scholarly journals Effector T cells in rheumatoid arthritis: Lessons from animal models

FEBS Letters ◽  
2011 ◽  
Vol 585 (23) ◽  
pp. 3649-3659 ◽  
Author(s):  
Saba Alzabin ◽  
Richard O. Williams
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Animal Models ◽  
Effector T Cells

scholarly journals Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal

2021 ◽  
Vol 9 (8) ◽  
pp. e002279
Author(s):  
Sho Isoyama ◽  
Shigeyuki Mori ◽  
Daisuke Sugiyama ◽  
Yasuhiro Kojima ◽  
Yasuko Tada ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Animal Models ◽  
T Cell Activation ◽  
Tumor Antigen ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Effector T Cells ◽  
Pi3k Inhibitor

BackgroundImmune checkpoint blockade (ICB) induces durable clinical responses in patients with various types of cancer. However, its limited clinical efficacy requires the development of better approaches. In addition to immune checkpoint molecules, tumor-infiltrating immunosuppressive cells including regulatory T cells (Tregs) play crucial roles in the immune suppressive tumor microenvironment. While phosphatidylinositol 3-kinase (PI3K) inhibition as a Treg-targeted treatment has been implicated in animal models, its effects on human Tregs and on the potential impairment of effector T cells are required to be clarified for successful cancer immunotherapy.MethodsThe impact of a selective-PI3K inhibitor ZSTK474 with or without anti-programmed cell death 1 (PD-1) monoclonal antibody on Tregs and CD8+ T cells were examined with in vivo animal models and in vitro experiments with antigen specific and non-specific fashions using peripheral blood from healthy individuals and cancer patients. Phenotypes and functions of Tregs and effector T cells were examined with comprehensive gene and protein expression assays.ResultsImproved antitumor effects by the PI3K inhibitor in combination with ICB, particularly PD-1 blockade, were observed in mice and humans. Although administration of the PI3K inhibitor at higher doses impaired activation of CD8+ T cells as well as Tregs, the optimization (doses and timing) of this combination treatment selectively decreased intratumoral Tregs, resulting in increased tumor antigen-specific CD8+ T cells in the treated mice. Moreover, on the administration of the PI3K inhibitor with the optimal dose for selectively deleting Tregs, PI3K signaling was inhibited not only in Tregs but also in activated CD8+ T cells, leading to the enhanced generation of tumor antigen-specific memory CD8+ T cells which contributed to durable antitumor immunity. These opposing outcomes between Tregs and CD8+ T cells were attributed to the high degree of dependence on T cell signaling in the former but not in the latter.ConclusionsPI3K inhibitor in the combination with ICB with the optimized protocol fine-tuned T cell activation signaling for antitumor immunity via decreasing Tregs and optimizing memory CD8+ T cell responses, illustrating a promising combination therapy.

scholarly journals Breach of self tolerance in rheumatoid arthritis: a role for Th17 effector T cells?

2011 ◽  
Vol 70 (Suppl 2) ◽  
pp. A50-A50
Author(s):  
A. Patakas ◽  
R. Benson ◽  
P. Conigliaro ◽  
J. Brewer ◽  
I. McInnes ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Effector T Cells ◽  
Self Tolerance

Decreased Circulating CD28-negative T Cells in Patients with Rheumatoid Arthritis Treated with Abatacept Are Correlated with Clinical Response

2010 ◽  
Vol 37 (5) ◽  
pp. 911-916 ◽  
Author(s):  
MIRKO SCARSI ◽  
TAMARA ZIGLIOLI ◽  
PAOLO AIRÒ
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Disease Activity Score ◽  
Absolute Number ◽  
Effector T Cells ◽  
T Cell Subsets ◽  
Reactive Protein ◽  
Cd28 Costimulation

