RESUMO
BACKGROUND: Kidney transplantation is the gold-standard treatment for patients with kidney failure. However, one-third of patients awaiting a kidney transplant are highly sensitized to human leukocyte antigens (HLA), resulting in an increased waiting time for a suitable kidney, more acute and chronic rejection, and a shorter graft survival compared to non-highly sensitised patients. Current standard immunosuppression protocols do not adequately suppress memory responses, and so alternative strategies are needed. Autologous polyclonally expanded regulatory T cells (Tregs) have been demonstrated to be safe in transplant settings and could be a potential alternative to modulate memory immune alloresponses. METHODS: The aim of this trial is to determine whether adoptive transfer of autologous Tregs into HLA sensitised patients can suppress memory T and B cell responses against specific HLA antigens. This is a two-part, multi-centre, prospective clinical trial, comprising an observational phase (Part 1) aiming to identify patients with unregulated cellular memory responses to HLA (Pure HLA Proteins) followed by an interventional phase (Part 2). The first 9 patients identified as being eligible in Part 1 will undergo baseline immune monitoring for 2 months to inform statistical analysis of the primary endpoint. Part 2 is an adaptive, open labelled trial based on Simon's two-stage design, with 21 patients receiving Good Manufacturing Practice (GMP)-grade polyclonally expanded Tregs to a dose of 5-10 × 106 cells/kg body weight. The primary EP is suppression of in vitro memory responses for 2 months post-infusion. 12 patients will receive treatment in stage 1 of Part 2, and 9 patients will receive treatment in stage 2 of Part 2 if ≥ 50% patients pass the primary EP in stage 1. DISCUSSION: This is a prospective study aiming to identify patients with unregulated cellular memory responses to Pure HLA Proteins and determine baseline variation in these patterns of response. Part 2 will be an adaptive phase IIa clinical trial with 21 patients receiving a single infusion of GMP-grade polyclonally expanded Tregs in two stages. It remains to be demonstrated that modulating memory alloresponses clinically using Treg therapy is achievable. TRIAL REGISTRATION: EudraCT Number: 2021-001,664-23. REC Number: 21/SC/0253. Trial registration number ISRCTN14582152.
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Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Linfócitos T Reguladores , Estudos Prospectivos , Rim , Terapia de Imunossupressão , Antígenos HLA , Estudos Observacionais como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
Introduction: Highly sensitised (HS) patients represent up to 30% of patients on the kidney transplant waiting list. When they are transplanted, they have a high risk of acute/chronic rejection and long-term allograft loss. Regulatory T cells (Tregs) (CD4+CD25hiCD127lo) are T cells involved in the suppression of immune alloresponses. A particular subset, called T follicular regulatory T cells (Tfr, CXCR5+Bcl-6+), is involved in regulating interactions between T effectors and B cells within the germinal centre and can be found in peripheral blood. Therefore, we wanted to identify specific subsets of Tregs in the peripheral blood of HS individuals. Methods: We recruited prospectively healthy volunteers (HV) (n = 9), non-sensitised patients on haemodialysis (HD) (n = 9) and HS individuals, all of whom were on haemodialysis (n = 15). Results: We compared the Treg phenotypes of HV, HD and HS. HS patients had more CD161+ Tregs (p = 0.02) and more CD45RA-CCR7- T effectors (Teffs) (p = 0.04, memory Teffs able to home to the germinal centre) compared to HVs. HS patients had more Bcl-6+ Tregs (p < 0.05), fewer Th1-like Tregs, more Th2-like Tregs (p < 0.001) and more CD161+ (p < 0.05) Tregs compared to HD patients. This population has been described to be highly suppressive. HD had a deficiency in a Th17-like CD161+ effector Treg cluster (cluster iii., CCR6+CCR4+CXCR3- CD39+CD15s+ICOS-CCR7-CD161+) (p < 0.05). Discussion: This is the first study presenting a deep Treg phenotype in HS patients. We confirmed that HS patients had more of a Th17-like CD161+ effector Treg from population III (CD4+CD25hiCD127loCD45RA-) compared to non-sensitised patients on HD. The clinical relevance of this highly suppressive Tregs population remains to be determined in the context of transplantation.
