A combination regimen of low-dose bortezomib and rapamycin prolonged the graft survival in a murine allogeneic islet transplantation model

So Hee Hong, Kihyun Kim, Jun Seop Shin, Hyunwoo Chung, Chunggyu Park

Research output: Contribution to journalArticle

Abstract

As the first FDA-approved proteasome inhibitor drug, bortezomib has been used for the treatment of multiple myeloma and lymphoma. However, its effects alone or in combination with other immunosuppressants on allogeneic islet transplantation have not been reported so far. In this study, we showed that the short-term combination treatment of low-dose bortezomib and rapamycin significantly prolonged the survival of islet allografts. Short-term treatment of low-dose (0.05 mg/kg or 0.1 mg/kg) bortezomib reduced the MHC class II expression in dendritic cells (DCs) of alloantigen-sensitized mice, and prolonged the islet allograft survival for up to 50 days in diabetic mice. Notably, when bortezomib was combined with rapamycin, it induced islet-specific immunological tolerance which allowed the acceptance of a second graft without additional immunosuppression. This regimen dramatically reduced the alloantigen-specific IFN-γ-producing T cells in the spleen, and increased regulatory T cells both at the graft site and in the spleen. Therefore, we propose that short-term treatment of low-dose bortezomib and rapamycin could be a new tolerance-promoting immunosuppressive regimen for allogeneic islet transplantation.

Original languageEnglish
Pages (from-to)21-27
Number of pages7
JournalImmunology Letters
Volume216
DOIs
StatePublished - 1 Dec 2019

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Islets of Langerhans Transplantation
Homologous Transplantation
Graft Survival
Sirolimus
Isoantigens
Immunosuppressive Agents
Allografts
Spleen
Transplants
Proteasome Inhibitors
Regulatory T-Lymphocytes
Therapeutics
Multiple Myeloma
Immunosuppression
Dendritic Cells
Lymphoma
Bortezomib
T-Lymphocytes
Pharmaceutical Preparations

Keywords

  • Bortezomib
  • Islet transplantation
  • Rapamycin
  • Tolerance

Cite this

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abstract = "As the first FDA-approved proteasome inhibitor drug, bortezomib has been used for the treatment of multiple myeloma and lymphoma. However, its effects alone or in combination with other immunosuppressants on allogeneic islet transplantation have not been reported so far. In this study, we showed that the short-term combination treatment of low-dose bortezomib and rapamycin significantly prolonged the survival of islet allografts. Short-term treatment of low-dose (0.05 mg/kg or 0.1 mg/kg) bortezomib reduced the MHC class II expression in dendritic cells (DCs) of alloantigen-sensitized mice, and prolonged the islet allograft survival for up to 50 days in diabetic mice. Notably, when bortezomib was combined with rapamycin, it induced islet-specific immunological tolerance which allowed the acceptance of a second graft without additional immunosuppression. This regimen dramatically reduced the alloantigen-specific IFN-γ-producing T cells in the spleen, and increased regulatory T cells both at the graft site and in the spleen. Therefore, we propose that short-term treatment of low-dose bortezomib and rapamycin could be a new tolerance-promoting immunosuppressive regimen for allogeneic islet transplantation.",
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A combination regimen of low-dose bortezomib and rapamycin prolonged the graft survival in a murine allogeneic islet transplantation model. / Hong, So Hee; Kim, Kihyun; Shin, Jun Seop; Chung, Hyunwoo; Park, Chunggyu.

In: Immunology Letters, Vol. 216, 01.12.2019, p. 21-27.

Research output: Contribution to journalArticle

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AU - Park, Chunggyu

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