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1.
Front Immunol ; 12: 682180, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456906

RESUMO

Vascularized 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 severe tissue loss in a selected group of patients. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in this type of quality-of-life transplant. The initial management of extensive soft tissue injury can lead to the development of anti-HLA antibodies through injury-related factors, transfusion and cadaveric grafting. The role of antibody-mediated rejection, donor-specific antibody (DSA) formation and graft rejection in the context of VCA still remain poorly understood. The most common antigenic target of preexisting alloantibodies are MHC mismatches, though recognition of ABO incompatible antigens, minor histocompatibility complexes and endothelial cells has also been shown to contribute to rejection. Mechanistically, alloantibody-mediated tissue damage occurs primarily through complement fixation as well as through antibody-dependent cellular toxicity. If DSA exist, activation of complement and coagulation cascades can result in vascular thrombosis and infarction and thus rejection and graft loss. Both preexisting DSA but especially de-novo DSA are currently considered as main contributors to late allograft injury and graft failure. Desensitization protocols are currently being developed for VCA, mainly including removal of alloantibodies whereas treatment of established antibody-mediated rejection is achieved through high dose intravenous immunoglobulins. The long-term efficacy of such therapies in sensitized VCA recipients is currently unknown. The current evidence base for sensitizing events and outcomes in reconstructive transplantation is limited. However, current data show that VCA transplantation has been performed in the setting of HLA-sensitization.


Assuntos
Dessensibilização Imunológica , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Alotransplante de Tecidos Compostos Vascularizados , Dessensibilização Imunológica/métodos , Gerenciamento Clínico , Rejeição de Enxerto/prevenção & controle , Antígenos HLA/imunologia , Humanos , Tolerância Imunológica/imunologia , Isoanticorpos/imunologia , Imunologia de Transplantes , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Alotransplante de Tecidos Compostos Vascularizados/métodos
2.
Eur J Cancer ; 151: 233-244, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34092349

RESUMO

BACKGROUND: Lymphoedema after cancer treatment is a chronic and disabling complication that presents a significant health care burden during survivorship with limited treatment options. Vascularised lymph node transfer (VLNT) can reconstruct lymphatic flow to reduce limb volumes, but limited higher-order evidence exists to support its effectiveness. AIM: The aim of the study was to systematically review and meta-analyse the effectiveness of VLNT in reducing upper limb (UL) or lower limb (LL) volume and cellulitis episodes in patients with cancer treatment-related lymphoedema (CTRL). METHODS: PubMed, Medline (Ovid) and Embase databases were searched between January 1974 and December 2019. Full-length articles where VLNT was the sole therapeutic procedure for CTRL, reporting volumetric limb, frequency of infection episodes and/or lymphoedema-specific quality-of-life data, were included in a random-effects meta-analysis of circumferential reduction rate (CRR). Methodological quality was assessed using STROBE/CONSORT, and a novel, lymphoedema-specific scoring tool was used to assess lymphoedema-specific methodological reporting. Sensitivity analyses on the site of VLNT harvest and recipient location were performed. RESULTS: Thirty-one studies (581 patients) were eligible for inclusion. VLNT led to significant limb volume reductions in UL (above elbow pooled CRRs [CRRP] = 42.7% [95% confidence interval (CI): 36.5-48.8]; below elbow CRRP = 34.1% [95% CI: 33.0-35.1]) and LL (above knee CRRP = 46.8% [95% CI: 43.2-50.4]; below knee CRRP = 54.6% [95% CI: 39.0-70.2]) CTRL. VLNT flaps from extra-abdominal donor sites were associated with greater volume reductions (CRRP = 49.5% [95% CI: 46.5-52.5]) than those from intra-abdominal donor sites (CRRP = 39.6% [95% CI: 37.2-42.0]) and synchronous autologous breast reconstruction/VLNT flaps (CRRP = 32.7% [95% CI: 11.1-54.4]) (p < 0.05). VLNT was also found to reduce the mean number of cellulitis episodes by 2.1 episodes per year (95% CI: -2.7- -1.4) and increased lymphoedema-specific quality-of-life scores (mean difference in Lymphoedema-Specific Quality of Life (LYMQOL) "overall domain" = +4.26). CONCLUSIONS: VLNT is effective in reducing excess limb volume and cellulitis episodes in both UL and LL lymphoedema after cancer treatment. However, significant heterogeneity exists in outcome reporting, and standardisation of reporting processes is recommended.