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Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel "cytotopic" agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.
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Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Transplante de Rim/efeitos adversos , Peptídeos/farmacologia , Microangiopatias Trombóticas/prevenção & controle , Animais , Humanos , Macaca mulatta , Masculino , Peptídeos/sangue , Perfusão , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/patologiaRESUMO
Allograft transplantation into sensitized recipients with antidonor antibodies results in accelerated antibody-mediated rejection (AMR), complement activation, and graft thrombosis. We have developed a membrane-localizing technology of wide applicability that enables therapeutic agents, including anticoagulants, to bind to cell surfaces and protect the donor endothelium. We describe here how this technology has been applied to thrombin inhibitors to generate a novel class of drugs termed thrombalexins (TLNs). Using a rat model of hyperacute rejection, we investigated the potential of one such inhibitor (thrombalexin-1 [TLN-1]) to prevent acute antibody-mediated thrombosis in the donor organ. TLN-1 alone was able to reduce intragraft thrombosis and significantly delay rejection. The results confirm a pivotal role for thrombin in AMR in vivo. This approach targets donor organs rather than the recipient and is intended to be directly translatable to clinical use.
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Rejeição de Enxerto/prevenção & controle , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Peptídeos/farmacologia , Trombina/antagonistas & inibidores , Trombose/prevenção & controle , Animais , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Testes de Função Renal , Masculino , Prognóstico , Ratos , Ratos Endogâmicos Lew , Fatores de Risco , Trombose/etiologiaRESUMO
We previously demonstrated PAR2 starts upstreamed with tissue factor (TF) and factor VII (FVII), inhibited autophagy via mTOR signaling in HCC. However, the mechanism underlying for merging functions of PAR2 with the coagulation system in HCC progression remained unclear. The present study aimed to investigate the role of TF, FVII and PAR2 in tumor progression of HCC. The expressions of TF, FVII and PAR2 from HCC specimens were evaluated by immunohistochemical stains and western blotting. We found that the expression of FVII, but not TF and PAR2, directly related to the vascular invasion and the clinical staging. Importantly, a lower level of FVII expression was significantly associated with the longer disease-free survival. The addition of FVII but not TF induced the expression of PAR2 and phosphorylation of ERK1/2, whereas knockdown of FVII decreased PAR2 expression and ERK1/2 phosphorylation in HCC cell lines. Furthermore, levels of phosphor-TSC2 (Ser664) were increased after treatment with FVII and PAR2 agonist whereas these were significantly abolished in the presence of a potent and specific MEK/ERK inhibitor U0126. Moreover, mTOR knockdown highly reduced Hep3B migration, which could be reverted by FVII but not TF and PAR2. These results indicated that FVII/PAR2 signaling through MEK/ERK and TSC2 axis for mTOR activation has potent effects on the migration of HCC cells. In addition, FVII/PAR2 signaling elicits an mTOR-independent signaling, which promotes hepatoma cell migration in consistent with the clinical observations. Our study indicates that levels of FVII, but not TF, are associated with tumor migration and invasiveness in HCC, and provides clues that evaluation of FVII expression in HCC may be useful as a prognostic indicator in patients with HCC and may form an alternative target for further therapy.
