feature that may underlie their known association with effective long-term immunity.- Published
- 2022
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23. Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis.
- Author
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Deng W, Bai Y, Deng F, Pan Y, Mei S, Zheng Z, Min R, Wu Z, Li W, Miao R, Zhang Z, Kupper TS, Lieberman J, and Liu X
- Subjects
- Animals, Bacterial Proteins metabolism, Mice, Streptococcus pyogenes, Exotoxins genetics, Exotoxins metabolism, Pyroptosis
- Abstract
Gasdermins, a family of five pore-forming proteins (GSDMA-GSDME) in humans expressed predominantly in the skin, mucosa and immune sentinel cells, are key executioners of inflammatory cell death (pyroptosis), which recruits immune cells to infection sites and promotes protective immunity
1,2 . Pore formation is triggered by gasdermin cleavage1,2 . Although the proteases that activate GSDMB, C, D and E have been identified, how GSDMA-the dominant gasdermin in the skin-is activated, remains unknown. Streptococcus pyogenes, also known as group A Streptococcus (GAS), is a major skin pathogen that causes substantial morbidity and mortality worldwide3 . Here we show that the GAS cysteine protease SpeB virulence factor triggers keratinocyte pyroptosis by cleaving GSDMA after Gln246, unleashing an active N-terminal fragment that triggers pyroptosis. Gsdma1 genetic deficiency blunts mouse immune responses to GAS, resulting in uncontrolled bacterial dissemination and death. GSDMA acts as both a sensor and substrate of GAS SpeB and as an effector to trigger pyroptosis, adding a simple one-molecule mechanism for host recognition and control of virulence of a dangerous microbial pathogen., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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24. Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis.
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Sun Z, Kim JH, Kim SH, Kim HR, Zhang K, Pan Y, Ko MK, Kim BM, Chu H, Lee HR, Kim HL, Kim JH, Fu X, Hyun YM, Yun KN, Kim JY, Lee DW, Song SY, Lin CP, Clark RA, Lee KH, Kupper TS, and Park CO
- Subjects
- Animals, Chemokine CXCL12 genetics, Dermatitis, Atopic genetics, Female, Gene Expression Profiling, Humans, Mice, Proteomics, Receptors, CXCR4 genetics, Chemokine CXCL12 immunology, Dermatitis, Atopic immunology, Natural Killer T-Cells immunology, Receptors, CXCR4 immunology, Skin immunology
- Abstract
Background: Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD)., Objective: We aimed to investigate the role of NKT cells in AD development, especially in skin., Methods: Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy-controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4
+ NKT cells was further evaluated in models of mice with AD by using CXCR4-conditionally deficient or CXCL12 transgenic mice., Results: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+ . Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4+ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD., Conclusions: CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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25. Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge.
- Author
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Pan Y, Liu L, Tian T, Zhao J, Park CO, Lofftus SY, Stingley CA, Yan Y, Mei S, Liu X, and Kupper TS
- Abstract
Modified Vaccinia Ankara (MVA) was recently approved as a smallpox vaccine. Variola is transmitted by respiratory droplets and MVA immunization by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with vaccinia virus (VACV) than any other route of delivery, and at lower doses. Comparisons of s.s. with intradermal, subcutaneous, or intramuscular routes showed that MVA
OVA s.s.-generated T cells were both more abundant and transcriptionally unique. MVAOVA s.s. produced greater numbers of lung Ova-specific CD8+ TRM and was superior in protecting mice against lethal VACVOVA respiratory challenge. Nearly as many lung TRM were generated with MVAOVA s.s. immunization compared to intra-tracheal immunization with MVAOVA and both routes vaccination protected mice against lethal pulmonary challenge with VACVOVA . Strikingly, MVAOVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via intra-tracheal immunization. Overall, our data suggest that heterologous MVA vectors immunized via s.s. are uniquely well-suited as vaccine vectors for respiratory pathogens, which may be relevant to COVID-19. In addition, MVA delivered via s.s. could represent a more effective dose-sparing smallpox vaccine.- Published
- 2021
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26. Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host disease.
- Author
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Divito SJ, Aasebø AT, Matos TR, Hsieh PC, Collin M, Elco CP, O'Malley JT, Bækkevold ES, Reims H, Gedde-Dahl T, Hagerstrom M, Hilaire J, Lian JW, Milford EL, Pinkus GS, Ho VT, Soiffer RJ, Kim HT, Mihm MC, Ritz J, Guleria I, Cutler CS, Clark RA, Jahnsen FL, and Kupper TS
- Subjects
- Adult, Allografts, Animals, Antigen-Presenting Cells immunology, Antigen-Presenting Cells pathology, Female, Graft vs Host Disease pathology, Humans, Interferon-gamma immunology, Interleukin-17 immunology, Male, Mice, Mice, Inbred NOD, Mice, SCID, Prospective Studies, Skin pathology, Skin Diseases pathology, T-Lymphocytes pathology, Graft vs Host Disease immunology, Hematopoietic Stem Cell Transplantation, Skin immunology, Skin Diseases immunology, T-Lymphocytes immunology
- Abstract
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis, but a contribution from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host derived. We next examined patient skin, colon, and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied, yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67+) and producing the proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD.
- Published
- 2020
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27. FABP5 as a possible biomarker in atopic march: FABP5-induced Th17 polarization, both in mouse model and human samples.
