RESUMEN
Type I interferons (IFNs) are pleiotropic cytokines with potent antiviral properties that also promote protective T cell and humoral immunity. Paradoxically, type I IFNs, including the widely expressed IFNß, also have immunosuppressive properties, including promoting persistent viral infections and treating T-cell-driven, remitting-relapsing multiple sclerosis. Although associative evidence suggests that IFNß mediates these immunosuppressive effects by impacting regulatory T (Treg) cells, mechanistic links remain elusive. Here, we found that IFNß enhanced graft survival in a Treg-cell-dependent murine transplant model. Genetic conditional deletion models revealed that the extended allograft survival was Treg cell-mediated and required IFNß signaling on T cells. Using an in silico computational model and analysis of human immune cells, we found that IFNß directly promoted Treg cell induction via STAT1- and P300-dependent Foxp3 acetylation. These findings identify a mechanistic connection between the immunosuppressive effects of IFNß and Treg cells, with therapeutic implications for transplantation, autoimmunity, and malignancy.
Asunto(s)
Interferón beta , Linfocitos T Reguladores , Acetilación , Aloinjertos , Animales , Factores de Transcripción Forkhead/metabolismo , Supervivencia de Injerto , Humanos , Interferón beta/metabolismo , RatonesRESUMEN
To investigate how the human γδ T cell pool is shaped during ontogeny and how it is regenerated after transplantation of hematopoietic stem cells (HSCs), we applied an RNA-based next-generation sequencing approach to monitor the dynamics of the repertoires of γδ T cell antigen receptors (TCRs) before and after transplantation in a prospective cohort study. We found that repertoires of rearranged genes encoding γδ TCRs (TRG and TRD) in the peripheral blood of healthy adults were stable over time. Although a large fraction of human TRG repertoires consisted of public sequences, the TRD repertoires were private. In patients undergoing HSC transplantation, γδ T cells were quickly reconstituted; however, they had profoundly altered TCR repertoires. Notably, the clonal proliferation of individual virus-reactive γδ TCR sequences in patients with reactivation of cytomegalovirus revealed strong evidence for adaptive anti-viral γδ T cell immune responses.
Asunto(s)
Evolución Clonal , Infecciones por Citomegalovirus/inmunología , Trasplante de Células Madre Hematopoyéticas , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Evolución Clonal/genética , Evolución Clonal/inmunología , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/virología , Reordenamiento Génico de Linfocito T , Supervivencia de Injerto , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Trasplante HomólogoRESUMEN
The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.
Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Neuronas Dopaminérgicas , Supervivencia de Injerto , Enfermedades Neuroinflamatorias , Enfermedad de Parkinson , Linfocitos T Reguladores , Tirosina 3-Monooxigenasa , Humanos , Dopamina/análogos & derivados , Dopamina/metabolismo , Neuronas Dopaminérgicas/inmunología , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/trasplante , Mesencéfalo/patología , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/prevención & control , Enfermedades Neuroinflamatorias/terapia , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/cirugía , Enfermedad de Parkinson/terapia , Tirosina 3-Monooxigenasa/deficiencia , Tirosina 3-Monooxigenasa/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/trasplante , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Animales , Ratones , Ratas , Oxidopamina/metabolismo , Supervivencia de Injerto/inmunología , Muerte Celular , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/inmunología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/trasplante , Neostriado/metabolismo , Factores de Tiempo , Proliferación Celular , Resultado del TratamientoRESUMEN
Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.