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BACKGROUND: CD34(+) α-smooth muscle actin (SMA)(+) cells mediate intimal hyperplasia (IH) after mechanical endoluminal injury. We previously found that IH is tissue factor (TF) dependent. The precise phenotype of the CD34(+) cells mediating IH is unknown and the mechanisms of TF are also unknown. OBJECTIVE: To define the phenotype of cells mediating IH and compare the effects of inhibiting TF on different subsets of CD34(+) cells. METHODS: Endoluminal injury was induced in C57BL/6 and two strains of mice expressing a human tissue factor pathway inhibitor (hTFPI) fusion protein on different subsets of CD34(+) cells. Confocal microscopy, immunocytofluorescence and real-time PCR were used to determine phenotype. RESULTS: Neointimal cells in C57BL/6 mice were defined as a subset of fibrocytes (CD34(+) CD45(+) collagen-1(+) ) expressing SMA, CD31, TIE-2, CXCR4 and CXCL12. Similar cells circulated post-injury and were also found in mice expressing hTFPI on CD34(+) CD31(+) cells, though in these mice, hTFPI inhibited CD31(+) fibrocyte hyperplasia, so no IH developed. Mice with hTFPI on all CD34(+) α-SMA(+) cells repaired arteries back to a pre-injured state. No CD31(+) fibrocytes were found in these mice unless an anti-hTFPI antibody was administered. Similar findings in protease activated receptor (PAR)-1-deficient mice suggested hTFPI prevented thrombin signaling through PAR-1. In vitro, thrombin increased the number of CD31(+) fibrocytes. CONCLUSIONS: Inhibition of TF on CD31(+) fibrocytes inhibits IH whereas inhibition on all CD34(+) α-SMA(+) cells (or PAR-1 deficiency) inhibits the appearance of CD31(+) fibrocytes and promotes repair. These data enhance our understanding of IH and suggest novel ways to promote regenerative repair.
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Fibroblastos/patologia , Hiperplasia/patologia , Tromboplastina/fisiologia , Túnica Íntima/patologia , Animais , Fibroblastos/imunologia , Imunofenotipagem , Camundongos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Invasive fungal diseases are a major cause of death in renal allograft recipients. We previously reported that adjunctive recombinant human interferon-γ therapy has clinical utility for invasive fungal diseases after renal transplantation. We have now developed a rapid peripheral blood-based quantitative real-time PCR assay that enables accurate profiling of cytokine imbalances. Our preliminary studies in renal transplant patients with invasive fungal diseases suggest that they fail to mount an adequate interferon-γ response to the fungal infection. In addition, they have reduced IL-10 and increased TNF-α when compared to stable renal transplant patients. These preliminary cytokine profiling-based observations provide a possible explanation for the therapeutic benefit of adjunctive human interferon-γ therapy in renal allograft recipients with invasive fungal diseases.
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Biomarcadores/sangue , Infecções por Citomegalovirus/diagnóstico , Rejeição de Enxerto/diagnóstico , Interferon gama/sangue , Transplante de Rim/efeitos adversos , Estudos de Casos e Controles , Citomegalovirus/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/microbiologia , DNA/sangue , DNA/genética , Seguimentos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Humanos , Interferon gama/genética , Interleucina-10/sangue , Interleucina-10/genética , Reação em Cadeia da Polimerase em Tempo Real , Transplante Homólogo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genéticaRESUMO
"Accommodation" refers to a vascularized transplant that has acquired resistance to antibody-mediated rejection (AMR). The term was coined in 1990, but the phenomenon was first described after clinical ABO-incompatible (ABOi) renal transplantation in the 1980s and is recognized as a common outcome in this context today. Because of the absence, until recently of reliable animal models of allograft accommodation, it has been studied extensively by investigators in the xenotransplantation field. With recent advances in the ability to recognize and diagnose AMR in human organs, the growth of desensitization programmes for transplantation into sensitized recipients and the availability of therapies that have the potential to promote accommodation, it is timely to review the literature in this area, identifying lessons that may inform preclinical and clinical studies in the future.
