Abstract
Clinical trials utilizing regulatory T cell (Treg) therapy in organ transplantation have shown promising results, however, the choice of a standard immunosuppressive regimen is still controversial. Calcineurin inhibitors (CNIs) are one of the most common immunosuppressants for organ transplantation, although they may negatively affect Tregs by inhibiting IL-2 production by conventional T cells. As a strategy to replace IL-2 signaling selectively in Tregs, we have introduced an engineered orthogonal IL-2 (ortho IL-2) cytokine/cytokine receptor (R) pair that specifically binds with each other but does not bind with their wild-type counterparts. Murine Tregs were isolated from recipients and retrovirally transduced with ortho IL-2Rβ during ex vivo expansion. Transduced Tregs (ortho Tregs) were transferred into recipient mice in a mixed hematopoietic chimerism model with tacrolimus administration. Ortho IL-2 treatment significantly increased the ortho IL-2Rβ(+) Treg population in the presence of tacrolimus without stimulating other T cell subsets. All the mice treated with tacrolimus plus ortho IL-2 achieved heart allograft tolerance, even after tacrolimus cessation, whereas those receiving tacrolimus treatment alone did not. These data demonstrate that Treg therapy can be adopted into a CNI-based regimen by utilizing cytokine receptor engineering.
Original language | English |
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Pages (from-to) | 3061-3068 |
Number of pages | 8 |
Journal | American Journal of Transplantation |
Volume | 22 |
Issue number | 12 |
Early online date | 28 Aug 2022 |
DOIs | |
Publication status | Published - Dec 2022 |
Externally published | Yes |
Keywords
- animal models: murine
- basic (laboratory) research/science
- bioengineering
- cellular biology
- cytokines/cytokine receptors
- immunobiology
- immunosuppressant – calcineurin inhibitor (CNI)
- immunosuppression/immune modulation
- tolerance: chimerism