- Author
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Lee J, Kim B, Chu H, Zhang K, Kim H, Kim JH, Kim SH, Pan Y, Noh JY, Sun Z, Lee J, Jeong KY, Park KH, Park JW, Kupper TS, Park CO, and Lee KH
- Subjects
- Adult, Animals, Antigens, Dermatophagoides adverse effects, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, Case-Control Studies, Cell Polarity, Cells, Cultured, Coculture Techniques, Dendritic Cells cytology, Dendritic Cells drug effects, Dendritic Cells immunology, Dermatitis, Atopic chemically induced, Dermatitis, Atopic genetics, Disease Models, Animal, Disease Progression, Female, Humans, Male, Mice, Middle Aged, Oligonucleotide Array Sequence Analysis, Up-Regulation, Young Adult, Antigens, Dermatophagoides immunology, Dermatitis, Atopic immunology, Fatty Acid-Binding Proteins genetics, Genetic Markers, Th17 Cells metabolism
- Abstract
Background: While the incidence of patients with atopic dermatitis (AD) with atopic march (AM) showing respiratory allergy is steadily rising, the pathomechanism is still unknown. There are currently no biomarkers to predict progression of AM., Methods: To explore the mechanism of AM, patients with AD and AM and healthy controls were recruited and RNA microarray, flow cytometry, quantitative real-time polymerase chain reaction, and immunofluorescence staining were performed. We also co-cultured dendritic cells and CD4
+ T cells with various Dermatophagoides farinae allergen fractions. Cytokine levels were evaluated using enzyme-linked immunosorbent assay., Findings: Both fatty-acid-binding protein 5 (FABP5) and Th17-related genes were more highly expressed in AM. FABP5 knockdown significantly decreased Th17-inducing cytokines in keratinocytes and IL-17A in T cells from AM patients. Further confirmation was obtained using an AM mice model compared to mice without AM. Der f 1, a major D. farinae allergen, increased FABP5 and IL-17A expression in T cells from AM patients. Higher serum FABP5 levels from AM patients were positively correlated with serum IL-17A levels., Interpretation: FABP5 expression, possibly enhanced by higher epicutaneous and respiratory sensitization to Der f 1, may directly promote Th17 responses in AD patients with AM. Thus, AM progression can be explained by Th17 reaction induced by FABP5. FABP5 was identified as a potential biomarker in AM., Funding: This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT; No. NRF-2017R1A2B4009568), grants of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, and the Republic of Korea (HI13C0010, HI14C1324, HI14C1799)., Competing Interests: Declaration of Competing Interest The authors state no conflict of interest. Author Contributions This study was designed and coordinated by Kwang Hoon Lee and Chang Ook park, as the principal investigators who provided conceptual and technical guidance for all aspects of this research project and contributed writing the article. Jungsoo Lee contributed literature search, study design, human data collection, mice experiment, analysis, interpretation and drafting the article. Bomi Kim performed experiments including BODIPY and contributed figures, tables, writing methods and statistical analysis. Howard Chu contributed literature search, data collection, analysis, interpretation and writing the article. KeLun Zhang performed experiments, data collection and data analysis. Hyeran Kim performed ELISA using house dust mite(HDM) fractions and data analysis and Ji Hye Kim contributed mice experiment and data analysis. Seo Hyeong Kim contributed IF-staining and data analysis. Ji Yeon Noh performed literature search, whole gene transcriptome analysis and provided experimental guidance. ZhengWang Sun, Jongsun Lee, Kyung Yong Jeong, Kyung Hee Park, Jung-Won Park contributed methacholine test and AHR analysis using mice model and provided of HDM extracts. Youdong Pan and Thomas S. Kupper provided conceptual guidance for FABP experiments., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2020
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28. IL1α Antagonizes IL1β and Promotes Adaptive Immune Rejection of Malignant Tumors.
- Author
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Tian T, Lofftus S, Pan Y, Stingley CA, King SL, Zhao J, Pan TY, Lock R, Marglous JW, Liu K, Widlund HR, Fuhlbrigge RC, Cichowski K, and Kupper TS
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Interleukin-1alpha metabolism, Interleukin-1beta metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Neoplasms immunology, Tumor Microenvironment, Adaptive Immunity, Antibodies, Monoclonal pharmacology, CD8-Positive T-Lymphocytes immunology, Interleukin-1alpha immunology, Interleukin-1beta immunology, Neoplasms therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
We assessed the contribution of IL1 signaling molecules to malignant tumor growth using IL1β
-/- , IL1α-/- , and IL1R1-/- mice. Tumors grew progressively in IL1R-/- and IL1α-/- mice but were often absent in IL1β-/- mice. This was observed whether tumors were implanted intradermally or injected intravenously and was true across multiple distinct tumor lineages. Antibodies to IL1β prevented tumor growth in wild-type (WT) mice but not in IL1R1-/- or IL1α-/- mice. Antibodies to IL1α promoted tumor growth in IL1β-/- mice and reversed the tumor-suppressive effect of anti-IL1β in WT mice. Depletion of CD8+ T cells and blockade of lymphocyte mobilization abrogated the IL1β-/- tumor suppressive effect, as did crossing IL1β-/- mice to SCID or Rag1-/- mice. Finally, blockade of IL1β synergized with blockade of PD-1 to inhibit tumor growth in WT mice. These results suggest that IL1β promotes tumor growth, whereas IL1α inhibits tumor growth by enhancing T-cell-mediated antitumor immunity., (©2020 American Association for Cancer Research.)- Published
- 2020
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29. Publisher Correction: Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence.
- Author
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Pruessmann W, Rytlewski J, Wilmott J, Mihm MC Jr, Attrill GH, Dyring-Andersen B, Fields P, Zhan Q, Colebatch AJ, Ferguson PM, Thompson JF, Kallenbach K, Yusko E, Clark RA, Robins H, Scolyer RA, and Kupper TS
- Published
- 2020
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30. Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence.