Assuntos
Celulite (Flegmão)/cirurgia , Aloenxertos Compostos/irrigação sanguínea , Aloenxertos Compostos/transplante , Linfonodos/irrigação sanguínea , Linfonodos/transplante , Linfedema/cirurgia , Neoplasias/terapia , Alotransplante de Tecidos Compostos Vascularizados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Celulite (Flegmão)/etiologia , Celulite (Flegmão)/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Linfedema/etiologia , Linfedema/patologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Adulto Jovem
3.
Medicine (Baltimore) ; 100(23): e25907, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34114986

RESUMO

ABSTRACT: If wounds are infected with bacteria resistant to an empirical antibiotic regimen, effective wound treatment will be delayed. This can delay wound healing and lengthen hospital stays, increasing the costs to patients. Long-term antibiotic use can also result in minor and major complications, such as diarrhea, antibiotic resistance, or life-threatening leukopenia. Multidrug-resistant (MDR) bacteria make wound treatment even more difficult. Traditionally, surgeons thought that adequate infection control should be established before soft tissue coverage. However, wounds infected by MDR do not heal well with this traditional method and there are no optimal treatment guidelines for MDR bacteria-contaminated wounds.We reviewed 203 patients who underwent vascularized flap surgery from 2012 to 2019 to cover wounds. Class IV and I wounds were compared according to the Centers for Disease Control and Prevention classification. Class IV was further classified as antibiotic-resistant (ARB) and antibiotic-sensitive (ASB) bacteria. Wound size, mode, location, pathogens, healing time, and basic demographics were evaluated. Data were compared using Cramer's V and one-way ANOVA or independent t tests.The average healing time was longer in the ARB (19.7 [range 7-44] days) and ASB (17.9 [range 2-36] days) groups than in the Clean group (16.5 [range 7-28] days). Healing time differed in the 3 groups (P = .036). It was longer in the class IV group than in the class I group (P = .01). However, it was not statistically different between the ARB and ASB groups (P = .164).In our study the difference in healing time was small when vascularized tissue transfer was done in ARB-infected wound compared with ASB-infected and clean wound. It is necessary to perform surgery using vascularized tissue for the infected wound of antibiotic-resistant bacteria.


Assuntos
Antibacterianos , Bactérias , Alotransplante de Tecidos Compostos Vascularizados , Infecção dos Ferimentos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/classificação , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/métodos , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , República da Coreia/epidemiologia , Retalhos Cirúrgicos , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Alotransplante de Tecidos Compostos Vascularizados/métodos , Cicatrização , Infecção dos Ferimentos/epidemiologia , Infecção dos Ferimentos/microbiologia , Infecção dos Ferimentos/fisiopatologia , Infecção dos Ferimentos/terapia
4.
J Clin Oncol ; 39(24): 2710-2719, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-33929874

RESUMO

PURPOSE: BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS: We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS: Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION: Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.


Assuntos
Cistite/tratamento farmacológico , Transtornos Hemorrágicos/tratamento farmacológico , Linfócitos T Citotóxicos/metabolismo , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
5.
Cell Rep ; 34(9): 108806, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33657374

RESUMO

Alloimmune responses in acute rejection are complex, involving multiple interacting cell types and pathways. Deep profiling of these cell types has been limited by technology that lacks the capacity to resolve this high dimensionality. Single-cell mass cytometry is used to characterize the alloimmune response in early acute rejection, measuring 37 parameters simultaneously, across multiple time points in two models: a murine cardiac and vascularized composite allotransplant (VCA). Semi-supervised hierarchical clustering is used to group related cell types defined by combinatorial expression of surface and intracellular proteins, along with markers of effector function and activation. This expression profile is mapped to visualize changes in antigen composition across cell types, revealing phenotypic signatures in alloimmune T cells, natural killer (NK) cells, and myeloid subsets that are conserved and that firmly distinguish rejecting from non-rejecting grafts. These data provide a comprehensive, high-dimensional profile of cellular rejection after allograft transplantation.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Coração/efeitos adversos , Linfócitos/imunologia , Monócitos/imunologia , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Doença Aguda , Animais , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Análise por Conglomerados , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Fenótipo , Receptores CCR6/metabolismo , Análise de Célula Única , Fatores de Tempo
6.
Transplantation ; 105(6): 1238-1249, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33141809

