What did we learn from CTLA‐4 insufficiency on the human immune system? DOI
Noriko Mitsuiki,

Charlotte Schwab,

Bodo Grimbacher

et al.

Immunological Reviews, Journal Year: 2018, Volume and Issue: 287(1), P. 33 - 49

Published: Dec. 18, 2018

Summary Cytotoxic‐T‐lymphocyte‐antigen‐4 ( CTLA ‐4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated activated cells. ‐4 inhibits cell activation by various suppressive functions including competition with CD 28, regulation of the inhibitory function Treg cells, such as transendocytosis, control adhesion motility. Intrinsic signaling has been controversially discussed, but so far no distinct pathway identified. The ‐4‐mediated suppression plays an important role in maintenance peripheral tolerance prevention autoimmune diseases. Human insufficiency caused heterozygous germline mutations 4 characterized complex dysregulation syndrome. Clinical studies mutation carriers showed reduced penetrance variable expressivity, suggesting modifying factor(s). One hundred forty‐eight have reported; patients hypogammaglobulinemia, recurrent infectious diseases, lymphocytic infiltration into multiple organs. expression level was reduced, while frequency increased ‐4‐insufficient patients. transendocytosis assay specific functional test for assessment newly identified gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, targeted therapy fusion proteins mechanistic target rapamycin mTOR ) inhibitors were applied; life‐threatening, treatment‐resistant symptoms underwent hematopoietic stem transplantation. fact that humans causes severe disease taught us amount molecules present in/on matters homeostasis. However, whether pathology‐causing lymphocytes are antigen‐specific unsolved question. ‐4, addition, diseases cancer. Anti‐ drugs employed checkpoint to forms Thus, clinical research human might provide deeper understanding mechanism(s) molecule disorders.

Language: Английский

Tregs: Where We Are and What Comes Next? DOI Creative Commons
Zhao Hai, Xuelian Liao,

Yan Kang

et al.

Frontiers in Immunology, Journal Year: 2017, Volume and Issue: 8

Published: Nov. 24, 2017

Regulatory T cells are usually recognized as a specialized subset of CD4+ functioning in establishment and maintanence immune tolerance. Meanwhile, there is emerging evidence that Tregs also present various non-lymphoid tissues, they have unique phenotypes credited with activities distinct from regulatory function. Their development function been described plenty manuscripts the last two decades. However, deepening research recent years, revealed some novel mechanisms about how exert their activities. Firstly, we discuss expanding family lymphocytes briefly then, try to interpret Foxp3 functions. Subsequently, another part our focus varieties tissue Tregs. Next, primarily on work faceted functions terms soluble mediators, functional proteins inhibitory receptors. In particular, unless otherwise noted, term "Treg" used here refer specially "CD4+CD25+Foxp3+" cells.

Language: Английский

Citations

169
Multispectral imaging for quantitative and compartment‐specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients DOI
Artur Mezheyeuski, Christian H. Bergsland, Max Backman

et al.

The Journal of Pathology, Journal Year: 2017, Volume and Issue: 244(4), P. 421 - 431

Published: Dec. 28, 2017

Abstract Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity response in cancer. Therefore, we evaluated a fluorescence‐based multiplexed immunohistochemical method combination with multispectral imaging system to quantify infiltrates situ environment non‐small‐cell lung cancer (NSCLC). A tissue microarray including 57 NSCLC cases was stained antibodies against CD8, CD20, CD4, FOXP3, CD45RO, and pan‐cytokeratin, cells were quantified epithelial stromal compartments. The results compared those conventional IHC, related corresponding RNA‐sequencing (RNAseq) expression values. We found strong correlation between visual digital quantification lymphocytes CD45RO (correlation coefficient: r = 0.52), FOXP3 ( 0.87), CD4 0.79), CD20 0.81) CD8 0.90) cells. RNAseq data (0.35–0.65) comparable or better than that (0.38–0.58). Combination signals five enabled further subpopulations be identified localized. specific pattern cell infiltration based either on spatial distribution (distance regulatory + T cells) relationships lymphocyte subclasses each other (e.g. cytotoxic/regulatory ratio) associated patient prognosis. In conclusion, fluorescence method, only one section, provided reliable localization tissue. application this technique clinical biopsies can provide basic characterization guide decisions era immunotherapy. Copyright © 2017 Pathological Society Great Britain Ireland. Published John Wiley & Sons, Ltd.

Language: Английский

Citations

169
Trial watch: Peptide-based vaccines in anticancer therapy DOI Open Access
Lucillia Bezu, Oliver Kepp, Giulia Cerrato

et al.

OncoImmunology, Journal Year: 2018, Volume and Issue: 7(12), P. e1511506 - e1511506

Published: Sept. 6, 2018

Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations minimize antigenicity and/or changes tumor microenvironment foster immunosuppression. Several strategies developed overcome such limitations, including use of immunostimulatory adjuvants, co-treatment cytotoxic therapies enable coordinated release damage-associated molecular patterns, and concomitant blockade checkpoints. Personalized are also being for activity clinic. Here, we review recent preclinical clinical progress as therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long TAA: antigen; TNA: neoantigen

Language: Английский

Citations

144
Disease tolerance: concept and mechanisms DOI Creative Commons
Justin L. McCarville,

JS Ayres

Current Opinion in Immunology, Journal Year: 2017, Volume and Issue: 50, P. 88 - 93

Published: Dec. 15, 2017

Language: Английский

Citations

137
What did we learn from CTLA‐4 insufficiency on the human immune system? DOI
Noriko Mitsuiki,

Charlotte Schwab,

Bodo Grimbacher

et al.

Immunological Reviews, Journal Year: 2018, Volume and Issue: 287(1), P. 33 - 49

Published: Dec. 18, 2018

Summary Cytotoxic‐T‐lymphocyte‐antigen‐4 ( CTLA ‐4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated activated cells. ‐4 inhibits cell activation by various suppressive functions including competition with CD 28, regulation of the inhibitory function Treg cells, such as transendocytosis, control adhesion motility. Intrinsic signaling has been controversially discussed, but so far no distinct pathway identified. The ‐4‐mediated suppression plays an important role in maintenance peripheral tolerance prevention autoimmune diseases. Human insufficiency caused heterozygous germline mutations 4 characterized complex dysregulation syndrome. Clinical studies mutation carriers showed reduced penetrance variable expressivity, suggesting modifying factor(s). One hundred forty‐eight have reported; patients hypogammaglobulinemia, recurrent infectious diseases, lymphocytic infiltration into multiple organs. expression level was reduced, while frequency increased ‐4‐insufficient patients. transendocytosis assay specific functional test for assessment newly identified gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, targeted therapy fusion proteins mechanistic target rapamycin mTOR ) inhibitors were applied; life‐threatening, treatment‐resistant symptoms underwent hematopoietic stem transplantation. fact that humans causes severe disease taught us amount molecules present in/on matters homeostasis. However, whether pathology‐causing lymphocytes are antigen‐specific unsolved question. ‐4, addition, diseases cancer. Anti‐ drugs employed checkpoint to forms Thus, clinical research human might provide deeper understanding mechanism(s) molecule disorders.

Language: Английский

Citations

135