RESUMEN
There is no cure for chronic rejection of transplanted organs. Macrophages are heavily involved in chronic rejection. Macrophages' movement into the graft depends on the actin cytoskeleton and its regulators the GTPase RhoA and its effector ROCK kinase. In this chapter, we describe how the interference with macrophage RhoA/ROCK pathway disrupts macrophage actin cytoskeleton, impairing their functions and migration to the allograft, and preventing the development of chronic rejection, and how such interference can be applied to clinical therapies.
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Rechazo de Injerto , Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Humanos , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Rechazo de Injerto/patología , Rechazo de Injerto/prevención & control , Enfermedad Crónica , Citoesqueleto de Actina/inmunología , Citoesqueleto de Actina/metabolismo , Movimiento Celular , Proteína de Unión al GTP rhoA/metabolismo , Quinasas Asociadas a rho/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Mycophenolic acid (MPA) is a common immunosuppressant used in children post-orthotopic heart transplant (OHT). Multiple MPA dosing strategies exist, with limited reports of comparisons between dosing strategies and patient outcomes. METHODS: We performed a retrospective review of heart transplant recipients ≤ 21 years from 2014 to 2022, comparing dose concordance and clinical outcomes of weight-based mycophenolate dosing (15 mg/kg/dose every 12 h) to body surface area (BSA)-based dosing (600 mg/m2/dose every 12 h). RESULTS: We analyzed 109 patients total (56% in the BSA-based cohort and 44% in the weight-based cohort). The BSA-based cohort received a higher total milligram dose (480 (IQR 200-563) vs. 636 (IQR 320-1000), p = 0.005), mg/kg dose (14.5 (IQR 13.7-16.1) vs. 20.7 (IQR 16.4-25.8), p < 0.001) and mg/m2 dose (382 (IQR 333-470) vs. 596 (IQR 572-612), p < 0.001) compared to the weight-based cohort. The BSA-based cohort experienced a lower hazard of rejection (HR 0.2, 95% CI 0.1-0.4 vs. weight-based) and a greater hazard for overall infection (HR 2.2, 95% CI 1.2-3.9). There was no significant difference in 1-year post-transplant mortality and incidence of post-transplant lymphoproliferative disorder (PTLD). CONCLUSIONS: This study demonstrates the discordance between two common mycophenolate dosing strategies (1200 mg/m2/day vs. 30 mg/kg/day) and its resultant impact on pediatric heart transplant-related outcomes. Further multicenter data would be useful to elucidate the impact on post-heart transplant morbidity and mortality.
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Rechazo de Injerto , Trasplante de Corazón , Inmunosupresores , Ácido Micofenólico , Complicaciones Posoperatorias , Humanos , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/mortalidad , Ácido Micofenólico/administración & dosificación , Estudios Retrospectivos , Masculino , Femenino , Niño , Inmunosupresores/administración & dosificación , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/prevención & control , Estudios de Seguimiento , Pronóstico , Adolescente , Preescolar , Supervivencia de Injerto/efectos de los fármacos , Factores de Riesgo , Lactante , Adulto Joven , Tasa de SupervivenciaRESUMEN
BACKGROUND: Polyomavirus-associated nephropathy (BKVAN) is a significant cause of graft dysfunction in pediatric kidney transplant recipients (PKTR). However, there is currently insufficient data regarding the appropriate frequency of screening and management in children. In this study, we present our experience in managing children with BK polyomavirus (BKV) DNAemia and BKVAN following kidney transplantation. We also assessed the incidence of rejection and the development of de novo donor-specific antibodies (dnDSA) and investigated the effectiveness of intravenous immunoglobulin (IVIG) as an adjunctive therapy for managing presumptive or confirmed BKVAN. METHODS: From March 2015 to December 2021, all PKTR underwent BKV plasma monitoring using