RESUMO

BACKGROUND: The role of regulatory T cells (Treg) in tolerance induction of vascularized composite allotransplantation (VCA) remains unclear. This study was designed to examine characteristics of Treg after VCA and their capacity to rescue allografts from rejection. METHODS: Osteomyocutaneous allografts were transplanted from Balb/c to C57BL/6 mice. All mice received costimulatory blockade and a short course of rapamycin. To elucidate the role of Treg for tolerance induction, Treg depletion was performed at postoperative day (POD) 0, 30, or 90. To assess capacity of Treg to rescue allografts from rejection, an injection of 2 × 106 Treg isolated from tolerant mice was applied. RESULTS: Eighty percent of VCA recipient mice using costimulatory blockade and rapamycin regimen developed tolerance. The tolerant recipients had a higher ratio of circulating Treg to effector T cells and elevated interleukin-10 at POD 30. A significantly higher rejection rate was observed when Treg were depleted at POD 30. But Treg depletion at POD 90 had no effect on tolerance. Treg from tolerant recipients showed stronger suppressive potential and the ability to rescue allografts from rejection. Furthermore, transplanted Treg-containing skin grafts from tolerant mice delayed rejection elicited by adoptively transferred effector T cells to Rag2-/- mice. CONCLUSIONS: Circulating Treg are crucial for inducing VCA tolerance in the early posttransplant phase, and allograft-residing Treg may maintain tolerance. Treg may, therefore, serve as a potential cellular therapeutic to improve VCA outcomes.


Assuntos
Aloenxertos Compostos/transplante , Fatores de Transcrição Forkhead/metabolismo , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto , Transplante de Pele , Linfócitos T Reguladores/metabolismo , Tolerância ao Transplante , Alotransplante de Tecidos Compostos Vascularizados , Transferência Adotiva , Animais , Células Cultivadas , Aloenxertos Compostos/imunologia , Aloenxertos Compostos/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacologia , Interleucina-10/sangue , Depleção Linfocítica , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais , Sirolimo/farmacologia , Transplante de Pele/efeitos adversos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Fatores de Tempo , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos
7.
Transplantation ; 105(6): 1250-1260, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33093401

RESUMO

BACKGROUND: Recent studies have demonstrated that inhibition of CD26 potentiates stromal cell-derived factor-1α (SDF-1α), promotes tissue regeneration, and suppresses the rejection of organ transplants. This study investigated whether the combination of a CD26 inhibitor (CD26i) with granulocyte colony-stimulating factor (G-CSF) and short-term immunosuppressants modulates vascularized composite tissue allotransplant survival in a rodent orthotopic hindlimb allotransplant model. METHODS: The hindlimb allotransplantation from Brown-Norway to Lewis rats was divided into 4 groups. Group 1 (controls) did not receive any treatment. Group 2 was treated with short-term antilymphocyte serum (ALS) and cyclosporine-A (CsA). Group 3 was administrated CD26i and G-CSF. Group 4 received a combination of CD26i/G-CSF/ALS/CsA. Each subgroup comprised 10 rats. Peripheral blood and sampling of transplanted tissues were collected for immunological and histological analysis. RESULTS: The results revealed that allotransplant survival was found to be significantly prolonged in group 4 with CD26i/G-CSF/ALS/CsA treatment compared with those in the other groups. The interleukin-10 and transforming growth factor-ßl levels, the percentage of CD4+/CD25+/FoxP3+ T cells, as well as the levels of SDF-1α expressions were significantly increased in group 4 compared with those in the other groups. Group 4 revealed a statistical increase in the percentage of donor cells (RT1n) expression in the recipient peripheral blood, and the mixed lymphocyte reaction showed hyporesponsiveness of the T cells to donor alloantigens. CONCLUSION: The combination of CD26i/G-CSF and short-term immunosuppressants prolongs allotransplant survival by inducing immunoregulatory effects and enhancing the percentage of SDF-1α expression. This immunomodulatory approach has great potential as a strategy to increase vascularized composite allotransplantation survival.