Asunto(s)
Inmunidad Innata , Linfocitos/inmunología , Adolescente , Adulto , Animales , Biomarcadores , Niño , Modelos Animales de Enfermedad , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Janus Quinasa 3/deficiencia , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Linfocitos/metabolismo , Linfopenia/sangre , Linfopenia/etiología , Ratones , Ratones Noqueados , Fenotipo , Inmunodeficiencia Combinada Grave/sangre , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/metabolismo , Inmunodeficiencia Combinada Grave/terapia , Piel/inmunología , Piel/patologíaRESUMEN
The ability of the immune system to discriminate self from non-self is essential for eradicating microbial pathogens but is also responsible for allograft rejection. Whether it is possible to selectively suppress alloresponses while maintaining anti-pathogen immunity remains unknown. We found that mice deficient in coronin 1, a regulator of naive T cell homeostasis, fully retained allografts while maintaining T cell-specific responses against microbial pathogens. Mechanistically, coronin 1-deficiency increased cyclic adenosine monophosphate (cAMP) concentrations to suppress allo-specific T cell responses. Costimulation induced on microbe-infected antigen presenting cells was able to overcome cAMP-mediated immunosuppression to maintain anti-pathogen immunity. In vivo pharmacological modulation of this pathway or a prior transfer of coronin 1-deficient T cells actively suppressed allograft rejection. These results define a coronin 1-dependent regulatory axis in T cells important for allograft rejection and suggest that modulation of this pathway may be a promising approach to achieve long-term acceptance of mismatched allografts.
Asunto(s)
Rechazo de Injerto/inmunología , Trasplante de Corazón , Infecciones/inmunología , Proteínas de Microfilamentos/metabolismo , Trasplante de Piel , Linfocitos T/inmunología , Aloinjertos/inmunología , Animales , Antígenos Bacterianos/inmunología , Antígenos Fúngicos/inmunología , Antígenos Virales/inmunología , Células Cultivadas , AMP Cíclico/inmunología , Supervivencia de Injerto , Homeostasis/genética , Humanos , Inmunidad , Terapia de Inmunosupresión , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Tolerancia al TrasplanteRESUMEN
Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8+ T cell-mediated immunity and promoted tolerogenic CD4+ regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6-specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance.
Asunto(s)
Supervivencia de Injerto/inmunología , Terapia de Inmunosupresión , Inflamación/inmunología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Trasplante de Órganos , Aloinjertos , Animales , Biomarcadores , Proteína HMGB1/genética , Tolerancia Inmunológica , Inmunidad Innata , Memoria Inmunológica , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Serina-Treonina Quinasas TOR/metabolismo , Vimentina/genéticaRESUMEN
Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice with conditional loss or gain of function, we uncovered that myeloid cell expression of HIF-2α was required for costimulatory blockade-induced transplantation tolerance. While HIF-2α was dispensable for mobilization of tolerogenic monocytes, which were sourced in part from the spleen, it promoted the expression of colony stimulating factor 1 receptor (CSF1R). CSF1R mediates monocyte differentiation into tolerogenic macrophages and was found to be a direct transcriptional target of HIF-2α in splenic monocytes. Administration of the HIF stabilizer, roxadustat, within micelles to target myeloid cells, increased HIF-2α in splenic monocytes, which was associated with increased CSF1R expression and enhanced cardiac allograft survival. These data support further exploration of HIF-2α activation in myeloid cells as a therapeutic strategy for transplantation tolerance.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Trasplante de Corazón , Macrófagos , Monocitos , Tolerancia al Trasplante , Animales , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Tolerancia al Trasplante/inmunología , Monocitos/inmunología , Monocitos/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Rechazo de Injerto/genética , Ratones Endogámicos C57BL , Regulación de la Expresión Génica/efectos de los fármacos , Supervivencia de Injerto/inmunología , Supervivencia de Injerto/efectos de los fármacos , MasculinoRESUMEN
Despite significant advances in the field of transplantation in the past two decades, current clinically available therapeutic options for immunomodulation remain fairly limited. The advent of calcineurin inhibitor-based immunosuppression has led to significant success in improving short-term graft survival; however, improvements in long-term graft survival have stalled. Solid organ transplantation provides a unique opportunity for immunomodulation of both the donor organ prior to implantation and the recipient post transplantation. Furthermore, therapies beyond targeting the adaptive immune system have the potential to ameliorate ischemic injury to the allograft and halt its aging process, augment its repair, and promote recipient immune tolerance. Other recent advances include expanding the donor pool by reducing organ discard, and bioengineering and genetically modifying organs from other species to generate transplantable organs. Therapies discussed here will likely be most impactful if individualized on the basis of specific donor and recipient considerations.