Objective.To verify the hypothesis that blockade of CD28 costimulation by treatment with abatacept in patients with rheumatoid arthritis (RA) might induce a reduction in the number of CD28– T cells, as well as other effector T cell populations. We evaluated whether these variations correlate with clinical response.Methods.Peripheral blood T cell subsets were longitudinally evaluated by flow cytometry through the analysis of CD28, CD45RA, and CCR7 expression in 16 patients with RA who were treated with abatacept.Results.After 48 weeks of treatment, the proportion and the absolute number of circulating CD8+CD28– T cells decreased (p = 0.008, p = 0.055, respectively, compared with baseline), as well as the proportion of the CD8+CD45RA+CCR7– cells, thought to represent terminally differentiated effector T cells (p = 0.03). Reductions of percentages of circulating CD4+CD28– and CD8+CD28– T cells, and (CCR7–) CD8+ total effector T cells were directly correlated with the reduction of Disease Activity Score 28 C-reactive protein (r = 0.58, p = 0.014; r = 0.47, p = 0.059; r = 0.59, p = 0.012, respectively).Conclusion.After therapy with abatacept, circulating CD28– T cells and other effector populations decrease in patients with RA. This decrease is correlated with clinical response.

Tim3+ Foxp3 + Treg Cells Are Potent Inhibitors of Effector T Cells and Are Suppressed in Rheumatoid Arthritis

Inflammation ◽  
2017 ◽  
Vol 40 (4) ◽  
pp. 1342-1350 ◽  
Author(s):  
Huaqiang Sun ◽  
Wenwu Gao ◽  
Wenping Pan ◽  
Qian Zhang ◽  
Gongteng Wang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Treg Cells ◽  
Effector T Cells

Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype–positive rheumatoid arthritis patients

2015 ◽  
Vol 7 (290) ◽  
pp. 290ra87-290ra87 ◽  
Author(s):  
Helen Benham ◽  
Hendrik J. Nel ◽  
Soi Cheng Law ◽  
Ahmed M. Mehdi ◽  
Shayna Street ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Phase 1 ◽  
Human Leukocyte ◽  
Nuclear Factor Κb ◽  
Intradermal Injection ◽  
Effector T Cells ◽  
Clinical Effects ◽  
Risk Genotype ◽  
Citrullinated Peptide

In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti–citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70% of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor κB (NF-κB) inhibitor exposed to four citrullinated peptide antigens, designated “Rheumavax,” in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype–positive RA patients with citrullinated peptide–specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observed a reduction in effector T cells and an increased ratio of regulatory to effector T cells; a reduction in serum interleukin-15 (IL-15), IL-29, CX3CL1, and CXCL11; and reduced T cell IL-6 responses to vimentin447–455–Cit450 relative to controls. Rheumavax did not induce disease flares in patients recruited with minimal disease activity, and DAS28 decreased within 1 month in Rheumavax-treated patients with active disease. This exploratory study demonstrates safety and biological activity of a single intradermal injection of autologous modified DCs exposed to citrullinated peptides, and provides rationale for further studies to assess clinical efficacy and antigen-specific effects of autoantigen immunomodulatory therapy in RA.

Quantification and phenotype of regulatory T cells in rheumatoid arthritis according to Disease Activity Score-28

Autoimmunity ◽  
2009 ◽  
pp. 1-1
Author(s):  
Jose Miguel Sempere-Ortells ◽  
Vicente Perez-Garcia ◽  
Gema Marin-Alberca ◽  
Alejandra Peris-Pertusa ◽  
Jose Miguel Benito ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Disease Activity ◽  
Disease Activity Score ◽  
Activity Score

CD4+CD25- effector T cells from healthy controls and MS patients do not differ in mRNA expression of IFN-γ, IL-2, and TNF-α

2004 ◽  
Vol 31 (S 1) ◽  
Author(s):  
A Hug ◽  
J Haas ◽  
A Viehöver ◽  
B Fritz ◽  
B Storch-Hagenlocher ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Effector T Cells ◽  
Healthy Controls ◽  
Tnf Α ◽  
Ifn Γ
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