Assuntos
Aloenxertos Compostos/transplante , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Membro Posterior/transplante , Imunossupressores/administração & dosagem , Alotransplante de Tecidos Compostos Vascularizados , Animais , Soro Antilinfocitário/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Quimiocina CXCL12/metabolismo , Aloenxertos Compostos/imunologia , Aloenxertos Compostos/metabolismo , Ciclosporina/administração & dosagem , Dipeptidil Peptidase 4/imunologia , Esquema de Medicação , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Membro Posterior/imunologia , Membro Posterior/metabolismo , Interleucina-10/metabolismo , Masculino , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismo , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos
8.
J Plast Reconstr Aesthet Surg ; 74(7): 1562-1571, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33376080

RESUMO

BACKGROUND: Cutaneous changes of facial vascularized composite allotransplants (fVCAs) are extensively described in the literature. Parts of the nose, nasal, and oral cavities are included in most fVCAs. Distinctively, the nose and mouth are lined by mucosa. Little is known about the histopathology and complications of the mucosa involved in fVCA patients. METHODS: The study constitutes a retrospective cohort study of nine fVCA patients. Medical records were reviewed for information about changes of oral and nasal mucous membranes. Types of mucosal lesions were recorded and analyzed. Uni- and multivariate generalized estimating equation (GEE) models were used to assess the odds of developing mucosal inflammation in the presence of clinico-pathologic variables. RESULTS: A total of 186 clinical encounters with examination of oral and nasal mucous membranes were included. Membranes were devoid of clinical pathology in 101 instances (53% of all clinical assessments). Ulcerations/erosions (27%), edema (18%), and erythema (14%) were the most common lesions. Oral lesions affected the lips (58%), buccal mucosa (38%), and palate (5%). Sinonasal processes predominantly affected nasal vestibules and septae. In univariate analysis, sirolimus, skin rejection, and skin Banff grade were associated with the presence of an acute inflammatory mucosal lesion (p<0.05). In multivariate analysis, skin Banff grade and sirolimus were independent predictors of mucosal inflammation. CONCLUSION: Pathologies of fVCA mucous membranes are more common than previously reported. Mucosal assessment plays an important role in the pleomorphic allograft rejection process evaluation rather than diagnosis and treatment based on cutaneous pathology.  A closer look at the pathophysiology of fVCA mucosal rejection and inflammation is warranted.


Assuntos
Aloenxertos Compostos/patologia , Face/cirurgia , Rejeição de Enxerto/patologia , Mucosa Bucal/patologia , Mucosa Nasal/patologia , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
Pharm Res ; 37(11): 222, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067715

RESUMO

AIM: The high doses of oral tacrolimus (TAC) (1,2) necessary to prevent acute rejection (AR) after vascularized composite allotransplantation (VCA) are associated with systemic adverse effects. The skin is the most antigenic tissue in VCA and the primary target of AR. However, the short-term use of topical TAC (Protopic®), as an off-label adjunct to oral TAC, to treat AR episodes pro re nata (PRN), has yielded inconsistent results. There is lack of data on the pharmacokinetics and tissue distribution of topical TAC in VCA, that hampers our understanding of the reasons for unreliable efficacy. Toward this goal, we evaluated the ability of topical TAC to achieve high local tissue concentrations at the site of application with low systemic concentrations. MATERIALS AND METHODS: We assessed the pharmacokinetics and tissue distribution of topical TAC (Protopic®, 0.03%) after single or repeated topical application in comparison to those after systemic delivery in rats. Animals received a single topical application of TAC ointment (Group 1) or an intravenous (IV) injection of TAC (Group 2) at a dose of 0.5 mg/kg. In another experiment, animals received daily topical application of TAC ointment (Group 3), or daily intraperitoneal (IP) injection of TAC (Group 4) at a dose of 0.5 mg/kg for 7 days. TAC concentrations in blood and tissues were analyzed by Liquid Chromatography-Mass Spectrometry (LC/MS-MS). RESULTS: Following single topical administration, TAC was absorbed slowly with a Tmax of 4 h and an absolute bioavailability of 11%. The concentrations of TAC in skin and muscle were several folds higher than whole blood concentrations. Systemic levels remained subtherapeutic (< 3 ng/ml) with repeated once daily applications. CONCLUSION: Topical application of TAC ointment (Protopic®, 0.03%) at a dose of 0.5 mg/kg/day provided high concentrations in the local tissues with low systemic exposure. Repeated topical administration of TAC is well tolerated with no local or systemic adverse effects. This study confirms the feasibility of topical application of TAC for site specific graft immunosuppression and enables future applications in VCA.


