Rapamycin and IL-10 treatment induces T regulatory type 1 (Tr1) cells in vivo that mediate antigen-specific transplantation tolerance

Islet transplantation is a cure for type 1 diabetes, but its
potential is limited by the need for constant immunosuppression.
One solution to this problem is the induction of
transplantation tolerance mediated by T regulatory cells. T
regulatory type 1 (Tr1) cells are characterized by their
production of high levels of interleukin (IL)-10, which is
crucial for their differentiation and suppressive function.
We investigated the effects of IL-10 administered in combination
with rapamycin on the induction of Tr1 cells that
could mediate a state of tolerance in diabetic mice after
pancreatic islet transplantation. The efficacy of this treatment
was compared with IL-10 alone and standard immunosuppression.
Stable long-term tolerance that was not
reversible by alloantigen rechallenge was achieved only in
mice treated with rapamycin plus IL-10. Tr1 cells that
produced high levels of IL-10 and suppressed T-cell proliferation
were isolated from splenocytes of rapamycin plus
IL-10–treated mice after treatment withdrawal. In rapamycin
plus IL-10–treated mice, endogenous IL-10 mediated an
active state of tolerance, as was observed when the blockade
of IL-10 activity rapidly induced graft rejection >100
days after transplantation. CD4 T-cells from rapamycin
plus IL-10–treated mice transferred antigen-specific tolerance
in mice that received new transplants. Thus rapamycin
plus IL-10 not only prevented allograft rejection but
also induced Tr1 cells that mediated stable antigen-specific,
long-term tolerance in vivo