Rapamycin combined with anti-CD45RB mAB and IL-10 or with G-CSF induces tolerance in a stringent mouse model of islet transplantation

Nicola Gagliani, Silvia Gregori, Tatiana Jofra, Andrea Valle, Angela Stabilini, David M. Rothstein, Mark Atkinson, Maria Grazia Roncarolo, Manuela Battaglia

Research output: Contribution to journalArticle

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Abstract

Background: A 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 Findings: Diabetic 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/Significance: The 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.

Original languageEnglish
Article numbere28434
JournalPLoS One
Volume6
Issue number12
DOIs
Publication statusPublished - Dec 9 2011

Fingerprint

Islets of Langerhans Transplantation
Granulocyte Colony-Stimulating Factor
Sirolimus
interleukin-10
Interleukin-10
Regulatory T-Lymphocytes
animal models
T-cells
mice
T-lymphocytes
Transplants
interleukin-4
Interleukin-4
T-Lymphocytes
islets of Langerhans
Islets of Langerhans
Inbred C57BL Mouse
Grafts
cells
Spleen

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Rapamycin combined with anti-CD45RB mAB and IL-10 or with G-CSF induces tolerance in a stringent mouse model of islet transplantation. / Gagliani, Nicola; Gregori, Silvia; Jofra, Tatiana; Valle, Andrea; Stabilini, Angela; Rothstein, David M.; Atkinson, Mark; Roncarolo, Maria Grazia; Battaglia, Manuela.

In: PLoS One, Vol. 6, No. 12, e28434, 09.12.2011.

Research output: Contribution to journalArticle

Gagliani, Nicola ; Gregori, Silvia ; Jofra, Tatiana ; Valle, Andrea ; Stabilini, Angela ; Rothstein, David M. ; Atkinson, Mark ; Roncarolo, Maria Grazia ; Battaglia, Manuela. / Rapamycin combined with anti-CD45RB mAB and IL-10 or with G-CSF induces tolerance in a stringent mouse model of islet transplantation. In: PLoS One. 2011 ; Vol. 6, No. 12.
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AU - Gagliani, Nicola

AU - Gregori, Silvia

AU - Jofra, Tatiana

AU - Valle, Andrea

AU - Stabilini, Angela

AU - Rothstein, David M.

AU - Atkinson, Mark

AU - Roncarolo, Maria Grazia

AU - Battaglia, Manuela

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