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

Gagliani, N and Gregori, S and Jofra, T and Valle, A and Stabilini, A and Rothstein, DM and Atkinson, M and Roncarolo, MG and Battaglia, M (2011) Rapamycin combined with anti-CD45RB mAB and IL-10 or with G-CSF induces tolerance in a stringent mouse model of islet transplantation. PLoS ONE, 6 (12).

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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. © 2011 Gagliani et al. + + + + - + + - + + -


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gagliani, N
Gregori, S
Jofra, T
Valle, A
Stabilini, A
Rothstein, DMdmr53@pitt.eduDMR53
Atkinson, M
Roncarolo, MG
Battaglia, M
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorEltzschig, Holger KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 9 December 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 12
DOI or Unique Handle: 10.1371/journal.pone.0028434
Refereed: Yes
MeSH Headings: Animals; Antibodies, Monoclonal--immunology; Antigens, CD4--metabolism; Antigens, CD45--immunology; Drug Therapy, Combination; Epitopes--immunology; Female; Forkhead Transcription Factors--metabolism; Granulocyte Colony-Stimulating Factor--pharmacology; Humans; Immune Tolerance--drug effects; Interleukin-10--pharmacology; Interleukin-2 Receptor alpha Subunit--metabolism; Islets of Langerhans Transplantation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Animal; Sirolimus--pharmacology; Spleen--drug effects; Spleen--immunology; T-Lymphocytes, Regulatory--drug effects; T-Lymphocytes, Regulatory--metabolism; Time Factors; Transplantation, Homologous
Other ID: NLM PMC3235119
PubMed Central ID: PMC3235119
PubMed ID: 22174806
Date Deposited: 07 Sep 2012 19:41
Last Modified: 30 Mar 2021 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/14002

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