Abstract
BackgroundA large pool of preexisting alloreactive effector T cells can cause allogeneic graft rejection following transplantation. However, it is possible to induce transplant tolerance by altering the balance between effector and regulatory T (Treg) cells. Among the various Treg-cell types, Foxp3+Treg and IL-10–producing T regulatory type 1 (Tr1) cells have frequently been associated with tolerance following transplantation in both mice and humans. Previously, we demonstrated that rapamycin+IL-10 promotes Tr1-cell–associated tolerance in Balb/c mice transplanted with C57BL/6 pancreatic islets. However, this same treatment was unsuccessful in C57BL/6 mice transplanted with Balb/c islets (classified as a stringent transplant model). We accordingly designed a protocol that would be effective in the latter transplant model by simultaneously depleting effector T cells and fostering production of Treg cells. We additionally developed and tested a clinically translatable protocol that used no depleting agent.Methodology/Principal FindingsDiabetic C57BL/6 mice were transplanted with Balb/c pancreatic islets. Recipient mice transiently treated with anti-CD45RB mAb+rapamycin+IL-10 developed antigen-specific tolerance. During treatment, Foxp3+Treg cells were momentarily enriched in the blood, followed by accumulation in the graft and draining lymph node, whereas CD4+IL-10+IL-4− T (i.e., Tr1) cells localized in the spleen. In long-term tolerant mice, only CD4+IL-10+IL-4− T cells remained enriched in the spleen and IL-10 was key in the maintenance of tolerance. Alternatively, recipient mice were treated with two compounds routinely used in the clinic (namely, rapamycin and G-CSF); this drug combination promoted tolerance associated with CD4+IL-10+IL-4− T cells.Conclusions/SignificanceThe anti-CD45RB mAb+rapamycin+IL-10 combined protocol promotes a state of tolerance that is IL-10 dependent. Moreover, the combination of rapamycin+G-CSF induces tolerance and such treatment could be readily translatable into the clinic.
Highlights
T regulatory (Treg) cells typically control immune responses, and they are capable of establishing tolerance to non-self molecules that are deliberatively introduced into the host, as occurs in allogeneic transplantation settings [1,2]
The current study demonstrates that, in a stringent model of islet transplantation, the combination of anti-CD45RB monoclonal antibody (mAb) with rapamycin+IL-10 promotes a unique state of tolerance IL-10 dependent and associated with two types of Treg cells
Anti-CD45RB mAb transiently depletes circulating T cells [18], which are responsible for allograft rejection [19,24]; at the same time, it fits the regulatory action of Treg cells [20,25]
Summary
T regulatory (Treg) cells typically control immune responses, and they are capable of establishing tolerance to non-self molecules that are deliberatively introduced into the host, as occurs in allogeneic transplantation settings [1,2]. Endogenous Treg cells do not usually occur in sufficient numbers to control the large population of pre-existing alloreactive T effector cells in recipients, and this imbalance increases the potential for graft rejection [3]. Immunosuppressive drugs block/ deplete alloreactive T effector cells, and are currently used in the clinic to prevent graft rejection [4]. Most of these drugs necessitate life-long administration and increase the risk of undesirable side effects (e.g., infections and lymphomas). We designed a protocol that would be effective in the latter transplant model by simultaneously depleting effector T cells and fostering production of Treg cells. We developed and tested a clinically translatable protocol that used no depleting agent
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