Asunto(s)
Inmunomodulación , Trasplante de Órganos , Humanos , Tolerancia Inmunológica , Bioingeniería , Supervivencia de InjertoRESUMEN
BACKGROUND: Data showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited. METHODS: We conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation. RESULTS: A total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, -3 percentage points; 90% CI, -10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation. CONCLUSIONS: In this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.).
Asunto(s)
Muerte Encefálica , Trasplante de Corazón , Obtención de Tejidos y Órganos , Adulto , Humanos , Supervivencia de Injerto , Preservación de Órganos , Donantes de Tejidos , Muerte , Seguridad del PacienteRESUMEN
BACKGROUND: Therapeutic hypothermia in brain-dead organ donors has been shown to reduce delayed graft function in kidney recipients after transplantation. Data are needed on the effect of hypothermia as compared with machine perfusion on outcomes after kidney transplantation. METHODS: At six organ-procurement facilities in the United States, we randomly assigned brain-dead kidney donors to undergo therapeutic hypothermia (hypothermia group), ex situ kidney hypothermic machine perfusion (machine-perfusion group), or both (combination-therapy group). The primary outcome was delayed graft function in the kidney transplant recipients (defined as the initiation of dialysis during the first 7 days after transplantation). We also evaluated whether hypothermia alone was noninferior to machine perfusion alone and whether the combination of both methods was superior to each of the individual therapies. Secondary outcomes included graft survival at 1 year after transplantation. RESULTS: From 725 enrolled donors, 1349 kidneys were transplanted: 359 kidneys in the hypothermia group, 511 in the machine-perfusion group, and 479 in the combined-therapy group. Delayed graft function occurred in 109 patients (30%) in the hypothermia group, in 99 patients (19%) in the machine-perfusion group, and in 103 patients (22%) in the combination-therapy group. Adjusted risk ratios for delayed graft function were 1.72 (95% confidence interval [CI], 1.35 to 2.17) for hypothermia as compared with machine perfusion, 1.57 (95% CI, 1.26 to 1.96) for hypothermia as compared with combination therapy, and 1.09 (95% CI, 0.85 to 1.40) for combination therapy as compared with machine perfusion. At 1 year, the frequency of graft survival was similar in the three groups. A total of 10 adverse events were reported, including cardiovascular instability in 9 donors and organ loss in 1 donor owing to perfusion malfunction. CONCLUSIONS: Among brain-dead organ donors, therapeutic hypothermia was inferior to machine perfusion of the kidney in reducing delayed graft function after transplantation. The combination of hypothermia and machine perfusion did not provide additional protection. (Funded by Arnold Ventures; ClinicalTrials.gov number, NCT02525510.).
