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GIFT4 fusokine converts leukemic B cells into immune helper cells.
- Source :
-
Journal of translational medicine [J Transl Med] 2016 Apr 27; Vol. 14 (1), pp. 106. Date of Electronic Publication: 2016 Apr 27. - Publication Year :
- 2016
-
Abstract
- Background: Chronic lymphocytic leukemia (CLL) remains incurable with standard therapy, and is characterized by excessive expansion of monoclonal abnormal mature B cells and more regulatory immune properties of T cell compartment. Thus, developing novel strategies to enhance immune function merits further investigation as a possible therapy for CLL.<br />Methods: We generated a fusion cytokine (fusokine) arising from the combination of human GM-CSF and IL-4 (named GIFT4). Primary CLL cells were treated with GIFT4 or GM-CSG and IL-4 in vitro. GIFT4-triggered STAT5 signaling in CLL cells was examined by Western blot. The phenotype and secretome of GIFT4-treated CLL cells (GIFT4-CLL cells), and the immune stimulatory function of GIFT4-CLL cells on autologous T cells were analyzed by flow cytometry and luminex assay.<br />Results: GIFT4-CLL up-regulated the expression of co-stimulatory molecules CD40, CD80 and CD86 and adhesion molecule CD54. GIFT4-CLL cells secreted IL-1β, IL-6, ICAM-1 and substantial IL-2 relative to unstimulated CLL cells. GIFT4 treatment led to JAK1, JAK2 and JAK3-mediated hyper-phosphorylation of STAT5 in primary CLL cells, which is essential for GIFT4-triggered conversion of CLL cells. GIFT4-CLL cells directly propelled the expansion of autologous IFN-γ-producing CD314(+) cytotoxic T cells in vitro, and that these could lyse autologous CLL cells. Furthermore, administration of GIFT4 protein promoted the expansion of human T cells in NOD-scid IL2Rγ(null) immune deficient mice adoptively pre-transferred with peripheral blood mononuclear cells from subjects with CLL.<br />Conclusion: GIFT4 has potent capability to converts primary CLL cells into APC-like immune helper cells that initiate a T cell driven anti-CLL immune response.
- Subjects :
- Adult
Aged
Animals
Antigen-Presenting Cells drug effects
Antigen-Presenting Cells metabolism
Cell Proliferation drug effects
Cross-Priming drug effects
Cytotoxicity, Immunologic drug effects
Female
Humans
Janus Kinases metabolism
Male
Mice
Middle Aged
Phenotype
Proteome metabolism
STAT5 Transcription Factor metabolism
Signal Transduction drug effects
T-Lymphocytes, Helper-Inducer cytology
T-Lymphocytes, Helper-Inducer drug effects
Granulocyte-Macrophage Colony-Stimulating Factor pharmacology
Interleukin-4 pharmacology
Leukemia, Lymphocytic, Chronic, B-Cell immunology
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Recombinant Fusion Proteins pharmacology
T-Lymphocytes, Helper-Inducer immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1479-5876
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 27118475
- Full Text :
- https://doi.org/10.1186/s12967-016-0865-1