Assuntos
Inibidores de Calcineurina/farmacocinética , Aloenxertos Compostos/transplante , Imunossupressores/farmacocinética , Tacrolimo/farmacocinética , Alotransplante de Tecidos Compostos Vascularizados , Administração Tópica , Animais , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/sangue , Aloenxertos Compostos/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Injeções Intravenosas , Masculino , Músculo Esquelético/metabolismo , Estudo de Prova de Conceito , Ratos Endogâmicos Lew , Pele/metabolismo , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Distribuição Tecidual , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos
10.
PLoS One ; 15(6): e0235266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32589662

RESUMO

BACKGROUND: Chronic rejection remains the Achilles heel in vascularized composite allotransplantation. Animal models to specifically study chronic rejection in vascularized composite allotransplantation do not exist so far. However, there are established rat models to study chronic rejection in solid organ transplantation such as allogeneic transplantation between the rat strains Lewis and Fischer344. Thus, we initiated this study to investigate the applicability of hindlimb transplantation between these strains to imitate chronic rejection in vascularized composite allotransplantation and identify potential markers. METHODS: Allogeneic hindlimb transplantation were performed between Lewis (recipient) and Fischer344 (donor) rats with either constant immunosuppression or a high dose immunosuppressive bolus only in case of acute skin rejections. Histology, immunohistochemistry, microarray and qPCR analysis were used to detect changes in skin and muscle at postoperative day 100. RESULTS: We were able to demonstrate significant intimal proliferation, infiltration of CD68 and CD4 positive cells, up-regulation of inflammatory cytokines and initiation of muscular fibrosis in the chronic rejection group. Microarray analysis and subsequent qPCR identified CXC ligands 9-11 as potential markers of chronic rejection. CONCLUSIONS: The Fischer344 to Lewis hindlimb transplantation model may represent a new option to study chronic rejection in vascularized composite allotransplantation in an experimental setting. CXC ligands 9-11 deserve further research to investigate their role as chronic rejection markers.


Assuntos
Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Animais , Biomarcadores/metabolismo , Doença Crônica , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica , Rejeição de Enxerto/patologia , Membro Posterior/patologia , Ratos , Pele/patologia
11.
Plast Reconstr Surg ; 145(4): 757e-768e, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32221215

RESUMO

BACKGROUND: Transplantation of vascularized composite allografts is limited mainly by the need for life-long immunosuppression. The consequent side effects and looming specter of chronic rejection portend eventual allograft loss. Development of tolerogenic protocols is thus of utmost importance to the field of vascularized composite allograft transplantation. METHODS: With a modified delayed tolerance induction protocol, 10 cynomolgus macaques received hand (n = 2) or face vascularized composite allografts across both full and haploidentical major histocompatibility complex barriers before donor bone marrow transplantation at a later date. Protocol and for-cause allograft skin biopsies were performed for immunohistochemical analysis and analysis of donor-recipient leukocyte contribution; mixed chimerism in peripheral blood and in vitro immune responses were assessed serially. RESULTS: Before bone marrow transplantation, maintenance immunosuppression for 4 months led to lethal complications, including posttransplant lymphoproliferative disorder (in two of four recipients), which necessitated early study termination. Shortening the maintenance period to 2 months was clinically relevant and allowed all subsequent subjects (n = 6) to complete the delayed tolerance induction protocol. Acute rejection developed within the first 2 to 4 weeks after transplantation, with corresponding near-complete turnover of allograft leukocytes from donor to recipient origin, but donor-specific antibodies remained negative. After bone marrow transplantation, mixed chimerism failed to develop, although carboxyfluorescein succinimidyl ester mixed lymphocyte reaction demonstrated generalized unresponsiveness. However, the accrual of subsequent rejection episodes eventually culminated in graft vasculopathy and irreversible allograft loss. CONCLUSIONS: Despite the various advantages of the delayed tolerance induction protocol, it failed to reliably induce mixed chimerism and thus immunologic tolerance to vascularized composite allografts, given currently available immunosuppression treatment options. Ongoing work shows promise in overcoming these limitations.


Assuntos
Aloenxertos Compostos/imunologia , Rejeição de Enxerto/prevenção & controle , Tolerância Imunológica , Condicionamento Pré-Transplante/métodos , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Animais , Biópsia , Transplante de Medula Óssea/métodos , Aloenxertos Compostos/patologia , Aloenxertos Compostos/transplante , Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/imunologia , Humanos , /métodos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Leucócitos/imunologia , Teste de Cultura Mista de Linfócitos , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/etiologia , Macaca fascicularis , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Pele/irrigação sanguínea , Pele/imunologia , Pele/patologia , Quimeras de Transplante/imunologia , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo/efeitos adversos , Falha de Tratamento , Alotransplante de Tecidos Compostos Vascularizados/métodos
12.
J Surg Res ; 250: 119-124, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32044508

