Topical treatment of mild to moderate plaque psoriasis with 0·3% tacrolimus gel and 0·5% tacrolimus cream: the effect on SUM score, epidermal proliferation, keratinization, T-cell subsets and HLA-DR expression

AbstractAneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Devastating post-SAH complications, such as cerebral vasospasm (CVS), delayed cerebral ischemia or seizures to mention a few, are mainly responsible for the poor clinical outcome. Inflammation plays an indispensable role during early brain injury (EBI) and delayed brain injury (DBI) phases over which these complications arise. T helper cells are the major cytokine secreting cells of adaptive immunity that can polarize to multiple functionally unique sub-populations. Here, we investigate different CD4+ T cell subsets during EBI and DBI phases after SAH, and their dynamics during post-SAH complications. Peripheral venous blood from 15 SAH patients during EBI and DBI phases, was analyzed by multicolour flowcytometry. Different subsets of CD3+ CD4+ T cells were characterized by differential cell surface expression of CXCR3 and CCR6 into Th1, Th2, Th17, whereas Tregs were defined by CD25hiCD127lo. The analysis of activation states was done by the expression of stable activation markers CD38 and HLA-DR. Interestingly, compared to healthy controls, Tregs were significantly increased during both EBI and DBI phases. Different activation states of Tregs showed differential significant increase during EBI and DBI phases compared to controls. HLA-DR− CD38+ Tregs were significantly increased during DBI phase compared to EBI phase in SAH patients developing CVS, seizures and infections. However, HLA-DR− CD38− Tregs were significantly reduced during EBI phase in patients with cerebral ischemia (CI) compared to those without CI. HLA-DR− CD38− Th2 cells were significantly increased during EBI phase compared to controls. A significant reduction in Th17/Tregs and HLA-DR− CD38+ Th17/Tregs ratios was observed during both EBI and DBI phases compared to controls. While HLA-DR− CD38− Th17/Tregs and HLA-DR− CD38− Th1/Th2 ratios were impaired only during EBI phase compared to controls. In conclusion, CD4+ T cell subsets display dynamic and unique activation patterns after SAH and during the course of the manifestation of post-SAH complications, which may be helpful for the development of precision neurovascular care. However, to claim this, confirmatory studies with larger patient cohorts, ideally from different ethnic backgrounds, are required. Moreover, our descriptive study may be the grounds for subsequent lab endeavors to explore the underlying mechanisms of our observations.

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Transcriptomic profiling of plaque psoriasis and cutaneous T cell subsets during treatment with secukinumab

JID Innovations ◽

10.1016/j.xjidi.2021.100094 ◽

2021 ◽

pp. 100094

Author(s):

Jared Liu ◽

Hsin-Wen Chang ◽

Robby Grewal ◽

Daniel D. Cummins ◽

Audrey Bui ◽

...

Keyword(s):

T Cell ◽

Plaque Psoriasis ◽

T Cell Subsets ◽

Transcriptomic Profiling

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T-cell activation and subset patterns are altered in B-CLL and correlate with the stage of the disease

Blood ◽

10.1182/blood.v74.2.786.786 ◽

1989 ◽

Vol 74 (2) ◽

pp. 786-792 ◽

Cited By ~ 64

Author(s):