Asunto(s)
Hipotermia Inducida , Hipotermia , Trasplante de Riñón , Riñón , Preservación de Órganos , Perfusión , Humanos , Muerte Encefálica , Funcionamiento Retardado del Injerto/etiología , Funcionamiento Retardado del Injerto/prevención & control , Supervivencia de Injerto , Hipotermia Inducida/efectos adversos , Hipotermia Inducida/métodos , Riñón/cirugía , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Preservación de Órganos/efectos adversos , Preservación de Órganos/métodos , Perfusión/efectos adversos , Perfusión/métodos , Donantes de TejidosRESUMEN
CD4+ T cells orchestrate immune responses and destruction of allogeneic organ transplants, but how this process is regulated on a transcriptional level remains unclear. Here, we demonstrated that interferon regulatory factor 4 (IRF4) was a key transcriptional determinant controlling T cell responses during transplantation. IRF4 deletion in mice resulted in progressive establishment of CD4+ T cell dysfunction and long-term allograft survival. Mechanistically, IRF4 repressed PD-1, Helios, and other molecules associated with T cell dysfunction. In the absence of IRF4, chromatin accessibility and binding of Helios at PD-1 cis-regulatory elements were increased, resulting in enhanced PD-1 expression and CD4+ T cell dysfunction. The dysfunctional state of Irf4-deficient T cells was initially reversible by PD-1 ligand blockade, but it progressively developed into an irreversible state. Hence, IRF4 controls a core regulatory circuit of CD4+ T cell dysfunction, and targeting IRF4 represents a potential therapeutic strategy for achieving transplant acceptance.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Trasplante de Corazón , Factores Reguladores del Interferón/inmunología , Animales , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Diferenciación Celular , Movimiento Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Rechazo de Injerto/genética , Rechazo de Injerto/mortalidad , Rechazo de Injerto/patología , Granzimas/genética , Granzimas/inmunología , Factores Reguladores del Interferón/deficiencia , Factores Reguladores del Interferón/genética , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/inmunología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Análisis de Supervivencia , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Trasplante HomólogoRESUMEN
BACKGROUND: Much of our knowledge of organ rejection after transplantation is derived from rodent models. METHODS: We used single-nucleus RNA sequencing to investigate the inflammatory myocardial microenvironment in human pediatric cardiac allografts at different stages after transplantation. We distinguished donor- from recipient-derived cells using naturally occurring genetic variants embedded in single-nucleus RNA sequencing data. RESULTS: Donor-derived tissue resident macrophages, which accompany the allograft into the recipient, are lost over time after transplantation. In contrast, monocyte-derived macrophages from the recipient populate the heart within days after transplantation and form 2 macrophage populations: recipient MP1 and recipient MP2. Recipient MP2s have cell signatures similar to donor-derived resident macrophages; however, they lack signatures of pro-reparative phagocytic activity typical of donor-derived resident macrophages and instead express profibrotic genes. In contrast, recipient MP1s express genes consistent with hallmarks of cellular rejection. Our data suggest that recipient MP1s activate a subset of natural killer cells, turning them into a cytotoxic cell population through feed-forward signaling between recipient MP1s and natural killer cells. CONCLUSIONS: Our findings reveal an imbalance of donor-derived and recipient-derived macrophages in the pediatric cardiac allograft that contributes to allograft failure.
Asunto(s)
Aloinjertos , Rechazo de Injerto , Trasplante de Corazón , Macrófagos , Humanos , Trasplante de Corazón/efectos adversos , Macrófagos/metabolismo , Rechazo de Injerto/inmunología , Rechazo de Injerto/genética , Masculino , Femenino , Niño , Preescolar , Miocardio/patología , Supervivencia de Injerto , Lactante , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , AdolescenteRESUMEN
BACKGROUND AND AIMS: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplant (post-LT) outcomes in Europe. APPROACH AND RESULTS: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years, with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). CONCLUSIONS: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes.
Asunto(s)
Síndrome de Budd-Chiari , Supervivencia de Injerto , Trasplante de Hígado , Sistema de Registros , Humanos , Síndrome de Budd-Chiari/cirugía , Trasplante de Hígado/estadística & datos numéricos , Masculino , Sistema de Registros/estadística & datos numéricos , Femenino , Europa (Continente)/epidemiología , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven , Adolescente , Estudios RetrospectivosRESUMEN
Limiting CD4+ T cell responses is important to prevent solid organ transplant rejection. In a mouse model of costimulation blockade-dependent cardiac allograft tolerance, we previously reported that alloreactive CD4+ conventional T cells (Tconvs) develop dysfunction, losing proliferative capacity. In parallel, induction of transplantation tolerance is dependent on the presence of regulatory T cells (Tregs). Whether susceptibility of CD4+ Tconvs to Treg suppression is modulated during tolerance induction is unknown. We found that alloreactive Tconvs from transplant tolerant mice had augmented sensitivity to Treg suppression when compared with memory T cells from rejector mice and expressed a transcriptional profile distinct from these memory T cells, including down-regulated expression of the transcription factor Special AT-rich sequence-binding protein 1 (Satb1). Mechanistically, Satb1 deficiency in CD4+ T cells limited their expression of CD25 and IL-2, and addition of Tregs, which express higher levels of CD25 than Satb1-deficient Tconvs and successfully competed for IL-2, resulted in greater suppression of Satb1-deficient than wild-type Tconvs in vitro. In vivo, Satb1-deficient Tconvs were more susceptible to Treg suppression, resulting in significantly prolonged skin allograft survival. Overall, our study reveals that transplantation tolerance is associated with Tconvs' susceptibility to Treg suppression, via modulated expression of Tconv-intrinsic Satb1. Targeting Satb1 in the context of Treg-sparing immunosuppressive therapies might be exploited to improve transplant outcomes.