- Author
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Pruessmann W, Rytlewski J, Wilmott J, Mihm MC Jr, Attrill GH, Dyring-Andersen B, Fields P, Zhan Q, Colebatch AJ, Ferguson PM, Thompson JF, Kallenbach K, Yusko E, Clark RA, Robins H, Scolyer RA, and Kupper TS
- Subjects
- Humans, T-Lymphocytes pathology, Melanoma genetics
- Abstract
Primary melanomas >1 mm thickness are potentially curable by resection, but can recur metastatically. We assessed the prognostic value of T cell fraction (TCFr) and repertoire T cell clonality, measured by high-throughput-sequencing of the T cell receptor beta chain (TRB) in T2-T4 primary melanomas (n=199). TCFr accurately predicted progression-free survival (PFS) and was independent of thickness, ulceration, mitotic rate, or age. TCFr was second only to tumor thickness in its predictive value, using a gradient boosted model. For accurate PFS prediction, adding TCFr to tumor thickness was superior to adding any other histopathological variable. Furthermore, a TCFr >20% was protective regardless of tumor ulceration status, mitotic rate or presence of nodal disease. TCFr is a quantitative molecular assessment that predicts metastatic recurrence in primary melanoma patients whose disease has been resected surgically. This study suggests that a successful T cell-mediated antitumor response can be present in primary melanomas.
- Published
- 2020
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31. Radiotherapy Eradicates Malignant T Cells and Is Associated with Improved Survival in Early-Stage Mycosis Fungoides.
- Author
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O'Malley JT, de Masson A, Lowry EL, Giobbie-Hurder A, LeBoeuf NR, Larocca C, Gehad A, Seger E, Teague JE, Fisher DC, Kupper TS, Devlin PM, and Clark RA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Lymphoma, T-Cell, Cutaneous pathology, Lymphoma, T-Cell, Cutaneous radiotherapy, Male, Middle Aged, Mycosis Fungoides pathology, Mycosis Fungoides radiotherapy, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local radiotherapy, Prospective Studies, Receptors, Antigen, T-Cell, gamma-delta genetics, Retrospective Studies, Skin Neoplasms pathology, Skin Neoplasms radiotherapy, Survival Rate, Treatment Outcome, Young Adult, Biomarkers, Tumor analysis, Lymphoma, T-Cell, Cutaneous mortality, Mycosis Fungoides mortality, Neoplasm Recurrence, Local mortality, Radiotherapy mortality, Skin Neoplasms mortality, T-Lymphocyte Subsets radiation effects
- Abstract
Purpose: Mycosis fungoides is the most common subtype of cutaneous T-cell lymphoma. Skin-directed treatments often improve but do not cure mycosis fungoides skin lesions. The purpose of this study was to (i) assess whether remission was associated with malignant T-cell clone depletion at treated sites using either low-dose radiotherapy (LDRT, 8 Gy) or topical steroids and (ii) assess whether a clone-ablative therapy, like LDRT, is associated with overall survival in patients with high-risk early-stage CTCL., Experimental Design: Pre- and posttreatment biopsies from 20 lesional skin samples of 18 patients with mycosis fungoides who received either 8 Gy LDRT ( n = 16) or topical steroids ( n = 4) underwent high-throughput T-cell receptor sequencing of the TCRB gene to quantify the malignant T-cell clone. For the retrospective chart review, overall survival of 47 high-risk early-stage patients was compared between patients who did or did not receive radiation., Results: LDRT eradicated the clone in 5 of 16 lesions and reduced it >90% in 11 of 16; there were no recurrences in these lesions. Patients treated with topical steroids appeared to clinically improve, but the malignant clone persisted. We found that the number of residual malignant T cells predicted lesion recurrence. A retrospective review showed that early-stage high-risk patients who received radiation as part of their treatment regimen had prolonged overall survival compared with patients who did not., Conclusions: These findings demonstrate that LDRT can eradicate malignant T cells in mycosis fungoides, provides robust disease control, and is associated with improved survival in high-risk early-stage patients., (©2019 American Association for Cancer Research.)
- Published
- 2020
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32. Resident Memory T Cells in the Tumor Microenvironment.
- Author
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Williams JB and Kupper TS
- Subjects
- CD8-Positive T-Lymphocytes, Humans, Lymphocytes, Tumor-Infiltrating, Neoplasms therapy, T-Lymphocytes immunology, Immunologic Memory, Neoplasms immunology, T-Lymphocytes cytology, Tumor Microenvironment immunology
- Abstract
Tissue-resident memory T (T
RM ) cells are strategically positioned within the epithelial layers of many tissues to provide enduring site-specific immunological memory. This unique T-cell lineage is endowed with the capacity to rapidly respond to tissue perturbations and has a well-documented role in eradicating pathogens upon reexposure. Emerging evidence has highlighted a key role for TRM cells in cancer immunity. Single-cell approaches have identified TRM cells among other CD8+ tumor-infiltrating lymphocyte (TIL) subsets, and their presence is a positive indicator of clinical outcome in cancer patients. Furthermore, recent preclinical studies have elegantly demonstrated that TRM cells are a critical component of the antitumor immune response. Given their unique functional abilities, TRM cells have emerged as a potential immunotherapeutic target. Here, we discuss TRM cells in the framework of the cancer-immunity cycle and in the context of the T cell- and non-T cell-inflamed tumor microenvironments (TME). We highlight how their core features make TRM cells uniquely suited to function within the metabolically demanding TME. Finally, we consider potential therapeutic avenues that target TRM cells to augment the antitumor immune response.- Published
- 2020
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33. Mogamulizumab Forecast: Clearer Patients, with a Slight Chance of Immune Mayhem.