TH Totterman ◽

M Carlsson ◽

B Simonsson ◽

M Bengtsson ◽

K Nilsson

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Healthy Subjects ◽

Lymphocytic Leukemia ◽

Stage Ii ◽

T Cell Subsets ◽

Cd8 Cells ◽

Hla Dr ◽

The Absolute

Abstract Two-color FACS analysis was used to study activated and “functional” T and natural killer (NK) cell subsets of circulating lymphocytes in 23 patients with B-type chronic lymphocytic leukemia (B-CLL) and in 30 healthy subjects. As compared with controls, B-CLL patients had increased absolute numbers of phenotypically activated, HLA-DR+ CD4+ and CD8+ cells and T suppressor/effector (CD11b+CD8+) cells. When patients in Rai stages II through IV (n = 11) were compared with cases in Rai stages O through I (n = 12), the former group of patients had higher numbers of activated CD4+ and CD8+ T cells and decreased levels of suppressor/effector T cells. The absolute numbers of T suppressor/inducer (CD45R+CD4+) cells were elevated in patients with stage O through I disease but within normal range in stage II through IV leukemia. We further showed that the absolute numbers of NK-like (CD16+) cells and their activated counterparts (DR+CD16+) are elevated in B-CLL patients as compared with healthy subjects. The comparison of relative T and NK subsets in the blood of patients and controls showed that the proportions of CD4+, CD8+, and CD16+ cells expressing the activation marker HLA-DR were increased in B-CLL. Furthermore, the percentage of T-suppressor/inducer (CD45R+) cells within the CD4+ population was decreased in the patients. The proportion of T- suppressor/effector (CD11b+) cells within the CD8+ subset was reduced in subjects with stage II-IV disease only. When stimulated in vitro with the T-cell-dependent inducer TPA, B-CLL cells from patients in Rai stages II through IV secreted larger amounts of IgM as compared with cells from stage O through I patients. A positive correlation was observed between the degree of phenotypic activation of CD4+ T-helper cells and their functional capacity to augment IgM secretion by autologous B-CLL cells. Our findings indicate a tumor cell-directed regulatory role of T cells (and possibly NK cells as well) in B-CLL. Furthermore, monitoring of phenotypically activated and functional T- cell subsets may be helpful in the prediction of disease progression and timing of therapy in B-CLL.

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A Phase II Study of the Purine Nucleoside Phosphorylase (PNP) Inhibitor RO5092888 (BCX-4208) in Patients with Moderate to Severe Chronic Plaque Psoriasis: Safety, Tolerability and Lymphocyte Effects

Blood ◽

10.1182/blood.v112.11.2583.2583 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2583-2583

Author(s):

Joseph P Gomes ◽

Angela Georgy ◽

Sharon Passe ◽

Adrienne Farid ◽

Shanta Bantia ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Plaque Psoriasis ◽

Apoptotic Cell ◽

Study Drug ◽

T Cell Subsets ◽

Upper Respiratory Tract ◽

Chronic Plaque Psoriasis ◽

Double Blind ◽

Tract Infections

Abstract Introduction: PNP is a purine-metabolizing enzyme that catalyzes the phosphorolysis of 2′-deoxyguanosine [dGuo] to guanine and deoxyribose-1-phosphate. In T-cells, PNP inhibition leads to accumulation of deoxyguanosine triphosphate (dGTP), triggering apoptotic cell death. Chronic-plaque type psoriasis (psoriasis) is an autoimmune disorder, in which T-cells contribute, at least in part, to the manifestations and maintenance of the disease. Therefore, targeting T-cells may be a beneficial treatment strategy. Since for chronic inflammatory diseases the safety of potential immunosuppressive drugs is a major consideration, we conducted this study to investigate safety and tolerability of oral RO5092888 (BCX-4208) in patients with moderate to severe chronic plaque psoriasis. Methods: This was a randomized, double-blind, placebo-controlled, dose-ranging study. Sixty-six patients 18 to 70 years old were randomized into one of three groups: placebo, 20mg/d or 120mg/d. The study was conducted from August 2007 to June 2008. Patients received study drug over six weeks and were observed over an additional 4 weeks. Assessments for safety included tracking of adverse events (AEs) including infections; vital signs; ECGs; chemistry panel; LFTs; hematologic parameters including peripheral blood (PB) lymphocyte subsets CD3+, CD4+, CD8+, CD56+, CD20+; and urinalysis. Results: 65 of the 66 enrolled patients were analyzed. One serious AE was observed in the 20mg/d group, a deep vein thrombosis (DVT) in a patient with a history of DVTs, and was considered unrelated to study drug. The percentage of patients experiencing at least one adverse event (AE) of any grade was placebo: 33% (7/21), 20mg: 41% (9/22), and 120mg: 59% (13/22). During treatment, two infections occurred in the placebo group (influenza and sinusitis), one in the 20mg group (nasopharyngitis), and 4 in the 120mg group (2-upper respiratory tract infections, 1 bronchitis, and 1 otitis externa). Reductions in PB lymphocytes and subsets were observed (Table 1). Nine patients showed decreased levels of CD4+ lymphocytes, below 350 cells/μL (20mg/d, 3; 120mg/d, 6). Conclusion: Daily oral administration of 20 mg or 120 mg of RO5092888 for up to 6 weeks demonstrated adequate safety and tolerability. Reductions in PB T cells, T cell subsets and B cells were observed. Further investigation of RO5092888 is warranted in both T-cell and B-cell diseases. Lymphocyte subpopulation Mean Nadir (% change from baseline) Placebo (n=21) 20 mg (n=22) 120 mg (n=22) CD3+ 24.0 30.6 47.5 CD4+ 23.6 28.9 44.9 CD8+ 26.1 31.8 53.9 CD20+ 37.5 42.6 64.2 CD56+ 40.1 47.7 72.6 Table 1

