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Regulatory T cells engineered with TCR signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter
- Source :
- Science Translational Medicine, 12(569):4744, 1-16. AMER ASSOC ADVANCEMENT SCIENCE
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Abstract
- Adoptive cell transfer of ex vivo expanded regulatory T cells (T-r(egs)) has shown immense potential in animal models of auto- and alloimmunity. However, the effective translation of such T-reg therapies to the clinic has been slow. Because T-reg homeostasis is known to require continuous T cell receptor (TCR) ligation and exogenous interleukin-2 (IL-2), some investigators have explored the use of low-dose IL-2 injections to increase endogenous T-reg responses. Systemic IL-2 immunotherapy, however, can also lead to the activation of cytotoxic T lymphocytes and natural killer cells, causing adverse therapeutic outcomes. Here, we describe a drug delivery platform, which can be engineered to autostimulate T-regs with IL-2 in response to TCR-dependent activation, and thus activate these cells in sites of antigen encounter. To this end, protein nanogels (NGs) were synthesized with cleavable bis(N-hydroxysuccinimide) cross-linkers and IL-2/Fc fusion (IL-2) proteins to form particles that release IL-2 under reducing conditions, as found at the surface of T cells receiving stimulation through the TCR. T-regs surface-conjugated with IL-2 NGs were found to have preferential, allograft-protective effects relative to unmodified T-regs or T-regs stimulated with systemic IL-2. We demonstrate that murine and human NG-modified T-regs carrying an IL-2 cargo perform better than conventional T-regs in suppressing alloimmunity in murine and humanized mouse allotransplantation models. In all, the technology presented in this study has the potential to improve T-reg transfer therapy by enabling the regulated spatiotemporal provision of IL-2 to antigen-primed T-regs.
- Subjects :
- 0301 basic medicine
Adoptive cell transfer
allograft-rejection
medicine.medical_treatment
T cell
Receptors, Antigen, T-Cell
Nanogels
chemical and pharmacologic phenomena
in-vitro
T-Lymphocytes, Regulatory
memory
03 medical and health sciences
Mice
0302 clinical medicine
foxp3
medicine
Cytotoxic T cell
Animals
dose interleukin-2 therapy
tolerance
Chemistry
T-cell receptor
Alloimmunity
FOXP3
hemic and immune systems
autoimmune
General Medicine
Immunotherapy
030104 developmental biology
medicine.anatomical_structure
messenger-rna
030220 oncology & carcinogenesis
Humanized mouse
Cancer research
Interleukin-2
activation
Signal Transduction
transplantation
Subjects
Details
- ISSN :
- 19466234
- Database :
- OpenAIRE
- Journal :
- Science Translational Medicine, 12(569):4744, 1-16. AMER ASSOC ADVANCEMENT SCIENCE
- Accession number :
- edsair.doi.dedup.....b533ccd15beae2291f33c01c12057052