- Author
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Larocca C, Kupper TS, and LeBoeuf NR
- Subjects
- Antibodies, Monoclonal, Humanized, Humans, Mycosis Fungoides, Sezary Syndrome, Skin Neoplasms
- Abstract
Mogamulizumab, approved by the FDA for relapsed or refractory mycosis fungoides and Sézary syndrome, improves progression-free survival compared with vorinostat in the largest trial to date in cutaneous T-cell lymphoma, with particular efficacy in leukemic disease, but carries a risk of immune-mediated toxicities with concomitant depletion of regulatory T cells. See related article by Kasamon et al., p. 7275 ., (©2019 American Association for Cancer Research.)
- Published
- 2019
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34. T cells and the skin: from protective immunity to inflammatory skin disorders.
- Author
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Ho AW and Kupper TS
- Subjects
- Animals, Humans, Immunologic Memory, Inflammation immunology, Skin immunology, Skin Diseases immunology, T-Lymphocytes immunology
- Abstract
Skin is our primary interface with the environment, and T cells are crucial for orchestrating host immune responses against pathogenic microorganisms at this site. Effective skin immune responses require the generation of antigen-specific effector T cells, which home to cutaneous sites of injury or infection. Long-lasting immunity against future immune challenges is mediated by memory T cells. Among the memory T cells found in skin are both recirculating cells that transit between skin and blood and tissue-resident memory T (T
RM ) cells, which remain in skin for long periods of time and mediate durable protective immunity. These TRM cells also appear to drive many inflammatory diseases of skin. Here, we consider how a better understanding of cutaneous T cell responses can aid in the development of effective new therapies for immune-mediated cutaneous diseases.- Published
- 2019
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35. Publisher Correction: Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling.
- Author
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Eaglesham JB, Pan Y, Kupper TS, and Kranzusch PJ
- Abstract
In this Letter, Supplementary Fig. 1 was missing. This error has been corrected online.
- Published
- 2019
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36. Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling.
- Author
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Eaglesham JB, Pan Y, Kupper TS, and Kranzusch PJ
- Subjects
- Animals, Baculoviridae enzymology, Butterflies enzymology, Cell Line, Conserved Sequence, Crystallography, X-Ray, DNA, Viral immunology, Female, Genes, Viral genetics, Humans, Immune Evasion, Immunity, Innate immunology, Mice, Mice, Inbred C57BL, Models, Molecular, Moths enzymology, Second Messenger Systems, Vaccinia virus genetics, Vaccinia virus growth & development, Vaccinia virus immunology, Virus Replication genetics, Deoxyribonucleases chemistry, Deoxyribonucleases metabolism, Membrane Proteins metabolism, Nucleotides, Cyclic metabolism, Nucleotidyltransferases metabolism, Signal Transduction immunology, Vaccinia virus enzymology
- Abstract
Cytosolic DNA triggers innate immune responses through the activation of cyclic GMP-AMP synthase (cGAS) and production of the cyclic dinucleotide second messenger 2',3'-cyclic GMP-AMP (cGAMP)
1-4 . 2',3'-cGAMP is a potent inducer of immune signalling; however, no intracellular nucleases are known to cleave 2',3'-cGAMP and prevent the activation of the receptor stimulator of interferon genes (STING)5-7 . Here we develop a biochemical screen to analyse 24 mammalian viruses, and identify poxvirus immune nucleases (poxins) as a family of 2',3'-cGAMP-degrading enzymes. Poxins cleave 2',3'-cGAMP to restrict STING-dependent signalling and deletion of the poxin gene (B2R) attenuates vaccinia virus replication in vivo. Crystal structures of vaccinia virus poxin in pre- and post-reactive states define the mechanism of selective 2',3'-cGAMP degradation through metal-independent cleavage of the 3'-5' bond, converting 2',3'-cGAMP into linear Gp[2'-5']Ap[3']. Poxins are conserved in mammalian poxviruses. In addition, we identify functional poxin homologues in the genomes of moths and butterflies and the baculoviruses that infect these insects. Baculovirus and insect host poxin homologues retain selective 2',3'-cGAMP degradation activity, suggesting an ancient role for poxins in cGAS-STING regulation. Our results define poxins as a family of 2',3'-cGAMP-specific nucleases and demonstrate a mechanism for how viruses evade innate immunity.- Published
- 2019
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37. T-cell trafficking plays an essential role in tumor immunity.
- Author
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Aires DJ, Yoshida M, Richardson SK, Bai M, Liu L, Moreno R, Lazar AJF, Wick JA, Rich BE, Murphy G, Blumberg RS, Fuhlbrigge RC, and Kupper TS
- Subjects
- Allografts, Animals, Cell Line, Tumor, Fucosyltransferases metabolism, Integrin beta Chains metabolism, Mice, Inbred BALB C, Mice, Knockout, Neoplasm Transplantation, Neoplasms immunology, T-Lymphocytes physiology
- Abstract
Distinct populations of effector memory T cells use different homing receptors to traffic to the skin and gut. Whether tissue-selective T cells are needed for early rejection of a neoplasm growing in these tissues remains an open question. We chose to study an allogeneic tumor model because growth of such a fully mismatched tumor would signify a profound immune deficit. We implanted allogeneic tumor cells in the skin or gut of mice deficient in either α(1,3) fucosyltransferases IV and VII, enzymes critical for generating E-selectin ligands on skin-homing T cells, or β7 integrin, a component of the α4β7 integrin ligand for the mucosal adressin MAdCAM. During the first 9 days after tumor implantation, FucTVII
-/- mice showed a profoundly impaired capacity to reject tumors growing in the skin, but readily rejected tumors implanted in the gut. Rejection of tumors in the skin was even more impaired in mice deficient in both FucTIV and FucTVII. This impairment was corrected by infusion of T cells from normal mice. By contrast, β7 integrin-/- mice showed profoundly impaired rejection of tumors in the gut, but no defect in the skin tumor rejection. These differences were unrelated to antigen recognition or effector function of T cells, since all strains of mice were capable of generating tumor-specific CTLs in vitro against the tumor cell line used in vivo. These results demonstrate that T-cell homing defects in vivo impair immune surveillance of peripheral epithelial tissues in a specific and selective fashion.- Published
- 2019
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38. Staged development of long-lived T-cell receptor αβ T H 17 resident memory T-cell population to Candida albicans after skin infection.