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Supervivencia de Injerto , Proteínas de Unión a la Región de Fijación a la Matriz , Linfocitos T Reguladores , Factores de Transcripción , Tolerancia al Trasplante , Animales , Supervivencia de Injerto/genética , Supervivencia de Injerto/inmunología , Memoria Inmunológica/genética , Interleucina-2/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/inmunología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tolerancia al Trasplante/genética , Tolerancia al Trasplante/inmunologíaRESUMEN
Ischemia-reperfusion injury (IRI) is an inevitable pathophysiological phenomenon in kidney transplantation. Necroptosis is an undoubtedly important contributing mechanism in renal IRI. We first screened differentially expressed necroptosis-related genes (DENRGs) from public databases. Eight DENRGs were validated by independent datasets and verified by qRT-PCR in a rat IRI model. We used univariate and multivariate Cox regression analyses to establish a prognostic signature, and graft survival analysis was performed. Immune infiltrating landscape analysis and gene set enrichment analysis (GSEA) were performed to understand the underlying mechanisms of graft loss, which suggested that necroptosis may aggravate the immune response, resulting in graft loss. Subsequently, a delayed graft function (DGF) diagnostic signature was constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) and exhibited robust efficacy in validation datasets. After comprehensively analyzing DENRGs during IRI, we successfully constructed a prognostic signature and DGF predictive signature, which may provide clinical insights for kidney transplant.
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Trasplante de Riñón , Ratas , Animales , Trasplante de Riñón/efectos adversos , Funcionamiento Retardado del Injerto/diagnóstico , Funcionamiento Retardado del Injerto/genética , Necroptosis , Riñón , Supervivencia de Injerto/fisiologíaRESUMEN
Lesion scores on procurement donor biopsies are commonly used to guide organ utilization for deceased-donor kidneys. However, frozen sections present challenges for histological scoring, leading to inter- and intra-observer variability and inappropriate discard. Therefore, we constructed deep-learning based models to recognize kidney tissue compartments in hematoxylin & eosin-stained sections from procurement needle biopsies performed nationwide in years 2011-2020. To do this, we extracted whole-slide abnormality features from 2431 kidneys and correlated with pathologists' scores and transplant outcomes. A Kidney Donor Quality Score (KDQS) was derived and used in combination with recipient demographic and peri-transplant characteristics to predict graft loss or assist organ utilization. The performance on wedge biopsies was additionally evaluated. Our model identified 96% and 91% of normal/sclerotic glomeruli respectively; 94% of arteries/arterial intimal fibrosis; 90% of tubules. Whole-slide features of Sclerotic Glomeruli (GS)%, Arterial Intimal Fibrosis (AIF)%, and Interstitial Space Abnormality (ISA)% demonstrated strong correlations with corresponding pathologists' scores of all 2431 kidneys, but had superior associations with post-transplant estimated glomerular filtration rates in 2033 and graft loss in 1560 kidneys. The combination of KDQS and other factors predicted one- and four-year graft loss in a discovery set of 520 kidneys and a validation set of 1040 kidneys. By using the composite KDQS of 398 discarded kidneys due to "biopsy findings", we suggest that if transplanted, 110 discarded kidneys could have had similar survival to that of other transplanted kidneys. Thus, our composite KDQS and survival prediction models may facilitate risk stratification and organ utilization while potentially reducing unnecessary organ discard.
