Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model
Abstract Background Off-the-shelf major histocompatibility complex (MHC)-matched iPS cells (iPSC) can potentially initiate host immune responses because of the existence of numerous minor antigens. To suppress allo-immune responses, combination of immunosuppressants is usually used, but its efficacy...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-02-01
|
| Series: | Inflammation and Regeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s41232-021-00190-7 |
| _version_ | 1818499481333661696 |
|---|---|
| author | Tomoki Kamatani Ryo Otsuka Tomoki Murata Haruka Wada Takeshi Takahashi Akihiro Mori Soichiro Murata Hideki Taniguchi Ken-ichiro Seino |
| author_facet | Tomoki Kamatani Ryo Otsuka Tomoki Murata Haruka Wada Takeshi Takahashi Akihiro Mori Soichiro Murata Hideki Taniguchi Ken-ichiro Seino |
| author_sort | Tomoki Kamatani |
| collection | DOAJ |
| description | Abstract Background Off-the-shelf major histocompatibility complex (MHC)-matched iPS cells (iPSC) can potentially initiate host immune responses because of the existence of numerous minor antigens. To suppress allo-immune responses, combination of immunosuppressants is usually used, but its efficacy to the allogeneic iPSC-based transplantation has not been precisely evaluated. Methods Three transplantation models were used in this study; MHC-matched, minor antigen-mismatched mouse skin or iPSC-graft transplantation, and fully allogeneic human iPSC-derived liver organoid transplantation in immune-humanized mice. The recipients were treated with triple drugs combination (TDC; tacrolimus, methylprednisolone, and mycophenolate mofetil) or co-stimulatory molecule blockade (CB) therapy with some modifications. Graft survival as well as anti-donor T and B cell responses was analyzed. Results In the mouse skin transplantation model, immunological rejection caused by the minor antigen-mismatch ranged from mild to severe according to the donor-recipient combination. The TDC treatment could apparently control the mild skin graft rejection when combined with a transient T cell depletion, but unexpected anti-donor T or B cell response was observed. On the other hand, CB therapy, particularly when combined with rapamycin treatment, was capable of attenuating both mild and severe skin graft rejection and allowing them to survive long-term without any unfavorable anti-donor immune responses. The efficacy of the CB therapy was confirmed in both mouse and human iPSC-derived graft transplantation. Conclusions The findings suggest that the CB-based treatment seems suitable to well manage the MHC-matched allogeneic iPSC-based transplantation. The TDC-based treatment may be also used to suppress the rejection, but screening of its severity prior to the transplantation seems to be needed. |
| first_indexed | 2024-12-10T20:30:09Z |
| format | Article |
| id | doaj.art-921a43b21ced413aa7e86b9447892ae7 |
| institution | Directory Open Access Journal |
| issn | 1880-8190 |
| language | English |
| last_indexed | 2024-12-10T20:30:09Z |
| publishDate | 2022-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Inflammation and Regeneration |
| spelling | doaj.art-921a43b21ced413aa7e86b9447892ae72022-12-22T01:34:44ZengBMCInflammation and Regeneration1880-81902022-02-0142111310.1186/s41232-021-00190-7Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation modelTomoki Kamatani0Ryo Otsuka1Tomoki Murata2Haruka Wada3Takeshi Takahashi4Akihiro Mori5Soichiro Murata6Hideki Taniguchi7Ken-ichiro Seino8Division of Immunobiology, Institute for Genetic Medicine, Hokkaido UniversityDivision of Immunobiology, Institute for Genetic Medicine, Hokkaido UniversityDivision of Immunobiology, Institute for Genetic Medicine, Hokkaido UniversityDivision of Immunobiology, Institute for Genetic Medicine, Hokkaido UniversityCentral Institute for Experimental Animals (CIEA)Department of Regenerative Medicine, Yokohama City University Graduate School of MedicineDepartment of Regenerative Medicine, Yokohama City University Graduate School of MedicineDepartment of Regenerative Medicine, Yokohama City University Graduate School of MedicineDivision of Immunobiology, Institute for Genetic Medicine, Hokkaido UniversityAbstract Background Off-the-shelf major histocompatibility complex (MHC)-matched iPS cells (iPSC) can potentially