quantitative polymerase chain reaction (qPCR) every 2 weeks for the first 3 months, monthly for the remainder of the first year, and then every 3 months thereafter. If the BKV DNAemia level was between 1000 and 5000 IU/mL, a 50% decrease in mycophenolate mofetil (MMF) was implemented. If BKV DNAemia remained above 5000 IU/mL but below 10 000 IU/mL in the second test, MMF was discontinued. In cases where BKV DNAemia was ≥ $$ \ge $$ 10 000 IU/mL, IVIG was administered. RESULTS: Among the 93 patients included in this study, 32% developed BKV DNAemia at a median of 90 days (Inter Quartile Range [IQR] = 30, 300 days) posttransplantation. The median peak of BKV DNAemia was 10 446 copies at a median of 14 days after the first positive PCR. The incidence of dnDSA was common in our cohort but was not significantly different between patients with and without BKV DNAemia (26.7% vs. 24%, p = 0.8). The median time to BKV DNAemia clearance was similar between the IVIG and non-IVIG groups (86 vs. 70 days, p = 0.1014). No graft loss was reported at the median follow-up of 43 (IQR = 22, 62) months in either group. CONCLUSION: The findings of our study suggest a potential benefit of stringent BKV screening and considering timely and intensive treatments before graft dysfunction becomes apparent. Our research also indicates that IVIG might be effective in managing both confirmed and presumptive BKVAN cases, as evidenced by the similar graft outcome observed after a 3-year follow-up period post BKV DNAmia. Notably, despite more frequent adjustments to immunosuppressants and a higher rate of human leukocyte antigen (HLA) mismatch in the BKV DNAemia group, the incidence of dnDSA formation appeared to be comparable between the two groups. These observations warrant controlled trials to confirm their broad applicability.
Asunto(s)
Virus BK , Inmunoglobulinas Intravenosas , Enfermedades Renales , Trasplante de Riñón , Infecciones por Polyomavirus , Complicaciones Posoperatorias , Infecciones Tumorales por Virus , Humanos , Trasplante de Riñón/efectos adversos , Inmunoglobulinas Intravenosas/uso terapéutico , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones por Polyomavirus/diagnóstico , Masculino , Niño , Virus BK/aislamiento & purificación , Incidencia , Femenino , Factores de Riesgo , Adolescente , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/diagnóstico , Preescolar , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/virología , Lactante , Inmunosupresores/uso terapéutico , Isoanticuerpos/sangre , ADN Viral/sangre , Enfermedades Renales/virologíaRESUMEN
PURPOSE OF REVIEW: After many decades of experimental studies and the advent of genetic engineering for pig organs, xenotransplantation has finally reached clinical application. Clinical trials are beginning, and a review of the recent preclinical and clinical studies is paramount. More specifically, reviewing the pathologic findings in biopsies and terminal samples of transplanted pig organs are integral to assessing xenograft acceptance and clinical success. RECENT FINDINGS: This review aims to summarize the current literature in xenotransplantation and enumerate both typical and novel pathological findings in xenografts. This holds an opportunity to identify both diagnostic clues and gaps that are critical to treatment protocol modifications and to improving xenograft survival. While thrombotic microangiopathy and antibody mediated rejection are known pathologic entities in xenograft pathology, we re-examine their occurrence in the context of other diagnostic parameters, and we revisit the importance of integrating clinical findings and molecular techniques to aid pathological diagnosis. We also describe the novel findings in xenografts from both nonhuman primate and human recipients. SUMMARY: With the recently observed pathological features, a structured approach to xenograft pathology diagnosis can be proposed for use in clinical practice and is an effort that can impact therapeutic and genetic modification strategies.