- Author
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Park CO, Fu X, Jiang X, Pan Y, Teague JE, Collins N, Tian T, O'Malley JT, Emerson RO, Kim JH, Jung Y, Watanabe R, Fuhlbrigge RC, Carbone FR, Gebhardt T, Clark RA, Lin CP, and Kupper TS
- Subjects
- Adaptive Immunity, Adult, Animals, Cell Differentiation, Cell Movement, Cells, Cultured, Disease Models, Animal, Humans, Immunocompetence, Immunologic Memory, Infant, Newborn, Interleukin-17 metabolism, Mice, Mice, Inbred C57BL, Receptors, Antigen, T-Cell, alpha-beta metabolism, Skin microbiology, Candida albicans physiology, Candidiasis immunology, Skin immunology, T-Lymphocyte Subsets physiology, Th17 Cells physiology
- Abstract
Background: Candida albicans is a dimorphic fungus to which human subjects are exposed early in life, and by adulthood, it is part of the mycobiome of skin and other tissues. Neonatal skin lacks resident memory T (T
RM ) cells, but in adults the C albicans skin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-free conditions are naive to C albicans and have been shown recently to have an immune system resembling that of neonatal human subjects., Objective: We studied the evolution of the adaptive cutaneous immune response to Candida species., Methods: We examined both human skin T cells and the de novo and memory immune responses in a mouse model of C albicans skin infection., Results: In mice the initial IL-17-producing cells after C albicans infection were dermal γδ T cells, but by day 7, αβ TH 17 effector T cells were predominant. By day 30, the majority of C albicans-reactive IL-17-producing T cells were CD4 TRM cells. Intravital microscopy showed that CD4 effector T cells were recruited to the site of primary infection and were highly motile 10 days after infection. Between 30 and 90 days after infection, these CD4 T cells became increasingly sessile, acquired expression of CD69 and CD103, and localized to the papillary dermis. These established TRM cells produced IL-17 on challenge, whereas motile migratory memory T cells did not. TRM cells rapidly clear an infectious challenge with C albicans more effectively than recirculating T cells, although both populations participate. We found that in normal human skin IL-17-producing CD4+ TRM cells that responded to C albicans in an MHC class II-restricted fashion could be identified readily., Conclusions: These studies demonstrate that C albicans infection of skin preferentially generates CD4+ IL-17-producing TRM cells, which mediate durable protective immunity., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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39. Metabolic Reprogramming and Longevity of Tissue-Resident Memory T Cells.
- Author
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Pan Y and Kupper TS
- Abstract
Tissue-resident memory T cells (T
RM ) persist in peripheral tissues for long periods of time in the absence of antigenic stimulation. Upon re-encounter with cognate antigen, TRM trigger an immediate immune response at the local tissue microenvironment and provide the first line of host defense. TRM have been reported to play significant roles in host antimicrobial infection, cancer immunotherapy, and pathogenesis of a number of human autoimmune diseases, such as psoriasis, vitiligo, and atopic dermatitis. TRM display a distinct gene transcriptome with unique gene expression profiles related to cellular metabolism that is different from naive T cells (TN ), central memory T cells (TCM ), and effector memory T cells (TEM ). Skin CD8+ TRM upregulate expression of genes associated with lipid uptake and metabolism and utilize mitochondria fatty acid β-oxidation to support their long-term survival (longevity) and function. In this review, we will summarize the recent progresses in the metabolic programming of TRM and will also discuss the potential to target the unique metabolic pathways of TRM to treat TRM -mediated diseases.- Published
- 2018
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40. High-throughput sequencing of the T cell receptor β gene identifies aggressive early-stage mycosis fungoides.