RESUMO

BACKGROUND: Vascularized composite allograft has emerged as a reconstructive option for patients who have suffered severe tissue loss. Animal models are critical for understanding the unique mechanisms of rejection in vascularized composite allograft. We present a functional mouse model of orthotopic hind limb transplantation using end-to-side anastomoses of the donor aorta and inferior vena cava to the respective recipient vessels. To the best of our knowledge, this approach has not been reported in the scientific literature. MATERIALS AND METHODS: A single surgeon performed all transplants (J.W.). A total of 13 syngeneic and 10 fully mismatched allogeneic transplants were performed without immunosuppression. Skin samples from the grafts were collected at the time of euthanasia. RESULTS: Five syngeneic mice survived for more than 90 d after transplant. All allografts displayed clinical and histologic signs of acute rejection such as a rash at the time of graft excision. The overall technical success rate of all transplants in this study was 74% (17 of 23). CONCLUSIONS: We demonstrate the feasibility of end-to-side anastomoses of the donor aorta and inferior vena cava with functional recovery of the transplant in a mouse model of orthotopic hind limb transplantation.


Assuntos
Aloenxertos Compostos/transplante , Rejeição de Enxerto/prevenção & controle , Membro Posterior/transplante , Alotransplante de Tecidos Compostos Vascularizados/métodos , Anastomose Cirúrgica/efeitos adversos , Anastomose Cirúrgica/métodos , Animais , Aorta/cirurgia , Modelos Animais de Doenças , Estudos de Viabilidade , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Membro Posterior/irrigação sanguínea , Humanos , Masculino , Camundongos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Veia Cava Inferior/cirurgia
13.
Transplantation ; 104(12): 2616-2624, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32053572

RESUMO

BACKGROUND: Facial vascularized composite allotransplantation (fVCA) presents an established approach to restore form and function of patients with catastrophic facial defects. Skin is one of the target tissues of the rejection process, and due to its easy accessibility has become the gold standard in the diagnosis of rejection. Mucosal rejection frequently occurs; however, the added value of mucosal rejection assessment for patient management is unknown. METHODS: We conducted a systematic review of manuscripts listed in the MEDLINE/PubMed and GoogleScholar databases to identify articles that provide data on mucosal rejection following fVCA. For inclusion, papers had to be available as full-text and written in English. Non-VCA studies and animal studies were excluded. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: We included 17 articles that described changes in allotransplanted mucosa of fVCAs. These articles yielded data on 168 BANFF graded biopsies of corresponding skin and mucosa biopsies. Rejection grades were consistently higher in mucosal biopsies. Concordance between allograft skin and mucosa biopsy grades increased with an increasing skin-BANFF grade. Mucosa rejection grades were on average lower in the early stages of the posttransplant period (postoperative mo 12). CONCLUSIONS: The mucosa of facial allotransplants is one of the primary targets of rejection. The data indicates that higher-grade skin rejection does not occur in absence of mucosal rejection. Further investigations are needed to elucidate the exact role of mucosal biopsies for fVCA patient management.


Assuntos
Aloenxertos Compostos/transplante , Transplante de Face/efeitos adversos , Rejeição de Enxerto/imunologia , Membrana Mucosa/transplante , Transplante de Pele/efeitos adversos , Pele/imunologia , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Adulto , Biópsia , Aloenxertos Compostos/imunologia , Aloenxertos Compostos/patologia , Feminino , Rejeição de Enxerto/patologia , Rejeição de Enxerto/terapia , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/imunologia , Membrana Mucosa/patologia , Pele/patologia , Resultado do Tratamento
14.
Transplantation ; 104(10): 2003-2010, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32039965

RESUMO

Initially overlooked in favor of T cell-mediated rejection, the importance of the humoral alloimmune response has progressively emerged. As a result, antibody-mediated rejection is now widely recognized as the main cause of late allograft loss in most (if not all) types of solid-organ transplantation. Over the last 2 decades, vascularized composite allotransplantation (VCA) has appeared for replacing tissue defects in patients for whom no other satisfactory reconstructive options were available. Although it is now clear that VCA recipients can develop donor-specific antibodies, conclusions made in solid organ transplantation regarding antibody-mediated rejection may not systematically apply to VCA. Here, we propose to use the experience gained in organ transplantation to shed light on the path that shall be followed to evaluate and manage humoral alloreactivity in VCA recipients.