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Incompatibilidade de Grupos Sanguíneos/prevenção & controle , Rejeição de Enxerto/imunologia , Imunologia de Transplantes/imunologia , Transplante Heterólogo/imunologia , Animais , Humanos , Transplante HomólogoRESUMO
It has been shown that low-level preformed donor-specific antibodies (DSAbs) detected by luminex beads in the setting of a negative CDC and flow cytometry crossmatch (CDC/FCXM) are associated with inferior allograft outcomes. The relevance of preformed DSAbs in patients receiving alemtuzumab induction and tacrolimus monotherapy has not been studied. Four hundred and eighty renal transplant recipients with a negative CDC/FCXM had their pretransplant sera retrospectively screened for DSAbs. 45/480 (9.4%) of patients were found to have preformed DSAbs. Females and patients receiving regrafts were more likely to have a DSAb (p = 0.008 and p < 0.0001, respectively). Patients with DSAbs had inferior allograft survival (p = 0.047), increased incidence of antibody-mediated rejection (p < 0.0001) and inferior allograft function at 6 months posttransplant (p = 0.017). Patients with HLA class I DSAb (alone or in combination with a Class II DSAb) with high mean fluorescence intensities (MFIs) were at highest risk. We conclude that patients with preformed DSAb are at high risk of adverse outcomes when receiving a minimal immunosuppressive regime incorporating alemtuzumab induction. Patients found to have a preformed DSAb despite a negative crossmatch might benefit from augmented immunosuppression.
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Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Isoanticorpos/sangue , Transplante de Rim/imunologia , Tacrolimo/uso terapêutico , Doadores de Tecidos , Alemtuzumab , Anticorpos Monoclonais Humanizados , Feminino , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transplante Homólogo/imunologia , Resultado do TratamentoRESUMO
Consumptive coagulopathy (CC) remains a challenge in pig-to-primate organ xenotransplantation (Tx). This study investigated the role of tissue factor (TF) expression on circulating platelets and peripheral blood mononuclear cells (PBMCs). Baboons (n = 9) received a kidney graft from pigs that were either wild-type (n = 2), alpha1,3-galactosyltransferase gene-knockout (GT-KO; n = 1) or GT-KO and transgenic for the complement-regulatory protein, CD46 (GT-KO/CD46, n = 6). In the baboon where the graft developed hyperacute rejection (n = 1), the platelets and PBMCs expressed TF within 4 h of Tx. In the remaining baboons, TF was detected on platelets on post-Tx day 1. Subsequently, platelet-leukocyte aggregation developed with formation of thrombin. In the six baboons with CC, TF was not detected on baboon PBMCs until CC was beginning to develop. Graft histopathology showed fibrin deposition and platelet aggregation (n = 6), but with only minor or no features indicating a humoral immune response (n = 3), and no macrophage, B or T cell infiltration (n = 6). Activation of platelets to express TF was associated with the initiation of CC, whereas TF expression on PBMCs was concomitant with the onset of CC, often in the relative absence of features of acute humoral xenograft rejection. Prevention of recipient platelet activation may be crucial for successful pig-to-primate kidney Tx.
Assuntos
Coagulação Intravascular Disseminada/patologia , Transplante de Rim/efeitos adversos , Tromboplastina/genética , Transplante Heterólogo/efeitos adversos , Animais , Anticorpos Monoclonais/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Ligante de CD40/imunologia , Famotidina/uso terapêutico , Galactosiltransferases/genética , Técnicas de Inativação de Genes , Rejeição de Enxerto/patologia , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Imunossupressores/uso terapêutico , Papio/imunologia , Ativação Plaquetária , Agregação Plaquetária , Suínos , Trombina/biossínteseRESUMO
BACKGROUND: Intravascular thrombosis remains a barrier to successful xenotransplantation. Tissue factor (TF) expression on porcine aortic endothelial cells (PAECs), which results from their activation by xenoreactive antibodies (Abs) to Galα1,3Gal (Gal) and subsequent complement activation, plays an important role. OBJECTIVES: The present study aimed to clarify the role of Abs directed against nonGal antigens in the activation of PAECs to express functional TF and to investigate selected methods of inhibiting TF activity. METHODS: PAECs from wild-type (WT), α1,3-galactosyltransferase gene-knockout (GT-KO) pigs, or pigs transgenic for CD46 or tissue factor pathway inhibitor (TFPI), were incubated with naïve baboon serum (BS) or sensitized BS (with high anti-nonGal Ab levels). TF activity of PAECs was assessed. RESULTS: Only fresh, but not heat-inactivated (HI), naïve BS activated WT PAECs to express functional TF. Similarly, PAECs from CD46 pigs were resistant to activation by naïve BS, but not to activation by fresh or HI sensitized BS. HI sensitized BS also activated GT-KO PAECs to induce TF activity. TF expression on PAECs induced by anti-nonGal Abs was inhibited if serum was pretreated with (i) an anti-IgG Fab Ab or (ii) atorvastatin, or (iii) when PAECs were transgenic for TFPI. CONCLUSIONS: Anti-nonGal IgG Abs activated PAECs to induce TF activity through a complement-independent pathway. This implies that GT-KO pigs expressing a complement-regulatory protein may be insufficient to prevent the activation of PAECs. Genetic modification with an 'anticoagulant' gene (e.g. TFPI) or a therapeutic approach (e.g. atorvastatin) will be required to prevent coagulation dysregulation after pig-to-primate organ transplantation.
