Rapamycin combined with anti-CD45RB mAb and IL-10 or with G-CSF induces tolerance in a stringent mouse model of islet transplantation
Standard
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, Jahrgang 6, Nr. 12, 2011, S. e28434.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Rapamycin combined with anti-CD45RB mAb and IL-10 or with G-CSF induces tolerance in a stringent mouse model of islet transplantation
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
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Antibodies, Monoclonal
KW - CD4 Antigens
KW - Drug Therapy, Combination
KW - Epitopes
KW - Female
KW - Forkhead Transcription Factors
KW - Granulocyte Colony-Stimulating Factor
KW - Humans
KW - Immune Tolerance
KW - Interleukin-10
KW - Interleukin-2 Receptor alpha Subunit
KW - Islets of Langerhans Transplantation
KW - Leukocyte Common Antigens
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Models, Animal
KW - Sirolimus
KW - Spleen
KW - T-Lymphocytes, Regulatory
KW - Time Factors
KW - Transplantation, Homologous
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1371/journal.pone.0028434
DO - 10.1371/journal.pone.0028434
M3 - SCORING: Journal article
C2 - 22174806
VL - 6
SP - e28434
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 12
ER -