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Aprendizaje Profundo , Trasplante de Riñón , Obtención de Tejidos y Órganos , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Selección de Donante , Riñón/patología , Donantes de Tejidos , Biopsia , Fibrosis , Supervivencia de InjertoRESUMEN
There is a worldwide shortage of deceased-donor kidneys available for transplantation, with too many patients dying while on waiting lists for organs. Meanwhile, and particularly in the United States, many recovered kidneys are discarded, often based on results of frozen section evaluation of a screening biopsy read by an on-call pathologist with limited renal pathology experience. A study in this month's issue of Kidney International uses an artificial intelligence-based approach to evaluate these biopsies, which not only improved correlation between biopsy findings and short-to-intermediate term graft survival, but also demonstrated the potential to reduce biopsy-associated organ discard rates by 25% to 30%.
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Trasplante de Riñón , Obtención de Tejidos y Órganos , Humanos , Estados Unidos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Secciones por Congelación , Inteligencia Artificial , Selección de Donante/métodos , Donantes de Tejidos , Riñón/patología , Biopsia , Supervivencia de InjertoRESUMEN
Organ shortage is a major challenge in kidney transplantation but the use of older donors, often with co-morbidities, is hampered by inconsistent outcomes. Methods of accurately stratifying marginal donor organs by clinical and histological assessment are lacking. To better understand organ variability, we profiled the transcriptomes of 271 kidneys from deceased donors at retrieval. Following correction for biopsy composition, we assessed molecular pathways that associated with delayed, and sub-optimal one-year graft function. Analysis of cortical biopsies identified an adaptive immune gene-rich module that significantly associated with increasing age and worse outcomes. Cellular deconvolution using human kidney reference single cell transcriptomes confirmed an increase in kidney-specific B and T cell signatures, as well as kidney macrophage, myofibroblast and fibroblast gene sets in this module. Surprisingly, innate immune pathway and neutrophil gene signature enrichment was associated with better outcomes. Thus, our work uncovers cellular molecular features of pathological organ ageing, identifiable at kidney retrieval, with translational potential.
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Perfilación de la Expresión Génica , Trasplante de Riñón , Riñón , Transcriptoma , Humanos , Trasplante de Riñón/efectos adversos , Riñón/patología , Riñón/inmunología , Biopsia , Persona de Mediana Edad , Masculino , Adulto , Femenino , Perfilación de la Expresión Génica/métodos , Anciano , Factores de Edad , Donantes de Tejidos , Envejecimiento/patología , Envejecimiento/genética , Envejecimiento/inmunología , Patología Molecular/métodos , Inmunidad Innata , Inmunidad Adaptativa/genética , Adulto Joven , Análisis de la Célula Individual , Supervivencia de Injerto/inmunologíaRESUMEN
The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.
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Rechazo de Injerto , Trasplante de Hígado , Humanos , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Supervivencia de Injerto , AloinjertosRESUMEN
The OPTN/SRTR 2022 Annual Data Report presents the status of the solid organ transplant system in the United States from 2011 through 2022. Organ-specific chapters are presented for kidney, pancreas, liver, intestine, heart, and lung transplant. Each organ-specific chapter is organized to present waitlist information, donor information (both deceased and living, as appropriate), transplant information, and patient outcomes. Data pertaining to pediatric patients are generally presented separately from the adult data. In addition to the organ-specific chapters, the reader will find chapters dedicated to deceased organ donation, vascularized composite allografts, and the COVID-19 pandemic. The data presented in the Annual Data Report are descriptive in nature. In other words, most tables and figures present raw data without statistical adjustment for possible confounding or changes over time. Therefore, the reader should keep in mind the observational nature of the data when attempting to draw inferences before trying to ascribe a cause to any observed patterns or trends. This introduction provides a brief overview of trends in waitlist and transplant activity from 2012 through 2022. More detailed descriptions can be found in the respective organ-specific chapters.