- Author
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de Masson A, O'Malley JT, Elco CP, Garcia SS, Divito SJ, Lowry EL, Tawa M, Fisher DC, Devlin PM, Teague JE, Leboeuf NR, Kirsch IR, Robins H, Clark RA, and Kupper TS
- Subjects
- Cellular Microenvironment, Clone Cells, Exome genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, T-Cell, Cutaneous genetics, Lymphoma, T-Cell, Cutaneous immunology, Lymphoma, T-Cell, Cutaneous pathology, Male, Middle Aged, Multivariate Analysis, Mycosis Fungoides pathology, Prognosis, Progression-Free Survival, Skin pathology, Skin Neoplasms pathology, Genes, T-Cell Receptor beta, High-Throughput Nucleotide Sequencing methods, Mycosis Fungoides genetics, Mycosis Fungoides immunology, Skin Neoplasms genetics, Skin Neoplasms immunology
- Abstract
Mycosis fungoides (MF), the most common cutaneous T cell lymphoma (CTCL) is a malignancy of skin-tropic memory T cells. Most MF cases present as early stage (stage I A/B, limited to the skin), and these patients typically have a chronic, indolent clinical course. However, a small subset of early-stage cases develop progressive and fatal disease. Because outcomes can be so different, early identification of this high-risk population is an urgent unmet clinical need. We evaluated the use of next-generation high-throughput DNA sequencing of the T cell receptor β gene ( TCRB ) in lesional skin biopsies to predict progression and survival in a discovery cohort of 208 patients with CTCL (177 with MF) from a 15-year longitudinal observational clinical study. We compared these data to the results in an independent validation cohort of 101 CTCL patients (87 with MF). The tumor clone frequency (TCF) in lesional skin, measured by high-throughput sequencing of the TCRB gene, was an independent prognostic factor of both progression-free and overall survival in patients with CTCL and MF in particular. In early-stage patients, a TCF of >25% in the skin was a stronger predictor of progression than any other established prognostic factor (stage IB versus IA, presence of plaques, high blood lactate dehydrogenase concentration, large-cell transformation, or age). The TCF therefore may accurately predict disease progression in early-stage MF. Early identification of patients at high risk for progression could help identify candidates who may benefit from allogeneic hematopoietic stem cell transplantation before their disease becomes treatment-refractory., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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41. Association of Patient Satisfaction With Medical Scribe Use in an Academic Dermatology Practice.
- Author
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Nambudiri VE, Watson AJ, Rubenstein MH, Kupper TS, and Yang FC
- Subjects
- Adult, Aged, Documentation methods, Efficiency, Organizational, Electronic Health Records, Female, Humans, Male, Middle Aged, Allied Health Personnel, Dermatology organization & administration, Patient Satisfaction
- Published
- 2018
- Full Text
- View/download PDF
42. A primary role for human central memory cells in tissue immunosurveillance.
- Author
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Gehad A, Teague JE, Matos TR, Huang V, Yang C, Watanabe R, O'Malley JT, Trimble CL, Kupper TS, and Clark RA
- Subjects
- Animals, Foreskin transplantation, Heterografts, Humans, Infant, Newborn, Inflammation, Lymph Nodes immunology, Male, Mice, Receptors, Lymphocyte Homing, Skin pathology, Immunologic Memory, Monitoring, Immunologic, T-Lymphocyte Subsets immunology
- Abstract
Central memory T cells (T
CM ) patrol lymph nodes, providing central immunosurveillance against known pathogens, but have not been described as conducting primary tissue immunosurveillance. We analyzed the expression of tissue-homing addressins in human TCM vs effector memory T cells (TEM ) from the same donors. In humans, the majority of human TCM were tropic for either skin or gut, and the overall tissue tropism of TCM was comparable to that of TEM TCM were present in healthy, noninflamed human skin, lung, colon, and cervix, suggesting a role for TCM in the primary immunosurveillance of peripheral tissues. TCM also had potent effector functions; 80% of CD8+ TCM produced TC1/TC2/TC17/TC22 cytokines. TCM injected into human skin-grafted mice migrated into skin and induced inflammatory eruptions comparable to TEM -injected mice. In summary, human TCM express peripheral tissue-homing receptors at levels similar to their effector memory counterparts, are found in healthy human tissues, have impressive effector functions, and can act alone to induce skin inflammation in human engrafted mice. Our studies support a novel role for human TCM in primary immunosurveillance of peripheral tissues and highlight the important role of this long-lived cell type in tissue-based immune responses., (© 2018 by The American Society of Hematology.)- Published
- 2018
- Full Text
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43. Medical Scribes in an Academic Dermatology Practice.
- Author
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Nambudiri VE, Watson AJ, Buzney EA, Kupper TS, Rubenstein MH, and Yang FC
- Subjects
- Confidence Intervals, Electronic Health Records, Female, Humans, Male, Pilot Projects, Time Factors, United States, Dermatologists organization & administration, Dermatology methods, Documentation methods, Practice Patterns, Physicians' organization & administration, Surveys and Questionnaires
- Published
- 2018
- Full Text
- View/download PDF
44. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones.
- Author
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Matos TR, O'Malley JT, Lowry EL, Hamm D, Kirsch IR, Robins HS, Kupper TS, Krueger JG, and Clark RA
- Subjects
- Amino Acid Sequence, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Base Sequence, Case-Control Studies, Cells, Cultured, Etanercept therapeutic use, Humans, Interleukin-17 metabolism, Psoriasis pathology, Psoriasis therapy, Receptors, Antigen, T-Cell metabolism, Skin immunology, Skin pathology, Psoriasis immunology, Th17 Cells physiology
- Abstract
In psoriasis, an IL-17-mediated inflammatory skin disease, skin lesions resolve with therapy, but often recur in the same locations when therapy is discontinued. We propose that residual T cell populations in resolved psoriatic lesions represent the pathogenic T cells of origin in this disease. Utilizing high-throughput screening (HTS) of the T cell receptor (TCR) and immunostaining, we found that clinically resolved psoriatic lesions contained oligoclonal populations of T cells that produced IL-17A in both resolved and active psoriatic lesions. Putative pathogenic clones preferentially utilized particular Vβ and Vα subfamilies. We identified 15 TCRβ and 4 TCRα antigen receptor sequences shared between psoriasis patients and not observed in healthy controls or other inflammatory skin conditions. To address the relative roles of αβ versus γδ T cells in psoriasis, we carried out TCR/δ HTS. These studies demonstrated that the majority of T cells in psoriasis and healthy skin are αβ T cells. γδ T cells made up 1% of T cells in active psoriasis, less than 1% in resolved psoriatic lesions, and less than 2% in healthy skin. All of the 70 most frequent putative pathogenic T cell clones were αβ T cells. In summary, IL-17-producing αβ T cell clones with psoriasis-specific antigen receptors exist in clinically resolved psoriatic skin lesions. These cells likely represent the disease-initiating pathogenic T cells in psoriasis, suggesting that lasting control of this disease will require suppression of these resident T cell populations.
