Utility of IL-2 Complexes in Promoting the Survival of Murine Orthotopic Forelimb Vascularized Composite Allografts

Xu, Heng; Dahiya, Satinder; Wang, Liqing; Akimova, Tatiana; Han, Rongxiang; Zhang, Tianyi; Zhang, Yixin; Qin, Ling; Levine, Matthew H.; Hancock, Wayne W.; Levin, L. Scott

doi:10.1097/tp.0000000000001852

Cited by 10 publications

(9 citation statements)

References 37 publications

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“…As mentioned earlier, short-term injection of IL-2/JES6-1 mab complexes to expand Tregs in vivo led to indefinite survival of islet allografts in most mice (14) and provided potent suppression in a number of other transplantation and autoimmune disease models (16,17,(38)(39)(40). However, this treatment conspicuously failed to enhance survival of skin allografts.…”

Section: Discussionmentioning

confidence: 92%

Treg-mediated prolonged survival of skin allografts without immunosuppression

Pilat

Wiletel

Weijler

et al. 2019

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

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Injection of Interleukin-2 (IL-2) complexed with a particular anti–IL-2 monoclonal antibody (mab) JES6-1 has been shown to selectively expand CD4+Foxp3+ T regulatory T cells (Tregs) in vivo. Although the potency of this approach with regard to transplantation has already been proven in an islet transplantation model, skin graft survival could not be prolonged. Since the latter is relevant to human allograft survival, we sought to improve the efficiency of IL-2 complex (cplx) treatment for skin allograft survival in a stringent murine skin graft model. Here, we show that combining low doses of IL-2 cplxs with rapamycin and blockade of the inflammatory cytokine IL-6 leads to long-term (>75 d) survival of major histocompatibility complex-different skin allografts without the need for immunosuppression. Allograft survival was critically dependent on CD25+FoxP3+ Tregs and was not accompanied by impaired responsiveness toward donor alloantigens in vitro after IL-2 cplx treatment was stopped. Furthermore, second donor-type skin grafts were rejected and provoked rejection of the primary graft, suggesting that operational tolerance is not systemic but restricted to the graft. These findings plus the lack of donor-specific antibody formation imply that prolonged graft survival was largely a reflection of immunological ignorance. The results may represent a potentially clinically translatable strategy for the development of protocols for tolerance induction.

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Section: Discussionmentioning

confidence: 92%

Treg-mediated prolonged survival of skin allografts without immunosuppression

Pilat

Wiletel

Weijler

et al. 2019

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

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“…In our previous mouse research, a limited survival period (<70 days) of VCA induced by interleukin-2 (IL-2)/anti-IL-2 administration was found, while in some other types of allograft, long-term (>100 days) survival was achieved. 27,34,35 In histology tests, milder skin inflammation showed that MSC might have immunomodulatory ability to suppress the acute rejection. But the most important and convincing data regarding allograft rejection time failed to support that BMMSC and GMSC could prolong VCA survival.…”

Section: Discussionmentioning

confidence: 99%

Robustness Testing of Mesenchymal Stem Cell Monotherapy Following Vascularized Composite Allotransplantation

Steinberger

Kazmers

et al. 2020

J Reconstr Microsurg

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Background Immunosuppression risks are a major concern with vascularized composite allotransplantation (VCA). As an emerging strategy, the antirejection role played by mesenchymal stem cells (MSCs) is receiving attention. However, the current literature reports are inconclusive regarding the robustness of the MSC monotherapy. Using a rat forelimb VCA model, this study tested the robustness of the immunomodulation efficacy of gingival-derived MSCs (GMSCs) and bone marrow–derived MSCs (BMMSCs). Methods Forelimbs were transplanted on pairs of major histocompatibility complex–incompatible rats (Wistar-Kyoto donor, Lewis [LEW] recipient). Twenty-four LEW rats were randomly divided into four groups, including control (no treatment) and three treatment groups: rapamycin (2 mg/kg/day for 28 days, postoperatively), BMMSC and GMSC, both of which received donor-derived stem cells administered intravenously on postoperative days (PODs) 0, 3, 7, and 14. Rejection was considered as 80% skin necrosis of the allograft. Microcomputed tomography (µCT) was performed to evaluate healing at osteosynthesis site. On POD 14, limbs from each group underwent histological analysis and rejection grading using the Banff system. Results Both BMMSC (15.0 days) and GMSC (14.7 days) treatment failed to prolong VCA survival in comparison with the control group (13.8 days; p > 0.050), while the rapamycin significantly delayed acute VCA rejection (24.5 days; p = 0.003). Micro-CT imaging revealed no gross visual difference across all groups. Histology revealed that the control group was most severely affected (grades III and IV) followed by MSC (grade II) and rapamycin (grade I). Conclusion MSC monotherapy, both BMMSC and GMSC, did not inhibit rejection in our VCA model. Skin immunogenicity is an important issue in promoting rejection, and a concomitant immunosuppression regimen should be considered to prolong allograft survival.

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“…Costimulation blockade was shown to induce tolerance in a small animal model of VCA [45] and a myeloablative conditioning combined with hematopoietic transplant-induced stable mixed chimerism in a large animal model [46]. In addition, IL-2-based immunosuppression appears to be another promising approach for promoting immune regulation posttransplant and immunosuppression minimization [47][48][49]. Cellbased therapies might also improve the immunologic outcomes in VCA [50][51][52].…”

Section: Discussionmentioning

confidence: 99%

Novel immunological and clinical insights in vascularized composite allotransplantation

Kollar

Pomahac

Riella

2019

Current Opinion in Organ Transplantation

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Purpose of reviewVascularized composite allotransplantation (VCA) is a promising approach to restore the quality of life of carefully selected patients that suffered extensive injury. Although acute rejection occurs very frequently, still little is known about the specific characteristics of the VCA immune response. This review aims to highlight the current development in the field of VCA concerning the immunobiology and management of upper extremity and face transplant recipients. Recent findingsT-cell mediated rejection is the predominant mechanism of allograft injury in VCA. As current histological classification does not differentiate types of rejection, novel evidence using NanoString has determined a molecular signature that helps identify antibody-mediated rejection in comparison to T-cell mediated rejection. Additionally, long-term follow-up of VCA patients progressively reveals various features of chronic rejection, and novel immunosuppressive approaches such as costimulation blockade found its way into immunosuppressive regimens of VCA recipients, unraveling its potential benefits as well as limitations. Finally, novel noninvasive biomarkers were recently evaluated and showed promise to differentiate the severity of acute rejection, and consequently, the intensity of treatment required.

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Utility of IL-2 Complexes in Promoting the Survival of Murine Orthotopic Forelimb Vascularized Composite Allografts

Abstract: Our studies involving different IL-2C-mediated Treg cell expansion strategies demonstrate that pre-Tx IL-2C therapy may be a useful component for developing strategies to promote VCA survival.

Cited by 10 publications

References 37 publications

Treg-mediated prolonged survival of skin allografts without immunosuppression

Treg-mediated prolonged survival of skin allografts without immunosuppression

Robustness Testing of Mesenchymal Stem Cell Monotherapy Following Vascularized Composite Allotransplantation

Novel immunological and clinical insights in vascularized composite allotransplantation

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