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Transcriptomic profiling of plaque psoriasis and cutaneous T cell subsets during treatment with secukinumab

10.1101/764118 ◽

2019 ◽

Author(s):

Jared Liu ◽

Hsin-Wen Chang ◽

Kristen M. Beck ◽

Sahil Sekhon ◽

Timothy H. Schmidt ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Plaque Psoriasis ◽

Immune Cell ◽

T Cell Subsets ◽

Skin Tissue ◽

Rapid Reduction ◽

Effector Cells ◽

Lesional Skin ◽

T Effector Cells

AbstractThe IL17A inhibitor secukinumab is efficacious for the treatment of psoriasis. In order to define its mechanism of action, it is important to understand its impact on psoriatic whole skin tissue as well as specific skin-resident immune cell populations such as T lymphocytes. In this study, we treated 15 moderate-to-severe plaque psoriasis patients with secukinumab and characterized the longitudinal transcriptomic changes of whole lesional skin tissue and cutaneous CD4+ T effector cells (Teffs), CD4+ T regulatory cells (Tregs), and CD8+ T effector cells during 12 weeks of treatment. Secukinumab was clinically effective, with 100%, 47%, and 27% of patients in the study achieving PASI75, PASI90, and PASI100 by week 12, respectively. At baseline prior to treatment, we observed that IL17A overexpression predominates in psoriatic CD8+ T cells rather than Teffs, supporting the importance of IL-17-secreting CD8+ T cells (Tc17) compared to IL-17-secreting CD4+ T cells (Th17) cells in the pathogenesis of psoriasis. Although secukinumab targets only IL17A, we observed rapid reduction of IL17A, IL17F, IL23A, IL23R, and IFNG expression in lesional skin as soon as 2 weeks after initiation of treatment and normalization of expression by week 12. Secukinumab treatment resulted in resolution of 89-97% of psoriasis-associated expression differences in both bulk tissue and T cell subsets by week 12 of treatment. Overall, secukinumab appears to rapidly reverse many of the molecular hallmarks of psoriasis.

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HIV-1-Specific CD11c+ CD8+ T Cells Display Low PD-1 Expression and Strong Anti-HIV-1 Activity

Frontiers in Immunology ◽

10.3389/fimmu.2021.757457 ◽

2021 ◽

Vol 12 ◽

Author(s):

An-Liang Guo ◽

Jin-Fang Zhao ◽

Lin Gao ◽

Hui-Huang Huang ◽

Ji-Yuan Zhang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Subset ◽

T Cell Subsets ◽

Hla Dr ◽

Tnf Α ◽

Treatment Naïve ◽

Vitro Analysis ◽

Hiv 1

Exhaustion of HIV-1-specific CD8+ T cells prevents optimal control of HIV-1 infection. Identifying unconventional CD8+ T cell subsets to effectively control HIV-1 replication is vital. In this study, the role of CD11c+ CD8+ T cells during HIV-1 infection was evaluated. The frequencies of CD11c+ CD8+ T cells significantly increased and were negatively correlated with viral load in HIV-1-infected treatment-naïve patients. HIV-1-specific cells were enriched more in CD11c+ CD8+ T cells than in CD11c- CD8+ T cells, which could be induced by HIV-1-derived overlapping peptides, marking an HIV-1-specific CD8+ T cell population. This subset expressed higher levels of activating markers (CD38 and HLA-DR), cytotoxic markers (granzyme B, perforin, and CD107a), and cytokines (IL-2 and TNF-α), with lower levels of PD-1 compared to the CD11c- CD8+ T cell subset. In vitro analysis verified that CD11c+ CD8+ T cells displayed a stronger HIV-1-specific killing capacity than the CD11c- counterparts. These findings indicate that CD11c+ CD8+ T cells have potent immunotherapeutic efficacy in controlling HIV-1 infection.