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Anticorpos Anti-Idiotípicos/química , Aorta/patologia , Coagulação Sanguínea/efeitos dos fármacos , Endotélio Vascular/citologia , Ácidos Heptanoicos/farmacologia , Lipoproteínas/genética , Lipoproteínas/metabolismo , Pirróis/farmacologia , Animais , Animais Geneticamente Modificados , Anticolesterolemiantes/farmacologia , Anticoagulantes , Atorvastatina , Galactosiltransferases/genética , Proteína Cofatora de Membrana/biossíntese , Papio , Suínos , TransgenesRESUMO
The incidence of invasive fungal infections (IFIs) in nonneutropenic solid organ transplant patients is increasing. We report our clinical experience with the use of interferon-gamma (IFN-gamma) immunotherapy in seven renal transplant patients who developed life threatening, disseminated IFIs refractory to conventional antifungal drug therapy. The infections were all microbiologically and histologically proven. The rapid cure of these disseminated infections with exogenous IFN-gamma injections was not associated with impaired kidney allograft function despite the use of liposomal amphotericin B in all cases. No clinical toxicity from the IFN-gamma immunotherapy was seen and no IFI relapsed during long-term follow-up. Our experience is both uncontrolled and in patients with unpredictable fungal infection-related outcomes. However, compared to standard approaches, the accelerated cure of life threatening, disseminated IFIs with 6 weeks of combination antifungal drug therapy and IFN-gamma immunotherapy saved lives, retained allograft function and led to substantial cost savings in this small patient group.
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Interferon gama/uso terapêutico , Transplante de Rim/efeitos adversos , Micoses/tratamento farmacológico , Adulto , Idoso , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Quimioterapia Combinada , Evolução Fatal , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-IdadeRESUMO
Thrombin can amplify inflammation induced by other stimuli, either through ischemia (consequent upon thrombosis), indirectly through generation of downstream mediators such as activated protein C, or directly via signals through protease activated receptors (PAR). This paper will summarize recent data from our laboratory indicating that thrombin is required to initiate CCR2-dependent leukocyte recruitment and that it is the principal determinant of the outcome after vascular injury, via PAR-1 activation of a distinct subset of smooth muscle cell progenitors. In both, tissue factor (TF) initiates thrombin generation and the thrombin acts locally, exemplifying that the initiation phase can generate autocrine or paracrine signalling molecules. Thrombin is an important constituent of innate immunity, able to amplify and modify responses to invading pathogens or tissue damage. With novel anti-thrombin therapeutics and agents to target PAR, a new understanding of the importance of thrombin may allow the development of innovative anti-inflammatory strategies.
