Vascularized composite allotransplantation combined with costimulation blockade induces mixed chimerism and reveals intrinsic tolerogenic potential

Oh, Byoung Chol; Furtmüller, Georg J.; Fryer, Madeline L.; Guo, Yinan; Messner, Franka; Krapf, Johanna; Schneeberger, Stefan; Cooney, Damon S.; Lee, W.P. Andrew; Raimondi, Giorgio; Brandacher, Gerald

doi:10.1172/jci.insight.128560

Cited by 11 publications

(21 citation statements)

References 48 publications

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“…41,42 Other strategies, such as co-stimulation blockade with CTLA4-Ig and anti CD154 monoclonal antibodies, have shown to be advantageous for immunomodulation in VCA. 43 The idea of using MSC in SOT and VCA is promising, and several clinical and preclinical studies support the need for further research.…”

Section: Discussionmentioning

confidence: 99%

“…Other cell therapies, such as purified Tregs or CD8+ CD28− suppressor T cells, have been studied to induce mixed chimerism; however, their scarcity and difficulty to expand make their clinical use difficult 41,42 . Other strategies, such as co‐stimulation blockade with CTLA4‐Ig and anti CD154 monoclonal antibodies, have shown to be advantageous for immunomodulation in VCA 43 …”

Section: Discussionmentioning

confidence: 99%

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Graft infusion of adipose‐derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study

Andrés

Stringa

Talayero

et al. 2021

Clinical Transplantation

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Background: Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose-derived MSC (Ad-MSC) in an experimental model of acute rejection in small bowel transplantation (SBT).Material/Methods: Heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad-MSC was intra-arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad-MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad-MSC (TAC_MSC) groups. Each Ad-MSC groups was subdivided in autologous and allogeneic third-party groups.Results: Rejection rate and severity were similar in MSC-treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T-cell (CD4, CD8, and Foxp3 subsets) and B-cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro-and anti-inflammatory cytokines and some

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Graft infusion of adipose‐derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study

Andrés

Stringa

Talayero

et al. 2021

Clinical Transplantation

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“…The addition of VBM, however, did not induce true VCA tolerance, as grafts were promptly rejected once IS was discontinued (19). However, this study served as proof of principle that the intragraft VBM component conferred an immunological benefit on VCA survival, since confirmed in murine models (26,27).…”

Section: Hematopoietic Cell Transplantationmentioning

confidence: 77%

Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes

et al. 2021

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Over the past twenty years, significant technical strides have been made in the area of vascularized composite tissue allotransplantation (VCA). As in solid organ transplantation, the allogeneic immune response remains a significant barrier to long-term VCA survival and function. Strategies to overcome acute and chronic rejection, minimize immunosuppression and prolong VCA survival have important clinical implications. Historically, large animals have provided a valuable model for testing the clinical translatability of immune modulating approaches in transplantation, including tolerance induction, co-stimulation blockade, cellular therapies, and ex vivo perfusion. Recently, significant advancements have been made in these arenas utilizing large animal VCA models. In this comprehensive review, we highlight recent immune strategies undertaken to improve VCA outcomes with a focus on relevant preclinical large animal models.

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“…In the aforementioned study, long graft survival was associated with increased number of T-regulatory cells (Tregs) and decreased CD4+ and CD8+ counts ( 97 ). More recently, Oh and colleagues tested the combination of CTLA4-Ig + anti-CD154 + total body irradiation in a fully MHC-mismatched mouse hindlimb model and reported a graft survival of over seven months compared to 82 days in the group treated with CTLA4-Ig + anti-CD154 only ( 98 ). Lastly, Schweizer et al used adipose-derived mesenchymal stem cells combined with CTLA4-Ig and antilymphocyte serum in a rat hindlimb model, in addition to tacrolimus, and achieved an over 4 months rejection free allograft survival compared to control groups (median graft survival <35 days) ( 99 ).…”

Section: Ctla4-ig and Belatacept In Vca Experimental Modelsmentioning

confidence: 99%

“…Costimulation blockade alone is ineffective in inducing long-term graft allograft survival or tolerance in animal transplant models ( 98 , 117 , 118 ). The inhibition of CD28/B7 costimulation pathway affects various immune cells, including Tregs and Th17 cells, while the time course and regimen intensity are critical predictors of the ultimate response ( 119 ).…”

Section: Belatacept In Vca: Advantages and Limitationsmentioning

confidence: 99%

Costimulation Blockade in Vascularized Composite Allotransplantation

2020

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Vascular composite allotransplantation (VCA) is a field under research and has emerged as an alternative option for the repair of severe disfiguring defects that result from infections or traumatic amputation in a selected group of patients. VCA is performed in centers with appropriate expertise, experience and adequate resources to effectively manage the complexity and complications of this treatment. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in VCA. VCA is considered a quality of life transplant and the risk-benefit ratio is dissimilar to life saving transplants. Belatacept seems a promising drug that prolongs patient and graft survival in kidney transplantation and it could also be an alternative approach to VCA immunosuppression. In this review, we are summarizing current literature about the role of costimulation blockade, with a focus on belatacept in VCA.

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Vascularized composite allotransplantation combined with costimulation blockade induces mixed chimerism and reveals intrinsic tolerogenic potential

Cited by 11 publications

References 48 publications

Graft infusion of adipose‐derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study

Graft infusion of adipose‐derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study

Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes

Costimulation Blockade in Vascularized Composite Allotransplantation

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