Novel immunological and clinical insights in vascularized composite allotransplantation

Kollar, Branislav; Pomahac, Bohdan; Riella, Leonardo V.

doi:10.1097/mot.0000000000000592

Cited by 28 publications

(28 citation statements)

References 55 publications

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“…An important element for the clinical advancement of vascularized composite allotransplantation (VCA) is the development of immunosuppression regimens that prevent rejection by targeting specific immune mechanisms known to influence the tissues transplanted in a VCA, while avoiding major toxicities of immunosuppressants [1]. Current standard immunotherapies in VCA rely on agents such as calcineurin inhibitors (CNIs) and steroids which are known to cause side effects including nephrotoxicity, hypertension, and diabetes [2].…”

Section: Introductionmentioning

confidence: 99%

Th17 cell inhibition in a costimulation blockade‐based regimen for vascularized composite allotransplantation using a nonhuman primate model

et al. 2020

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Vascularized composite allotransplantation (VCA) is challenged by the morbidity of immunosuppression required to prevent rejection. The use of highly specific biologics has not been well explored in VCA. Given that psoriasis is T-cell mediated, as is rejection of skin-containing VCAs, we sought to assess the role of ustekinumab and secukinumab, which are approved to treat psoriasis by inhibiting Th17 cells. We combined these agents with belatacept and steroids in a VCA nonhuman primate model. Group I consisted of belatacept and steroids, group II was belatacept, ustekinumab with steroid taper, and group III was belatacept, secukinumab with steroid taper. Three animals were transplanted in each group. In group I, the mean graft survival time until the first sign of rejection was 10 days whereas in group II and III it was 10.33 and 11 days, respectively. The immunohistochemistry analysis showed that the number of IL-17a + cells and the intensity of IL-17a expression were significantly reduced in both dermis and hypodermis parts in groups II and III when compared to group I (P < 0.01). Ustekinumab and secukinumab led to less T-cell infiltration and IL-17a expression in the allograft but provided no benefit to belatacept and steroids in VCA survival.

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Section: Introductionmentioning

confidence: 99%

Th17 cell inhibition in a costimulation blockade‐based regimen for vascularized composite allotransplantation using a nonhuman primate model

et al. 2020

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“…The diagnosis of AR in VCA frequently poses challenges. In contrast to solid organ transplantation, the transplanted faces, and extremities can be exposed to external conditions such as variations in temperature, humidity, ultraviolet light, chemical/natural agents, minor injuries/traumas, and skin microbiota (5–7). These factors might amplify the adaptive immune response leading to rejection but also just mimic alloimmune injury through non-specific local inflammation.…”

Section: Introductionmentioning

confidence: 99%

MMP3 Is a Non-invasive Biomarker of Rejection in Skin-Bearing Vascularized Composite Allotransplantation: A Multicenter Validation Study

et al. 2019

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Background: There is unmet need for non-invasive immunomonitoring to improve diagnosis and treatment of acute rejection in vascularized composite allotransplantation (VCA). Circulating matrix metalloproteinase 3 (MMP3) was described as a candidate non-invasive biomarker to predict treatment response to acute rejection in clinical VCA. However, larger validation studies are yet to be reported to allow for more definitive conclusions.Methods: We retrospectively measured MMP3 levels using ELISA in a total of 140 longitudinal serum samples from six internal and three external face transplant recipients, as well as three internal and seven external upper extremity transplant recipients. The control groups comprised serum samples from 36 kidney transplant recipients, 14 healthy controls, and 38 patients with autoimmune skin disease. A linear mixed model was used to study the effect of rejection state (pre-transplant, no-rejection, non-severe rejection (NSR), and severe rejection) on MMP3 levels.Results: In VCA, MMP3 levels increased significantly (p < 0.001) between pre- and post-transplant no-rejection states. A further increase occurred during severe rejection (p < 0.001), while there was no difference in MMP3 levels between non-severe and no-rejection episodes. A threshold of 5-fold increase from pre-transplant levels could discriminate severe from NSR with 76% sensitivity and 81% specificity (AUC = 0.79, 95% CI = 0.65–0.92, p < 0.001). In kidney transplantation, the MMP3 levels were significantly (p < 0.001) elevated during antibody-mediated rejection but not during T-cell mediated rejection (TCMR) (p = 0.547). MMP3 levels in healthy controls and autoimmune skin disease patients were comparable with either pre-transplant or no-rejection/NSR episodes of VCA patients.Conclusion: The results of this study suggest that serum MMP3 protein is a promising marker for stratifying patients according to severity of rejection, complementary to biopsy findings.

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“…Up to now, the mechanisms of GV in VCA have not been fully elucidated 10,19 . GV in VCA seems similar to cardiac allograft vasculopathy (CAV).…”

Section: Discussionmentioning

confidence: 99%

Graft vasculopathy in upper extremity allotransplantation: Results of a retrospective high‐resolution ultrasonographic study

Petruzzo

Luong

Kanitakis

et al. 2020

Clinical Transplantation

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Graft vasculopathy (GV) is the most severe pathologic change of chronic rejection in vascularized composite allotransplantation. Since 2012, the intimal media thickness (IMT) of radial and ulnar arteries was annually monitored by high‐resolution ultrasonography in seven bilateral upper extremity transplant (UET) patients. We also investigated the IMT of seven matched healthy subjects (controls). No significant difference between IMT values of controls and UET patients was found. The median IMT values of recipient radial and ulnar arteries were 0.23 mm and 0.25 mm, respectively, while the median IMT values of grafted radial and ulnar arteries were 0.27 mm and 0.30 mm, respectively. There was a statistically significant difference in the IMT values of the grafted and recipient ulnar arteries (p = .043), but this difference was no longer significant when patient #2 was excluded. He showed a significant difference between recipient and grafted arteries and significantly higher IMT values (p = .001) of his grafted arteries compared with those of all transplanted patients. This patient developed GV leading to graft loss 11 years after the transplantation. In conclusion, this study showed a significant IMT increase in an UET recipient who developed GV.

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Novel immunological and clinical insights in vascularized composite allotransplantation

Cited by 28 publications

References 55 publications

Th17 cell inhibition in a costimulation blockade‐based regimen for vascularized composite allotransplantation using a nonhuman primate model

Th17 cell inhibition in a costimulation blockade‐based regimen for vascularized composite allotransplantation using a nonhuman primate model

MMP3 Is a Non-invasive Biomarker of Rejection in Skin-Bearing Vascularized Composite Allotransplantation: A Multicenter Validation Study

Graft vasculopathy in upper extremity allotransplantation: Results of a retrospective high‐resolution ultrasonographic study

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