TY - JOUR
T1 - Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells
AU - Guggino, Giuliana
AU - Fazekasova, Henrieta
AU - Ratnasothy, Kulachelvy
AU - Fanelli, Giorgia
AU - Romano, Marco
AU - Lamperti, Estefania Nova
AU - Hoong, Sec Julie
AU - Sukthankar, Mitalee
AU - Scottà, Cristiano
AU - Afzali, Behdad
AU - Lechler, Robert I.
AU - Lombardi, Giovanna
AU - Becker, Pablo D.
AU - Fanelli, Giuditta
PY - 2016
Y1 - 2016
N2 - Immunosuppressive drugs in clinical transplantation are necessary to inhibit the immune response to donor antigens. Although they are effective in controlling acute rejection, they do not prevent long-term transplant loss from chronic rejection. In addition, immunosuppressive drugs have adverse side effects, including increased rate of infections and malignancies. Adoptive cell therapy with human Tregs represents a promising strategy for the induction of transplantation tolerance. Phase I/II clinical trials in transplanted patients are already underway, involving the infusion of Tregs alongside concurrent immunosuppressive drugs. However, it remains to be determined whether the presence of immunosuppressive drugs negatively impacts Treg function and stability. We tested in vitro and in vivo the effects of tacrolimus, mycophenolate and methylprednisolone (major ISDs used in transplantation) on ex vivo expanded, rapamycin-treated human Tregs. The in vitro results showed that these drugs had no effect on phenotype, function and stability of Tregs, although tacrolimus affected the expression of chemokine receptors and IL-10 production. However, viability and proliferative capacity were reduced in a dose-dependent manner by all the three drugs. The in vivo experiments using a humanized mouse model confirmed the in vitro results. However, treatment of mice with only rapamycin maintained the viability, function and proliferative ability of adoptively transferred Tregs. Taken together, our results suggest that the key functions of ex vivo expanded Tregs are not affected by a concurrent immunosuppressive therapy. However, the choice of the drug combination and their timing and dosing should be considered as an essential component to induce and maintain tolerance by Treg.
AB - Immunosuppressive drugs in clinical transplantation are necessary to inhibit the immune response to donor antigens. Although they are effective in controlling acute rejection, they do not prevent long-term transplant loss from chronic rejection. In addition, immunosuppressive drugs have adverse side effects, including increased rate of infections and malignancies. Adoptive cell therapy with human Tregs represents a promising strategy for the induction of transplantation tolerance. Phase I/II clinical trials in transplanted patients are already underway, involving the infusion of Tregs alongside concurrent immunosuppressive drugs. However, it remains to be determined whether the presence of immunosuppressive drugs negatively impacts Treg function and stability. We tested in vitro and in vivo the effects of tacrolimus, mycophenolate and methylprednisolone (major ISDs used in transplantation) on ex vivo expanded, rapamycin-treated human Tregs. The in vitro results showed that these drugs had no effect on phenotype, function and stability of Tregs, although tacrolimus affected the expression of chemokine receptors and IL-10 production. However, viability and proliferative capacity were reduced in a dose-dependent manner by all the three drugs. The in vivo experiments using a humanized mouse model confirmed the in vitro results. However, treatment of mice with only rapamycin maintained the viability, function and proliferative ability of adoptively transferred Tregs. Taken together, our results suggest that the key functions of ex vivo expanded Tregs are not affected by a concurrent immunosuppressive therapy. However, the choice of the drug combination and their timing and dosing should be considered as an essential component to induce and maintain tolerance by Treg.
KW - Animals; Cells
KW - Chemokine; T-Lymphocytes
KW - Cultured; Female; Gene Expression Regulation; Humans; Immunosuppressive Agents; Interleukin-10; Male; Mice; Mice
KW - Inbred BALB C; Mice
KW - Knockout; Receptors
KW - Regulatory; Adoptive Transfer
KW - Animals; Cells
KW - Chemokine; T-Lymphocytes
KW - Cultured; Female; Gene Expression Regulation; Humans; Immunosuppressive Agents; Interleukin-10; Male; Mice; Mice
KW - Inbred BALB C; Mice
KW - Knockout; Receptors
KW - Regulatory; Adoptive Transfer
UR - http://hdl.handle.net/10447/399898
UR - http://www.haematologica.org/content/haematol/101/1/91.full.pdf
M3 - Article
VL - 101
SP - 91
EP - 100
JO - Haematologica
JF - Haematologica
SN - 0390-6078
ER -