initiate host immune responses because of the existence of numerous minor antigens. To suppress allo-immune responses, combination of immunosuppressants is usually used, but its efficacy to the allogeneic iPSC-based transplantation has not been precisely evaluated. Methods Three transplantation models were used in this study; MHC-matched, minor antigen-mismatched mouse skin or iPSC-graft transplantation, and fully allogeneic human iPSC-derived liver organoid transplantation in immune-humanized mice. The recipients were treated with triple drugs combination (TDC; tacrolimus, methylprednisolone, and mycophenolate mofetil) or co-stimulatory molecule blockade (CB) therapy with some modifications. Graft survival as well as anti-donor T and B cell responses was analyzed. Results In the mouse skin transplantation model, immunological rejection caused by the minor antigen-mismatch ranged from mild to severe according to the donor-recipient combination. The TDC treatment could apparently control the mild skin graft rejection when combined with a transient T cell depletion, but unexpected anti-donor T or B cell response was observed. On the other hand, CB therapy, particularly when combined with rapamycin treatment, was capable of attenuating both mild and severe skin graft rejection and allowing them to survive long-term without any unfavorable anti-donor immune responses. The efficacy of the CB therapy was confirmed in both mouse and human iPSC-derived graft transplantation. Conclusions The findings suggest that the CB-based treatment seems suitable to well manage the MHC-matched allogeneic iPSC-based transplantation. The TDC-based treatment may be also used to suppress the rejection, but screening of its severity prior to the transplantation seems to be needed.https://doi.org/10.1186/s41232-021-00190-7iPS cell transplantationTransplantation immunologyMHC-matchedMinor antigenImmunosuppressive agentsCostimulatory molecule blockade |
| spellingShingle | Tomoki Kamatani Ryo Otsuka Tomoki Murata Haruka Wada Takeshi Takahashi Akihiro Mori Soichiro Murata Hideki Taniguchi Ken-ichiro Seino Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model Inflammation and Regeneration iPS cell transplantation Transplantation immunology MHC-matched Minor antigen Immunosuppressive agents Costimulatory molecule blockade |
| title | Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model |
| title_full | Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model |
| title_fullStr | Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model |
| title_full_unstemmed | Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model |
| title_short | Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model |
| title_sort | evaluation of immunosuppression protocols for mhc matched allogeneic ips cell based transplantation using a mouse skin transplantation model |
| topic | iPS cell transplantation Transplantation immunology MHC-matched Minor antigen Immunosuppressive agents Costimulatory molecule blockade |
| url | https://doi.org/10.1186/s41232-021-00190-7 |
| work_keys_str_mv | AT tomokikamatani evaluationofimmunosuppressionprotocolsformhcmatchedallogeneicipscellbasedtransplantationusingamouseskintransplantationmodel AT ryootsuka evaluationofimmunosuppressionprotocolsformhcmatchedallogeneicipscellbasedtransplantationusingamouseskintransplantationmodel AT tomokimurata evaluationofimmunosuppressionprotocolsformhcmatchedallogeneicipscellbasedtransplantationusingamouseskintransplantationmodel AT harukawada evaluationofimmunosuppressionprotocolsformhcmatchedallogeneicipscellbasedtransplantationusingamouseskintransplantationmodel AT takeshitakahashi evaluationofimmunosuppressionprotocolsformhcmatchedallogeneicipscellbasedtransplantationusingamouseskintransplantationmodel AT akihiromori evaluationofimmunosuppressionprotocolsformhcmatchedallogeneicipscellbasedtransplantationusingamouseskintransplantationmodel AT soichiromurata evaluationofimmunosuppressionprotocolsformhcmatchedallogeneicipscellbasedtransplantationusingamouseskintransplantationmodel AT hidekitaniguchi evaluationofimmunosuppressionprotocolsformhcmatchedallogeneicipscellbasedtransplantationusingamouseskintransplantationmodel AT kenichiroseino evaluationofimmunosuppressionprotocolsformhcmatchedallogeneicipscellbasedtransplantationusingamouseskintransplantationmodel |