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Rechazo de Injerto , Trasplante de Riñón , Riñón , Animales , Trasplante Heterólogo , Humanos , Trasplante de Riñón/efectos adversos , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Rechazo de Injerto/prevención & control , Rechazo de Injerto/genética , Supervivencia de Injerto , Xenoinjertos , Riñón/patología , Riñón/inmunología , Biopsia , Porcinos , Resultado del Tratamiento , Valor Predictivo de las Pruebas , Microangiopatías Trombóticas/patología , Microangiopatías Trombóticas/inmunologíaRESUMEN
BACKGROUND: Belatacept-treated kidney transplant recipients (KT) experience a lower incidence of de novo donor-specific anti-HLA antibody (DSA) formation despite their higher risk of acute cellular rejection. In vitro studies show that concentrations associated with half-maximal suppression (EC50) of target cells correlate with therapeutic trough concentrations (C0). PURPOSE: To determine whether belatacept inhibits B-cell alloantigen presentation and B-cell alloresponse at known therapeutic C0. METHODS: Peripheral blood leukocytes (PBL) from healthy adults were cultured with HLA-mismatched PBL or fluorochrome-labeled alloantigenic lysate and increasing belatacept concentrations. EC50 was calculated with best-fit four-parameter log-logistic function under a Poisson assumption, as described. RESULTS: After overnight allostimulation, frequencies of alloreactive CD154 + B-cells and their subsets decreased with increasing belatacept concentrations (n = 10). Median (range) EC50s were 1.3 (0.01-37) µg/ml for unfractionated B-cells, 2 (0.03-50) µg/ml for naïve, 3.6 (0.2-92) µg/ml for unswitched memory, 6.2 (0.05-32) µg.ml for transitional, and 7.8 (0.01-101) µg/ml for plasmablasts. Median EC50s were highest at 19 and 31 µg/ml, respectively for CD27- and CD27 + isotype-switched memory B-cells. No effect was seen on B-cell presentation of alloantigen. CONCLUSIONS: At lower C0 levels of < 10 µg/ml, belatacept suppresses alloresponses of B-cells and most B-cell subsets, thereby explaining lower levels of DSA in kidney transplant patients.
Asunto(s)
Abatacept , Subgrupos de Linfocitos B , Rechazo de Injerto , Inmunosupresores , Trasplante de Riñón , Humanos , Abatacept/farmacología , Abatacept/uso terapéutico , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/efectos de los fármacos , Adulto , Isoanticuerpos/inmunología , Antígenos HLA/inmunología , Isoantígenos/inmunología , Células Cultivadas , Masculino , Femenino , Activación de Linfocitos/efectos de los fármacos , Persona de Mediana EdadRESUMEN
The nature and severity of the inflammatory response influences the outcome of organ allotransplantation and xenotransplantation. In allotransplantation, the source of the allograft, for example, from a living, brain-dead, or circulatory death donor, influences the inflammatory response, as do such factors as the preexisting comorbidities and the length of the period of chronic kidney disease in the recipient and the management he/she has received. There is also inflammation associated with the transplant surgery, for example, as a result of ischemia-reperfusion injury. In xenotransplantation, inflammation associated with donor factors will be reduced and, as the patients will receive a pig graft at a much earlier stage of their chronic organ failure, the contribution of recipient factors should also be reduced. However, there is a well-documented systemic inflammatory response to the presence of a pig xenograft (probably associated with species molecular differences) that plays a role in activating the innate immune response. Indeed, there is a complex interaction between inflammation, coagulation dysfunction, and the innate and adaptive immune responses. Suppression of the inflammatory response, for example, by interleukin-6 receptor blockade, would appear to be beneficial after xenotransplantation. Several biomarkers of inflammation have been identified that may be valuable in assessing the response to therapy.
Asunto(s)
Inflamación , Trasplante de Riñón , Trasplante Heterólogo/efectos adversos , Humanos , Trasplante de Riñón/efectos adversos , Animales , Inflamación/inmunología , Inflamación/etiología , Porcinos , Trasplante Homólogo , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Inmunidad InnataRESUMEN
BACKGROUND: This study evaluated the efficacy of an optimized immunosuppressive regimen, including a higher dose of anti-CD154 monoclonal antibody (TNX-1500), in prolonging graft survival in pig-to-baboon kidney xenotransplantation. Despite advances in genetic engineering of organ-source pigs and immunosuppressive regimens, we report that the development of nephrotic-range proteinuria remains a significant problem. METHODS: We assessed the TNX-1500-based immunosuppressive regimen in 9 baboon recipients of gene-edited pig kidney transplants. The regimen included induction with antithymocyte globulin, anti-CD20 monoclonal antibody (rituximab), and C1 esterase inhibitor, and maintenance with TNX-1500, rapamycin, methylprednisolone, and anti-interleukin-6 receptor blockade (tocilizumab). RESULTS: Although an increased dose of TNX-1500 of 30 mg/kg (higher dose, nâ =â 6) versus 20 mg/kg (lower dose, nâ =â 3) improved overall survival (median 214 versus 86 d; P â <â 0.05), 4 of 9 baboons (including 3 with higher dose) developed persistent nephrotic-range proteinuria. The histopathology of these 4 grafts revealed focal glomerular thrombotic microangiopathy (4/4), transplant glomerulopathy (3/4), focal segmental glomerulosclerosis (2/4), and/or membranous nephropathy (1/4) but no definitive features of rejection. Proteinuria was associated with decreased serum albumin and, very importantly, with loss of TNX-1500 in the urine. CONCLUSIONS: Despite the efficacy of the immunosuppressive regimen, we suggest that proteinuria may lead to inadequate immunosuppressive therapy through loss of the therapeutic antibody, thus increasing the risk of rejection. Further research is needed to develop strategies to prevent this complication.