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HLA-DR Protein Expression Correlates with Non-Neoplastic T-Cell Infiltration and Predicts Survival in Patients with Primary Mediastinal Large B Cell Lymphoma (PMBCL) Treated with CHOP Chemotherapy.

Blood ◽

10.1182/blood.v114.22.133.133 ◽

2009 ◽

Vol 114 (22) ◽

pp. 133-133 ◽

Cited By ~ 2

Author(s):

Pedro Farinha ◽

Christian Steidl ◽

Lisa M. Rimsza ◽

Kerry J. Savage ◽

Joseph M. Connors ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Research Funding ◽

B Cell Lymphoma ◽

T Cell Subsets ◽

Cell Content ◽

Mhc Ii ◽

Hla Dr ◽

Multi Agent ◽

Large B Cell

Abstract 133 Background: PMBCL represents a unique lymphoma type in the WHO classification and shares overlapping histological and gene expression features with both diffuse large B-cell (DLBCL) and classical Hodgkin lymphoma. Similar to DLBCL, PMBCL may show loss of expression of the major histocompatibility class II (MHC II) antigens, which correlates with inferior patient survival (Rimsza, Blood 2006). MHC II proteins are expressed on antigen-presenting cells and are important in eliciting immune responses. In DLBCL, decreased expression of HLA-DR is related to loss of immunosurveillence. Our aim was to validate HLA-DR as an important prognostic biomarker in PMBCL and correlate it with immune response in a cohort of patients treated with multi-agent chemotherapy. Methods: A tissue microarray block was built with duplicate 0.6mm cores of paraffin embedded diagnostic biopsies from 103 patients treated with CHOP/CHOP-like chemotherapy at the BC Cancer Agency (1980-2005). Standard immunohistochemistry was performed with CD20, HLA-DR (IgG2b), CD3, CD4, CD8, CD57, CD68 and cytotoxic markers (TIA1 & Granzyme B). HLA-DR expression was evaluated using a histoscore (intensity of staining and % of positive malignant cells) and correlated with the content (%) of different non-neoplastic infiltrating T-cell subsets and macrophages. Univariate & multivariate analyses were used to characterize overall survival (OS) and progression free survival (PFS). Results: The median follow-up of living patients was 10 years. The IPI predicted OS (p=0.042) but not PFS. Of the 92 cases with interpretable staining, 32 were positive for HLA-DR and 60 negative, with 10-year OS of 86% vs. 61% (p=0.006) and 2-year PFS of 78% vs. 53% (p=0.018), respectively. A Cox multivariate model established both HLA-DR status and IPI as independent predictors of OS (RR=0.3, 95%CI=0.12–0.75, p=0.01; RR=2.9, 95%CI=1.2–6.9, p=0.06, respectively). HLA-DR expression correlated significantly with increased content of all analyzed T cell markers, especially CD3, CD8 and TIA1 (x2, p<0.001), but not with macrophage content (CD68). Of all non-malignant markers, only TIA1+ cell content significantly correlated with survival. Of the 83 cases with interpretable staining, 43 had more than 10% of infiltrating TIA1+ cells and 40 had less, with 10-year OS of 83% vs. 57% (p=0.0014) and 2-year PFS of 76% vs. 50% (p=0.014), respectively. In multivariate analysis, including IPI and HLA-DR and cytotoxic markers, only TIA1 status was an independent predictor of OS (RR=0.3, 95%CI=0.11–0.63, p=0.003). Conclusions: We validated the negative prognostic importance of loss of HLA-DR expression by neoplastic B cells in PMBCL patients treated with multi-agent chemotherapy in a single institution experience. Loss of HLA-DR expression correlated with decreased numbers of infiltrating benign T cell populations, especially CD8+ and TIA1+ cells, where decreased cytotoxic T cell content correlated independently with inferior survival. This study shows loss of immunogenicity and immunosurveillance are key mechanisms in the response to treatment of PMBCL patients and suggests that specific therapies focused on this pathway may benefit patients. Disclosures: Connors: Roche Canada (F Hoffmann-La Roche): Research Funding. Gascoyne:Roche Canada, Genentech, Lilly, Millennium : Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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