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Inflamação/etiologia , Trombina/fisiologia , Doença Aguda , Animais , Doença Crônica , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Doenças Vasculares/patologiaRESUMO
Vascular progenitor cells have been the focus of much attention in recent years; both from the point of view of their pathophysiological roles and their potential as therapeutic agents. However, there is as yet no definitive description of either endothelial or vascular smooth muscle progenitor cells. Cells with the ability to differentiate into mature endothelial and vascular smooth muscle reportedly reside within a number of different tissues, including bone marrow, spleen, cardiac muscle, skeletal muscle and adipose tissue. Within these niches, vascular progenitor cells remain quiescent, until mobilized in response to injury or disease. Once mobilized, these progenitor cells enter the circulation and migrate to sites of damage, where they contribute to the remodelling process. It is generally perceived that endothelial progenitors are reparative, acting to restore vascular homeostasis, while smooth muscle progenitors contribute to pathological changes. Indeed, the number of circulating endothelial progenitor cells inversely correlates with exposure to cardiovascular risk factors and numbers of animal models and human studies have demonstrated therapeutic roles for endothelial progenitor cells, which can be enhanced by manipulating them to overexpress vasculo-protective genes. It remains to be determined whether smooth muscle progenitor cells, which are less well studied than their endothelial counterparts, can likewise be manipulated to achieve therapeutic benefit. This review outlines our current understanding of endothelial and smooth muscle progenitor cell biology, their roles in vascular disease and their potential as therapeutic agents.
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Endotélio Vascular/citologia , Células-Tronco/citologia , Doenças Vasculares/patologia , Animais , Aterosclerose/patologia , Aterosclerose/terapia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Diferenciação Celular , Linhagem da Célula , Humanos , Músculo Liso Vascular/citologia , Transplante de Células-Tronco/métodos , Células-Tronco/fisiologia , Doenças Vasculares/terapiaRESUMO
Coagulation proteases are involved in generating fibrin after vascular injury (hemostasis) but they also have multiple other effects, many of which are mediated independently of fibrin generation, via interactions with specific cell membrane-expressed "protease activated receptors". In inflammation, this family of proteins has a complex influence, the facets of which are still incompletely understood, though a common feature in different models appears to be amplification of innate signals that are initially generated by pathogenic elements or, in the context of transplantation, ischemia or anti-graft antibodies, for instance. There is increasing evidence that these proteases may also have specific effects on cells involved in adaptive immunity and on cells that mediate chronic inflammation and fibrosis. Understanding whether these effects are relevant in the responses generated against transplanted organs is important, as it could lead ultimately to the development of novel ways to promote long-term graft survival.
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Fatores de Coagulação Sanguínea/fisiologia , Sobrevivência de Enxerto , Transplante de Órgãos , Peptídeo Hidrolases/fisiologia , Trombina/fisiologia , Trombose/enzimologia , Animais , Coagulação Sanguínea , Humanos , Imunidade , Imunossupressores/efeitos adversos , Inflamação/enzimologia , Inflamação/imunologia , Camundongos , Receptores de Trombina/agonistasRESUMO
Surgical and standard endourology options are limited in transplant patients with severe ureteric stenosis, particularly when access to the transplant renal pelvis is limited. The use of a silicone-polytetrafluoroethelene (PTFE)-bonded extraanatomic urinary tract stent for urinary tract drainage is described in two patients. This technique of ureteric reconstruction in renal transplantation may be considered when standard approaches have failed. It appears to be safe when performed by radiologists and urologists with expertise in percutaneous renal access.