Asunto(s)
Rechazo de Injerto , Supervivencia de Injerto , Inmunosupresores , Trasplante de Riñón , Proteinuria , Animales , Inmunosupresores/administración & dosificación , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Trasplante Heterólogo/efectos adversos , Proteinuria/inmunología , Proteinuria/etiología , Proteinuria/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Papio , Porcinos , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología , Ligando de CD40/inmunología , Ligando de CD40/antagonistas & inhibidores , Animales Modificados Genéticamente , Factores de TiempoRESUMEN
BACKGROUND: Acute rejection (AR) remains a major determinant of renal allograft outcomes, with the major histocompatibility complex (MHC) playing a pivotal role in its pathogenesis. Although immunosuppressive therapies have advanced, their reliance on high doses and lifelong administration increases the risks of infections, malignancies, and other serious complications. Normothermic machine perfusion (NMP) has emerged as a valuable tool in clinical transplantation, enabling organ preservation, functional assessment, and therapeutic intervention. Integrating NMP with genetic engineering approaches to modulate donor kidney MHC expression may offer a novel strategy for preventing AR. METHODS: We synthesized cholesterol-modified small interfering RNA targeting B2m and Ciita (si B2m -Chol and siCiita -Chol) and set cholesterol-modified negative control small interfering RNA (siNC-Chol) as control. Interfering with MHC expression in transplanted kidneys using NMP combined with siB2m-Chol and siCiita-Chol pretreatment of donor kidneys to prevent AR of posttransplant allografts, we evaluated the efficacy of this approach by assessing postoperative survival, renal function, histological features, and inflammatory responses. RESULTS: NMP combined with siB2m-Chol and siCiita-Chol significantly reduced MHC expression on postoperative day 3, improved allograft function, and prolonged recipient survival. By postoperative day 7, pathological damage was reduced, and T cells, macrophages, B cells, donor-specific antibodies, and inflammatory cytokine production were markedly lower in treated grafts compared with the siNC-Chol control group. CONCLUSIONS: These findings demonstrate that ex vivo NMP effectively delivers cholesterol-modified small interfering RNA to renal grafts, substantially downregulating both MHC class I and II expression and consequently attenuating AR.
