Acute rejection in vascularized composite allotransplantation

Fischer, Sebastian; Lian, Christine G.; Kueckelhaus, Maximilian; Strom, Terry B.; Edelman, Elazer R.; Clark, Russell A.; Murphy, Gëorge F.; Chandraker, Anil; Riella, Leonardo V.; Tullius, Stefan G.; Pomahac, Bohdan

doi:10.1097/mot.0000000000000140

Cited by 90 publications

(85 citation statements)

References 71 publications

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“…Although VCA surgical procedures have become highly successful, the high incidence of acute rejection within the first year after surgery 28 and the requirement for long-term and high-dose immunosuppression 28,29 remain obstacles to its widespread application. Current immunosuppression strategies applied in VCA are extrapolated from solid organ Tx regimens 30 , and since the toxicity of immunosuppressive therapies is a heightened concern in the context of a non life-saving procedure, an important goal in VCA research is the development of immune-sparing therapies.…”

Section: Discussionmentioning

confidence: 99%

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Targeted Complement Inhibition Protects Vascularized Composite Allografts From Acute Graft Injury and Prolongs Graft Survival When Combined With Subtherapeutic Cyclosporine A Therapy

et al. 2017

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Background Recipients of vascularized composite allografts require aggressive and life-long immunosuppression, and since the surgery is usually performed in nonlife threatening situations, the development of strategies to minimize immunosuppression is especially pertinent for this procedure. We investigated how complement affects acute graft injury, alloimmunity, and immunosuppressive therapy. Methods Vascularized composite allografts were transplanted from Balb/C to C57BL/6 mice that were complement deficient (C3 or double C3a Receptor (R)/C5aR), or treated with a targeted complement inhibitor (CR2-Crry). Allografts were analyzed for acute inflammation and injury, subacute T cell response, and survival in the absence and presence of CsA therapy. Results Allografts in C3-deficient or CR2-Crry treated recipients were protected from skin and muscle ischemia reperfusion injury (IRI). C3aR/C5aR deficient recipients were more modestly protected. IgM and C3d colocalized within allografts from wild type and C3aR/C5aR-deficient recipients indicating IgM-mediated complement activation, and C3d deposition was almost absent in allografts from C3-deficient and CR2-Crry treated recipients. Inflammatory cell infiltration and P-selectin expression was also significantly reduced in C3-deficient and CR2-Crry treated recipients. Acute treatment with CR2-Crry or with 3 mg/kg/day cyclosporine A (CsA) modestly, but significantly increased median allograft survival from 5.8 to 7.4 and 7.2 days, respectively. However, combined acute CR2-Crry treatment and CsA therapy increased mean graft survival to 17.2 days. Protection was associated with significantly reduced T cell infiltration of allografts and Tc1 cells in recipient spleens. Conclusions Complement-mediated IRI augments graft allogenicity, and appropriate complement inhibition ameliorates IRI, decreases alloimmune priming and allows more immune-sparing CsA dosing.

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Section: Discussionmentioning

confidence: 99%

“…Current therapeutic approaches in standard VCA protocols target primarily cell-mediated rejection 28 . We therefore also investigated the effect of complement inhibition in the context of immunosuppressive therapy with CsA.…”

Section: Discussionmentioning

confidence: 99%

Targeted Complement Inhibition Protects Vascularized Composite Allografts From Acute Graft Injury and Prolongs Graft Survival When Combined With Subtherapeutic Cyclosporine A Therapy

et al. 2017

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“…If observations of the outcome of organ transplantation are a valid source of guidance (12–14, 18, 27, 28), recipients of VCA should be at high risk for AMR. VCA often include skin, which is highly immunogenic and reliably elicits production of DSA (29).…”