- Published
- 2017
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45. Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma.
- Author
-
Jain S, Washington A, Leaf RK, Bhargava P, Clark RA, Kupper TS, Stroopinsky D, Pyzer A, Cole L, Nahas M, Apel A, Rosenblatt J, Arnason J, Kufe D, and Avigan D
- Subjects
- Animals, Apoptosis drug effects, Azacitidine administration & dosage, Cell Line, Tumor, Decitabine, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, T-Cell, Cutaneous genetics, Lymphoma, T-Cell, Cutaneous pathology, Mice, Mucin-1 drug effects, Oxidation-Reduction drug effects, Oxidative Stress genetics, Reactive Oxygen Species metabolism, Xenograft Model Antitumor Assays, Azacitidine analogs & derivatives, Lymphoma, T-Cell, Cutaneous drug therapy, Mucin-1 genetics, Oxidative Stress drug effects
- Abstract
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the Mucin 1 C-terminal subunit (MUC1-C) plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples, and xenograft models of CTCL were used to assess synergy of GO-203 with decitabine, a hypomethylating agent. Present studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) levels and decreased levels of scavenger molecules, NADP, NADPH, glutathione, and TIGAR, critical to intracellular redox homeostasis. Dual exposure to GO-203 and decitabine resulted in marked downregulation of DNA methyl transferases demonstrating significant synergy of these agents in inducing global and gene specific hypomethylation. Accordingly, treatment with decitabine and GO-203 upregulated the ROS generating enzymes, NADPH oxidase 4 and dual oxidase 2 potentially due to their effect on epigenomic regulation of these proteins. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death in CTCL cell lines, patient-derived primary samples and in a murine xenograft model. These findings indicate that decitabine intensifies MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for patients with CTCL. Mol Cancer Ther; 16(10); 2304-14. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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46. IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection.
- Author
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Tian T, Jin MQ, Dubin K, King SL, Hoetzenecker W, Murphy GF, Chen CA, Kupper TS, and Fuhlbrigge RC
- Subjects
- Administration, Cutaneous, Animals, CD8-Positive T-Lymphocytes immunology, Interleukin 1 Receptor Antagonist Protein genetics, Kaposi Varicelliform Eruption immunology, Kaposi Varicelliform Eruption physiopathology, Kaposi Varicelliform Eruption therapy, Mice, Mice, Inbred C57BL, Mice, Knockout, Skin anatomy & histology, Skin immunology, Skin virology, Vaccination, Vaccinia virus physiology, Virus Replication, Interleukin 1 Receptor Antagonist Protein deficiency, Interleukin 1 Receptor Antagonist Protein immunology, Skin pathology, Skin Diseases, Infectious immunology, Vaccinia immunology, Vaccinia virus immunology
- Abstract
The IL-1 superfamily of cytokines and receptors has been studied extensively. However, the specific roles of IL-1 elements in host immunity to cutaneous viral infection remain elusive. In this study, we applied vaccinia virus (VACV) by scarification to IL-1R1 knockout mice (IL-1R1
-/- ) and found that these mice developed markedly larger lesions with higher viral genome copies in skin than did wild-type mice. The phenotype of infected IL-1R1-/- mice was similar to eczema vaccinatum, a severe side effect of VACV vaccination that may develop in humans with atopic dermatitis. Interestingly, the impaired cutaneous response of IL-1R1-/- mice did not reflect a systemic immune deficiency, because immunized IL-1R1-/- mice survived subsequent lethal VACV intranasal challenge, or defects of T cell activation or T cell homing to the site of inoculation. Histologic evaluation revealed that VACV infection and replication after scarification were limited to the epidermal layer of wild-type mice, whereas lack of IL-1R1 permitted extension of VACV infection into dermal layers of the skin. We explored the etiology of this discrepancy and determined that IL-1R1-/- mice contained significantly more macrophages and monocyte-derived dendritic cells in the dermis after VACV scarification. These cells were vulnerable to VACV infection and may augment the transmission of virus to adjacent skin, thus leading to larger skin lesions and satellite lesions in IL-1R1-/- mice. These results suggest new therapeutic strategies for treatment of eczema vaccinatum and inform assessment of risks in patients receiving IL-1 blocking Abs for treatment of chronic inflammatory disorders., (Copyright © 2017 by The American Association of Immunologists, Inc.)- Published
- 2017
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47. Aprepitant for refractory cutaneous T-cell lymphoma-associated pruritus: 4 cases and a review of the literature.
- Author
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Song JS, Tawa M, Chau NG, Kupper TS, and LeBoeuf NR
- Subjects
- Adult, Aged, Aprepitant, Female, Humans, Lymphoma, T-Cell, Cutaneous complications, Lymphoma, T-Cell, Cutaneous genetics, Lymphoma, T-Cell, Cutaneous pathology, Male, Middle Aged, Neurokinin-1 Receptor Antagonists administration & dosage, Protein Binding drug effects, Pruritus genetics, Pruritus pathology, Substance P antagonists & inhibitors, Substance P genetics, Lymphoma, T-Cell, Cutaneous drug therapy, Morpholines administration & dosage, Pruritus drug therapy
- Abstract
Background: Aprepitant is an FDA-approved medication for chemotherapy-induced nausea and vomiting. It blocks substance P binding to neurokinin-1; substance P has been implicated in itch pathways both as a local and global mediator., Case Presentations: We report a series of four patients, diagnosed with cutaneous T-cell lymphoma, who experienced full body pruritus recalcitrant to standard therapies. All patients experienced rapid symptom improvement (within days) following aprepitant treatment., Conclusion: Aprepitant has been shown in small studies to be efficacious for treating chronic and malignancy-associated pruritus. Prior studies have shown no change in clinical efficacy of chemotherapeutics with concurrent aprepitant administration. These cases further demonstrate that aprepitant can be considered as a therapeutic option in malignancy-associated pruritus and further support the need for larger clinical trials.