Assuntos
Aloenxertos Compostos/transplante , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Histocompatibilidade , Imunidade Humoral , Isoanticorpos/sangue , Alotransplante de Tecidos Compostos Vascularizados , Animais , Aloenxertos Compostos/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Histocompatibilidade/efeitos dos fármacos , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunossupressores/uso terapêutico , Plasmaferese , Resultado do Tratamento , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos
15.
Medicine (Baltimore) ; 99(1): e18612, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895813

RESUMO

BACKGROUND: Uterus transplantation is a complex, multi-step experimental procedure used for the treatment of uterus absence or uterus anomaly that prevents embryo implantation or pregnancy completion. METHOD: To date, only 51 uterus transplants worldwide had been performed. When simplified, it is vascularized composite allograft transplantation. While it is still an experimental procedure with encouraging results for the future, there are still many issues that have to be clarified. The most serious complications of uterus transplantation are graft rejection or grafts vascular failure. RESULTS: So far, no reference to the atherosclerotic arterial infiltration of the uterus arteries was suggested and studied as one of the main causes of graft's failure. CONCLUSION: In this review we summarized current knowledge and possible role of uterus arterial damage, including atherosclerotic changes on the graft's survival.


Assuntos
Aterosclerose/etiologia , Artéria Uterina , Útero/transplante , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Feminino , Humanos , Óxido Nítrico/metabolismo , Túnica Íntima/metabolismo , Útero/irrigação sanguínea , Remodelação Vascular
16.
J Reconstr Microsurg ; 36(1): 9-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31302903

RESUMO

BACKGROUND: Prolonged cold ischemia associated with static cold storage (SCS) results in higher incidence of acute and chronic allograft rejection in solid organ transplantations. Deleterious effects of SCS on vascularized composite tissue allograft were studied with limited data on muscle structure and function. The aim of this study is to evaluate the long-term impact of SCS on muscle metabolism, structure, and force generation using a syngeneic rat hindlimb transplantation model. METHODS: Sixty-five male Lewis rats (250 ± 25 g) were distributed into five groups, including naive control, sciatic nerve denervation/repair, immediate transplantation, transplantation following static warm storage for 6 hours at room temperature, and transplantation following SCS for 6 hours at 4°C. Sciatic nerves were repaired in all transplantations. Muscle samples were taken for histology and metabolomics analysis following electromyography and muscle force measurements at 12 weeks after transplantation. RESULTS: All cold-preserved limbs remained viable at 12 weeks, whereas animals receiving limbs preserved in room temperature had no survivors. The SCS transplantation group showed a 73% injury score, significantly higher than groups receiving immediate transplants without cold preservation (50%, p < 0.05). A significant decline in muscle contractile force was also demonstrated in comparison to the immediate transplantation group (p < 0.05). In the SCS group, muscle energy reserves remained relatively well preserved in surviving fibers. CONCLUSION: SCS extends allograft survival but fails to preserve muscle structure and force.


Assuntos
Isquemia Fria/efeitos adversos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Preservação de Órgãos/efeitos adversos , Alotransplante de Tecidos Compostos Vascularizados , Animais , Criopreservação/métodos , Modelos Animais de Doenças , Eletromiografia , Sobrevivência de Enxerto/fisiologia , Membro Posterior/transplante , Masculino , Metabolômica , Contração Muscular/fisiologia , Força Muscular/fisiologia , Ratos , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/complicações , Neuropatia Ciática/etiologia , Neuropatia Ciática/patologia , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Alotransplante de Tecidos Compostos Vascularizados/métodos
17.
Nanomedicine (Lond) ; 14(20): 2713-2733, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31642386

RESUMO

Lifelong systemic immunosuppression remains the biggest challenge in vascularized composite allotransplantation (VCA) due to the adverse effects it causes. Since VCA is a life-enhancing procedure as compared with solid organ transplant which is life-saving; one needs to weigh the benefits and risks carefully. Thus, there is a huge unmet clinical need to design biomaterial-based vehicles that can deliver drugs more efficiently, topically and locally to eliminate adverse effects of systemic immune suppression. This review discusses several biomaterial-based systems that have been carefully designed, conceived and attempted to make VCA a more patient compliant approach. Variety of promising preclinical studies has shown the feasibility of the approaches, and clinical trials are required to bridge the gap. Several challenges for the future and new approaches have been discussed.