Section: Introductionmentioning

confidence: 99%

Accommodation and related conditions in vascularized composite allografts

Platt

Kaufman

Barbosa

et al. 2017

Current Opinion in Organ Transplantation

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Purpose of review The outcome of vascularized composite allografts (VCA) often appear unrelated to the presence of donor-specific antibodies (DSA) in blood of the recipient or deposition of complement in the graft. The attenuation of injury and the absence of rejection in other types of grafts despite manifest donor-specific immunity have been explained by accommodation (acquired resistance to immune-mediated injury), adaptation (loss of graft antigen) and/or enhancement (antibody-mediated antigen blockade). Whether and how accommodation, adaptation and/or enhancement impact on the outcome of vascularized composite allografts (VCA) is unknown. Here we consider how recent observations concerning accommodation in organ transplants might advance understanding and resolve uncertainties about the clinical course of VCA. Recent findings Investigation of the mechanisms through which kidney allografts avert antibody-mediated injury and rejection provide insights potentially applicable to VCA. Interaction of donor-specific antibodies (DSA) can facilitate replacement of donor by recipient endothelial cells, modulate or decrease synthesis of antigen, mobilize antigen that in turn blocks further immune recognition and limit the amount of bound antibody, allowing accommodation to ensue. These processes also can explain the apparent dissociation between the presence and levels of DSA in blood, deposition of C4d in grafts and antibody-mediated rejection. Over time the processes might also explain the inception of chronic graft changes. Summary The disrupted tissue in VCA and potential for re-population by endothelial cells of the recipient establish conditions that potentially decrease susceptibility to acute antibody-mediated rejection. These conditions include clonal suppression of donor-specific B cells, and adaptation, enhancement and accommodation. This setting also potentially highlights heretofore-unrecognized interactions between these “protective” processes.

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“…However, most recipients had acute rejection episodes in the first year, revealed as skin redness, swelling and nodules and papules. [54,71,72] In FAT, episodes of mild rejection may be easier to treat than in solid organ transplantation due to immediate visibility of the skin and easy inspection. Episodes of acute rejection were usually reversible with corticosteroids (bolus treatment), supplemented in some cases by topical drugs (steroids and tacrolimus).…”

Section: Inmunologymentioning

confidence: 99%

Current role in facial allograft transplantation: what have we learned?

Infante-Cossio¹,

Barrera-Pulido²,

Gómez-Cía³

et al. 2016

PAR

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Face transplant (FT) has evolved enormously in the last 10 years since the successful completion of the first facial transplant. This procedure has become a new reconstructive option for complex facial deformities to restore the anatomy of patients with severely disfigured faces. The authors review the literature and discuss the main surgical, immunological, and ethical aspects as well as the results described in patients undergoing FT. To date there have been more than thirty FT worldwide. The main indication was post-traumatic deformity. In all cases a standard immunosuppression was performed with three drugs, although acute rejection episodes were observed, that could be controlled with conventional immunosuppressive regimen. Overall, functional and aesthetic results have been excellent at short-term and high satisfaction rate exceeded initial expectations, although long-term data are still scarce. Major complications were opportunistic infections. Five deaths that occurred have reopened the ethical debate about the potential complications and concerns of providing informed consent to recipients. Continuous progresses in microsurgical techniques and preoperative planning have promoted the evolution from partial to full FT. All these are on the basis of accurate and careful selection of wellmotivated candidates. The next challenge will be getting new immunosuppressive treatment strategies. Although clinical experience has demonstrated the FT viability, it is still considered an experimental procedure in which we have much to learn to define its true role in the current reconstructive surgery and resolve major technical, medical and ethical problems involved.

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Acute rejection in vascularized composite allotransplantation

Cited by 90 publications

References 71 publications

Targeted Complement Inhibition Protects Vascularized Composite Allografts From Acute Graft Injury and Prolongs Graft Survival When Combined With Subtherapeutic Cyclosporine A Therapy

Targeted Complement Inhibition Protects Vascularized Composite Allografts From Acute Graft Injury and Prolongs Graft Survival When Combined With Subtherapeutic Cyclosporine A Therapy

Accommodation and related conditions in vascularized composite allografts

Current role in facial allograft transplantation: what have we learned?

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