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Transplante de Rim/efeitos adversos , Stents , Obstrução Ureteral/terapia , Adulto , Cateterismo/métodos , Feminino , Fluoroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia Intervencionista , Obstrução Ureteral/diagnóstico por imagem , Obstrução Ureteral/etiologiaRESUMO
BACKGROUND: Coagulation proteins promote neointimal hyperplasia and vascular remodelling after vessel injury, but the precise mechanisms by which they act in vivo remain undetermined. OBJECTIVES: This study, using an injury model in which the neointima is derived from bone marrow (BM)-derived cells, compared inhibition of tissue factor or thrombin on either BM-derived or existing vascular smooth muscle cells. METHODS: Two transgenic (Tg) mouse strains expressing membrane-tethered tissue factor pathway inhibitor (TFPI) or hirudin (Hir) fusion proteins driven by an alpha smooth muscle actin (SMA) promoter were generated (alpha-TFPI-Tg and alpha-Hir-Tg) and the phenotype after wire-induced endovascular injury was compared with that in wild-type (WT) controls. RESULTS: WT mice developed progressive neointimal expansion, whereas injury in either Tg was followed by repair back to a preinjured state. This was also seen when WT mice were reconstituted with BM from Tg mice but not when Tgs were reconstituted with WT BM, in which injury was followed by slowly progressive neointimal expansion. Injection of CD34+ cells from Tg mice into injured WT mice resulted in the accumulation of fusion protein-expressing cells from day 3 onwards and an absence of neointimal hyperplasia in those areas. CONCLUSIONS: Neointimal development after wire-induced endovascular injury in mice was completely inhibited when BM-derived cells infiltrating the damaged artery expressed membrane tethered anticoagulant fusion proteins under an alpha-SMA promoter. These findings enhance our understanding of the pathological role that coagulation proteins play in vascular inflammation.
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Anticoagulantes/metabolismo , Antígenos CD34/biossíntese , Células da Medula Óssea/metabolismo , Membrana Celular/metabolismo , Regulação da Expressão Gênica , Proteínas Recombinantes de Fusão/metabolismo , Células-Tronco/metabolismo , Animais , Aorta/metabolismo , Arteriosclerose/terapia , Vasos Sanguíneos/patologia , Artérias Carótidas/patologia , Humanos , Inflamação , Camundongos , Camundongos Transgênicos , Músculo Liso/metabolismo , FenótipoRESUMO
The immunosuppressive regimens that are used in solid organ transplantation are potent inhibitors of Th0 as well as Th1 and Th2 cell-mediated immune responses. This predisposes patients to disseminated cryptococcal infections. Mortality in such patients remains very high despite advances in anti-fungal chemotherapy. We describe a case of disseminated cryptococcal disease in a renal allograft recipient that failed to respond to prolonged treatment with several anti-fungal drugs. However, addition of the immuno-modulator, interferon-gamma, resulted in the formation of granulomas and the resolution of his disease within 4-6 weeks. As we cannot find a similar example of combination therapy for disseminated cryptococcal disease in the solid organ transplant literature, we propose that interferon-gamma could be used in synergy with anti-fungal drugs to cure disseminated cryptococcal infections in solid organ transplant patients.
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Antifúngicos/uso terapêutico , Antivirais/uso terapêutico , Criptococose , Interferon gama/uso terapêutico , Transplante de Rim/efeitos adversos , Adulto , Criptococose/microbiologia , Criptococose/fisiopatologia , Quimioterapia Combinada , Humanos , Masculino , Micoses/fisiopatologia , Micoses/virologia , Transplante HomólogoRESUMO
BACKGROUND: Vascular rejection occurring within the first few weeks after transplantation is still the major immunological barrier to the long term survival of xenografts. Currently there is no consensus about what to call this type of rejection (acute vascular rejection, delayed xenograft rejection or acute humoral xenograft rejection), nor about how to prevent or treat it. METHODS: A review of published evidence to define the heterogeneity of this phase of rejection and examine the role of antibodies, complement and graft-infiltrating inflammatory cells. RESULTS: i) antibodies are always involved in acute vascular rejection; ii) this antibody-mediated rejection may be complement-dependent or -independent; iii) inflammatory cells may mediate an antibody- and complement-independent phase of rejection in some small animal models (which, in its pure form cannot be called 'vascular rejection') iv) there remain significant questions about the relevance of 'accommodation' and the importance of coagulation abnormalities. CONCLUSIONS: Without doubt, future research would be helped by distinguishing between these different forms of delayed xenograft rejection, using terminology to reflect the involvement of specific pathophysiological mechanisms. An updated classification of the stages of xenograft rejection is proposed here.