- Published
- 2017
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48. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism.
- Author
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Pan Y, Tian T, Park CO, Lofftus SY, Mei S, Liu X, Luo C, O'Malley JT, Gehad A, Teague JE, Divito SJ, Fuhlbrigge R, Puigserver P, Krueger JG, Hotamisligil GS, Clark RA, and Kupper TS
- Subjects
- Animals, Biological Transport, CD8-Positive T-Lymphocytes immunology, Cell Survival, Fatty Acid-Binding Proteins deficiency, Fatty Acid-Binding Proteins metabolism, Female, Humans, Mice, Neoplasm Proteins deficiency, Neoplasm Proteins metabolism, Oxidation-Reduction, Psoriasis, Skin cytology, Skin immunology, Skin virology, Vaccinia immunology, Vaccinia prevention & control, Vaccinia virus immunology, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes metabolism, Fatty Acids, Nonesterified metabolism, Immunologic Memory immunology, Lipid Metabolism
- Abstract
Tissue-resident memory T (T
RM ) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of TRM cells are obscure. Here we show that mouse CD8+ TRM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8+ TRM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (TCM ) cells in lymph nodes. In vitro, CD8+ TRM cells, but not CD8+ TCM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8+ TRM cells. The persistence of CD8+ TRM cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo. Moreover, skin CD8+ TRM cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8+ TRM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8+ TRM cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8+ TRM cells, and suggest that CD8+ TRM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.- Published
- 2017
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49. Cross-Sectional Study Evaluating Skin, Hair, Nail, and Bone Disease in Patients with Focal Dermal Hypoplasia.
- Author
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Gunasekera NS, Divito JK, Kupper TS, Huang JT, and Divito SJ
- Subjects
- Adolescent, Child, Child, Preschool, Cross-Sectional Studies, Female, Hair, Humans, Infant, Male, Middle Aged, Nails, Skin, Bone Diseases complications, Bone Diseases pathology, Focal Dermal Hypoplasia complications, Focal Dermal Hypoplasia pathology
- Abstract
Focal dermal hypoplasia (FDH) is an X-linked dominant disease characterized by dermal thinning and fat herniation with other ectodermal and mesodermal abnormalities. There is limited literature regarding the symptomatology and progression of skin, hair, and nail disease. The risk of bone fragility has not been explored either. This cross-sectional survey-based study explored these gaps in knowledge and provides direction for future avenues of research in FDH., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2017
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50. Dermal γδ T Cells Do Not Freely Re-Circulate Out of Skin and Produce IL-17 to Promote Neutrophil Infiltration during Primary Contact Hypersensitivity.
- Author
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Jiang X, Park CO, Geddes Sweeney J, Yoo MJ, Gaide O, and Kupper TS
- Subjects
- Animals, Dermatitis, Contact genetics, Dermatitis, Contact pathology, Dermis pathology, Interleukin-17 genetics, Interleukins genetics, Interleukins immunology, Mice, Mice, Knockout, Neutrophils pathology, Receptors, Antigen, T-Cell, gamma-delta genetics, T-Lymphocytes pathology, Interleukin-22, Dermatitis, Contact immunology, Dermis immunology, Interleukin-17 immunology, Neutrophil Infiltration, Neutrophils immunology, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocytes immunology
- Abstract
The role of mouse dermal γδ T cells in inflammatory skin disorders and host defense has been studied extensively. It is known that dendritic epidermal T cells (DETC) have a monomorphic γδ T cell receptor (TCR) and reside in murine epidermis from birth. We asked if dermal γδ cells freely re-circulated out of skin, or behaved more like dermal resident memory T cells (TRM) in mice. We found that, unlike epidermal γδ T cells (DETC), dermal γδ cells are not homogeneous with regard to TCR, express the tissue resident T cell markers CD69 and CD103, bear skin homing receptors, and produce IL-17 and IL-22. We created GFP+: GFP- parabiotic mice and found that dermal γδ T cells re-circulate very slowly-more rapidly than authentic αβ TCR TRM, but more slowly than the recently described dermal αβ TCR T migratory memory cells (TMM). Mice lacking the TCR δ gene (δ-/-) had a significant reduction of 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS). We created mice deficient in dermal γδ T cells but not DETC, and these mice also showed a markedly reduced CHS response after DNFB challenge. The infiltration of effector T cells during CHS was not reduced in dermal γδ T cell-deficient mice; however, infiltration of Gr-1+CD11b+ neutrophils, as well as ear swelling, was reduced significantly. We next depleted Gr-1+ neutrophils in vivo, and demonstrated that neutrophils are required for ear swelling, the accepted metric for a CHS response. Depletion of IL-17-producing dermal Vγ4+ cells and neutralization of IL-17 in vivo, respectively, also led to a significantly reduced CHS response and diminished neutrophil infiltration. Our findings here suggest that dermal γδ T cells have an intermediate phenotype of T cell residence, and play an important role in primary CHS through producing IL-17 to promote neutrophil infiltration., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2017
- Full Text
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