Assuntos
Materiais Biocompatíveis/uso terapêutico , Procedimentos Cirúrgicos Reconstrutivos/métodos , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Materiais Biocompatíveis/química , Humanos , Tolerância Imunológica/efeitos dos fármacos , Transplantes/efeitos dos fármacos
18.
J Vasc Res ; 56(4): 163-180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266018

RESUMO

Vascularized composite allotransplantation (VCA) has emerged as a useful reconstructive option for patients suffering from major tissue defects and functional deficits. While the technical feasibility has been optimized and more than 130 VCAs have been performed during the last two decades, hurdles such as acute and chronic allograft rejection, graft deterioration, and eventual functional impairment need to be addressed. Recently, chronic graft rejection and progressive failure have been linked to vascular alterations observed in the allografts. Graft vasculopathy (GV) may play a pivotal role in long-term graft deterioration. The understanding of the underlying pathophysiological processes and their initial triggers is of utmost importance in the prevention, attenuation, and therapy of GV. While there are reports on the etiology and development of GV in solid organ transplantation, there are limited data with respect to chronic rejection and GV in the realm of VCA. Nevertheless, recent reports from long-term VCA recipients suggest that GV could truly jeopardize allografts in the follow-up evaluation. Chronic rejection and GV include different entities and might have different pathways in distinct organs. Herein, we reviewed the current literature on vascular changes during both acute and chronic allograft rejection, with a focus on their clinical and translational significance for VCA.


Assuntos
Aloenxertos Compostos/irrigação sanguínea , Rejeição de Enxerto/etiologia , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Doença Aguda , Animais , Doença Crônica , Aloenxertos Compostos/imunologia , Transplante de Face/efeitos adversos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Transplante de Mão/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
19.
Am Surg ; 85(6): 631-637, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31267905

RESUMO

The field of vascularized composite allotransplantation (VCA) has moved from a highly experimental procedure to, at least for some patients, one of the best treatment alternatives for catastrophic tissue loss or dysfunction. Although the worldwide experience is still limited, progress has been made in translation to the clinic, and hand transplantation was recently designated standard of care and is now covered in full by the British Health System. This progress is tempered by the long-term challenges of systemic immunosuppression, and the rapidly evolving indications for VCA such as urogenital transplantation. This update will cover the state of and recent changes in the field, and an update of the Louisville VCA program as our initial recipient, the first person to receive a hand transplant in the United States celebrates the 20th anniversary of his transplant. The achievements and complications encountered over the last two decades will be reviewed. In addition, potential directions for research and collaboration as well as practical issues of how third party payers and funding are affecting growth of the field are presented.


Assuntos
Imunossupressores/administração & dosagem , Procedimentos Cirúrgicos Reconstrutivos/métodos , Alotransplante de Tecidos Compostos Vascularizados/métodos , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Masculino , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/fisiopatologia , Prognóstico , Sociedades Médicas , Imunologia de Transplantes/fisiologia , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos
20.
Transplantation ; 103(9): 1746-1751, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31283672

RESUMO

Early results of hand and face transplants and other grafts such as those of uterus, penis, trachea, larynx, or abdominal wall have confirmed the potential for vascularized composite allotransplantation (VCA) to restore appearance, anatomy, function, independence, and social integration in patients suffering from devastating tissue deficits untreatable by conventional treatment options. Despite such promise, these novel and complex procedures face challenges and controversies that remain open to discussion and debate. Indeed, many barriers to clinical advancement and negative stakeholder perceptions still exist. The bioethical challenges surrounding VCA include but are not limited to justice and vulnerability of subjects, and their experiences with risks, benefits and outcomes, provider economy of fame, public awareness and attitudes toward transplantation, and policy and regulatory issues shaping progress of the field. The First International Workshop on Bioethical Challenges in Reconstructive Transplantation was organized by the Brocher Foundation in Hermance, Switzerland. VCA professionals representing teams from across the world examined bioethical issues in VCA related to standards for safety, efficacy, feasibility, privacy, confidentiality, and equitability. Key discussion topics from the workshop were included in a survey questionnaire implemented across VCA professionals attending the 13th Congress of International Society of VCA held in Salzburg, Austria. The insights from the Brocher workshop and International Society of VCA survey as presented here could help inform the future development of clinical practice and policy strategies in VCA to ensure value, accessibility, and acceptance of these procedures by potential donors, potential or actual recipients and their families, and providers and payers.


Assuntos
Tomada de Decisão Clínica/ética , Aloenxertos Compostos , Confidencialidade/ética , Consentimento Livre e Esclarecido/ética , Segurança do Paciente , Obtenção de Tecidos e Órgãos/ética , Alotransplante de Tecidos Compostos Vascularizados/ética , Sobrevivência de Enxerto , Humanos , Complicações Pós-Operatórias/etiologia , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos
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