Prolonged Mouse Cardiac Graft Cold Storage via Attenuating Ischemia-Reperfusion Injury Using a New Antioxidant-Based Preservation Solution

Cai, Shanshan; Ichimaru, Naotsugu; Zhao, Mingyi; Fujino, Masayuki; Ito, Hidenori; Ota, Urara; Nakajima, Motowo; Tanaka, Tohru; Nonomura, Norio; Li, Xiaokang; Takahara, Shiro

doi:10.1097/tp.0000000000001079

Cited by 11 publications

(10 citation statements)

References 41 publications

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“…It has been previously demonstrated that heart graft tissue survival can be prolonged to a maximum of 24 hours CIT using a solution containing antioxidant reagents or a modified histidine-tryptophan ketoglutarate solution. 19, 23 The advantages of normal saline solution are that it is readily available and does not enhance recovery. 27 This allowed for direct analysis of the efficacy of mitochondrial transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…One mL of heparin (100 IU/mL) was injected via the inferior vena cava and allowed to circulate for 10 min. 19 The heart grafts were then excised and stored in normal saline solution (Baxter, Deerfield, IL, USA) containing 1% Penicillin and 1% Streptomycin at 4°C. Following, 29 ± 0.3 hours CIT, the heart grafts were transplanted into the abdomen of C57BL/6J recipients and coronary circulation was re-established.…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial transplantation prolongs cold ischemia time in murine heart transplantation

Moskowitzova

Shin

Liu

et al. 2019

The Journal of Heart and Lung Transplantation

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BACKGROUND Cold ischemia time (CIT) causes ischemia-reperfusion injury to the mitochondria and detrimentally effects myocardial function and tissue viability. Mitochondrial transplantation replaces damaged mitochondria and enhances myocardial function and tissue viability. Herein, we investigate the efficacy of mitochondrial transplantation in enhancing graft function and viability after prolonged CIT. METHODS Heterotopic heart transplantation was performed in C57BL/6J mice. Upon heart harvesting from C57BL/6J donors, 0.5 mL of either mitochondria (1 × 108 in respiration buffer; Mitochondria) or respiration buffer (Vehicle) was delivered antegrade to the coronary arteries via injection to the coronary ostium. The hearts were excised and preserved for 29 ± 0.3 hours in cold saline (4°C). The hearts were heterotopically transplanted. A second injection of either mitochondria (1 × 108) or respiration buffer (Vehicle) was delivered antegrade to the coronary arteries 5 minutes after transplantation. Grafts were analyzed for 24 hours. Beating score, graft function and tissue injury were measured. RESULTS Beating score, calculated ejection fraction and shortening fraction were significantly enhanced (P < 0.05), while necrosis and neutrophil infiltration were significantly decreased (P < 0.05) in Mitochondria as compared to Vehicle at 24 hours of reperfusion. Transmission electron microscopy showed the presence of contraction bands in Vehicle but not in Mitochondria grafts. CONCLUSION Mitochondrial transplantation prolongs CIT to 29 hours in the murine heart transplantation model and significantly enhances graft function and decreases graft tissue injury. Mitochondrial transplantation may provide a means to reduce graft failure and improve transplantation outcomes after prolonged CIT.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mitochondrial transplantation prolongs cold ischemia time in murine heart transplantation

Moskowitzova

Shin

Liu

et al. 2019

The Journal of Heart and Lung Transplantation

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“…Heterotopic Heart Transplantation. Fully vascularized hearts from BALB/c mice were heterotopically transplanted to the abdominal cavity of recipient C57BL/ 6 (WT) or B6.Qa-1.D227K (D227K) mice using a microsurgical technique previously described (22). For the single-dose CTLA4-Ig protocol, 250 μg of CTLA4-Ig (Belatacept) was intravenously (i.v.)…”

Section: Methodsmentioning

confidence: 99%

Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

Choi

Eskandari

Cai

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)–CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1–restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection.

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“…As donor-derived MDSCs require 6 days of culture, the clinical application of our approach is more suitable for living donor transplantation, such as lung, kidney and liver. However, we employed in this study a very stringent, reproducible and well established mouse allogeneic cardiac transplantation to test our hypothesis 57 .…”

Section: Discussionmentioning

confidence: 99%

“…All transplant procedures were performed under anesthesia with isoflurane. Fully vascularized heterotopic hearts from BALB/c or C3H were transplanted into C57BL/6 recipients using a microsurgical technique 14 , 57 . Graft survival was considered complete at the time of cessation of a palpable heart beating and confirmed visually by laparotomy.…”

Section: Methodsmentioning

confidence: 99%

Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo

Cai

Choi

Borges

et al. 2020

Sci Rep

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Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current immunosuppression protocols are not designed to target antigen-specific alloimmunity and are uncapable of preventing chronic allograft injury. As myeloid-derived suppressor cells (MDSCs) are potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2K b , I-A b) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2K d , I-A d) or third-party (C3H, H2K k , I-A k) cardiac grafts. Spleens and allografts from C57BL/6 recipients were harvested for immune phenotyping, transcriptomic profiling and functional assays. Single injection of donor-derived MDSCs significantly prolonged the fully MHC mismatched allogeneic cardiac graft survival in a donor-specific fashion. Transcriptomic analysis of allografts harvested from donor-derived MDSCs treated recipients showed down-regulated proinflammatory cytokines. Immune phenotyping showed that the donor MDSCs administration suppressed effector T cells in recipients. Interestingly, significant increase in recipient endogenous CD11b + Gr1 + MDSC population was observed in the group treated with donorderived MDSCs compared to the control groups. Depletion of this endogenous MDSCs with anti-Gr1 antibody reversed donor MDSCs-mediated allograft protection. Furthermore, we observed that the allogeneic mixed lymphocytes reaction was suppressed in the presence of CD11b + Gr1 + MDScs in a donor-specific manner. Donor-derived MDSCs prolong cardiac allograft survival in a donor-specific manner via induction of recipient's endogenous MDSCs. Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. The Scientific Registry of Transplant Recipients (SRTR) reported that 14,313 kidney 1 , 7,483 liver 2 , 2,465 lung 3 , 432 heart 4 , 80 pancreas 5 , and 109 intestinal 6 transplants were performed in 2017 in the US (Feb 2019 updated). Nevertheless, number of challenges remain for organ recipients after the transplantation, as they suffer from acute and chronic rejection as well as complications of immunosuppression 7-9. One of the more critical issues pertains to the current state of standard immunosuppressive protocols. Calcineurin inhibitor (CNI) based immunosuppressive protocols are not designed to promote antigen-specific tolerance, and may exacerbate chronic allograft injury (i.e. calcineurin toxicity) 10. Therefore, there is an urgent need to establish safer anti-rejection strategies by targeting antigenspecific alloimmunity.

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Prolonged Mouse Cardiac Graft Cold Storage via Attenuating Ischemia-Reperfusion Injury Using a New Antioxidant-Based Preservation Solution

Abstract: The SS-II prolongs the acceptable cold storage time and protects the myocardium from I/R injury via inhibiting oxidative stress-associated damage. We believe that this novel preservation solution may be simple and safe for use in the clinical transplantation field.

Cited by 11 publications

References 41 publications

Mitochondrial transplantation prolongs cold ischemia time in murine heart transplantation

Mitochondrial transplantation prolongs cold ischemia time in murine heart transplantation

Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo

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