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Rechazo de Injerto , Trasplante de Riñón , Proteínas Nucleares , Preservación de Órganos , Perfusión , ARN Interferente Pequeño , Transactivadores , Trasplante de Riñón/efectos adversos , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología , Rechazo de Injerto/genética , Rechazo de Injerto/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/administración & dosificación , Masculino , Animales , Transactivadores/genética , Transactivadores/metabolismo , Perfusión/métodos , Perfusión/instrumentación , Perfusión/efectos adversos , Aloinjertos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Supervivencia de Injerto , Humanos , Riñón/patología , Riñón/inmunología , Riñón/metabolismo , Preservación de Órganos/métodos , Preservación de Órganos/instrumentación , Factores de Tiempo , Ratas Endogámicas LewRESUMEN
BACKGROUND: BK polyomavirus (BKPyV) nephropathy is a significant complication of kidney transplantation associated with high levels of BKPyV replication in plasma and poor graft survival. It is currently treated by reducing immunosuppression to restore the immune response. METHODS: We analyzed circulating T cells from 28 kidney transplant recipients with detectable levels of BKPyV DNA in the blood (BKPyV DNAemia). Immunosuppression was significantly reduced in all these patients. We evaluated BKPyV-specific T-cell functionality and phenotype and assessed graft outcomes prospectively. RESULTS: BKPyV DNAemia was rapidly controlled in 13 patients (controllers [C] group), whereas viral replication was sustained in the other 15, who were considered not to have responded to reduced immunosuppression (noncontroller [NC] group). The induction and maintenance therapies used were similar in the C and NC groups. The slope of renal function decline tended to be worse in the NC group than in the C group ( P â <â 0.055). BKPyV-specific T-cell functions (T-cell proliferation and cytokine secretion) were weaker in the NC group than in the C group. This functional impairment was associated with an overexpression of several inhibitory receptors (programmed cell death protein 1 [PD1], T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains, or T-cell immunoglobulin and mucin-containing protein 3 [TIM3]), highlighting an exhausted-like phenotype of BKPyV-specific CD4 and CD8 T cells in the NC group. T-cell inhibition was not overcome by a single blocking antibody against inhibitory receptors, whereas a combination of anti-PD1 and anti-TIM3 antibodies significantly restored BKPyV-specific CD8 T-cell functions ( P â <â 0.05). CONCLUSIONS: Sustained BKPyV DNAemia was associated with an exhausted phenotype of BKPyV-specific T cells despite immunosuppression reduction in kidney transplant recipients. We show that anti-BKPyV-specific CD8 functions can be restored ex vivo by blocking the PD1 and TIM3 pathways, paving the way for new treatment strategies.
Asunto(s)
Virus BK , Inhibidores de Puntos de Control Inmunológico , Trasplante de Riñón , Infecciones por Polyomavirus , Linfocitos T , Infecciones Tumorales por Virus , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Femenino , Virus BK/inmunología , Virus BK/genética , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/tratamiento farmacológico , Adulto , Anciano , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/virología , Inmunosupresores/efectos adversos , Inmunosupresores/administración & dosificación , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Estudios Prospectivos , Supervivencia de Injerto/efectos de los fármacos , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Infecciones Tumorales por Virus/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Linfocitos T CD8-positivos/efectos de los fármacos , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Rechazo de Injerto/virología , Resultado del Tratamiento , Agotamiento de Células TRESUMEN
Donor heart-resident C-C chemokine receptor 2 (CCR2+) macrophages induce the recruitment of CCR2+ monocytes to a transplanted hearts through the secretion of monocyte chemoattractant protein-1 (MCP-1), which mediates the incidence of acute rejection (AR). In this study, we synthesized MCP-1 peptide-modified polyethylene glycol-poly (lactic-co-glycolic) acid (PEG-PLGA) nanoparticles loaded with the sonosensitizer dihydroporphyrin e6 (Ce6) and administered them via intramyocardial injection and used in combination with sonodynamic therapy (SDT) to selectively deplete donor cardiac-resident and infiltrating CCR2+ macrophages. In vitro experiments confirmed that Ce6-NP-MCP-1 targets and has chemotactic effects on CCR2+ macrophages, thereby enhancing the therapeutic efficacy of STD. In mouse heart grafts, the chemotactic effect of Ce6-NP-MCP-1 on CCR2+ macrophages has been used to induce donor heart-resident and infiltrating CCR2+ macrophages to aggregate and phagocytose nanoparticles in combination with SDT to induce macrophage apoptosis. This therapy inhibits the number of donor heart-resident CCR2+ macrophages and downregulates the expression of proinflammatory cytokines and inflammatory infiltration. In addition, it significantly prolongs the allograft survival time. Therefore, CCR2-targeted nanoparticles combined with SDT for the selective depletion of donor heart-resident CCR2+ macrophages provide a promising paradigm for AR target treatment.
Asunto(s)
Rechazo de Injerto , Trasplante de Corazón , Nanopartículas , Receptores CCR2 , Terapia por Ultrasonido , Animales , Trasplante de Corazón/efectos adversos , Receptores CCR2/metabolismo , Nanopartículas/química , Rechazo de Injerto/terapia , Rechazo de Injerto/prevención & control , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos BALB C , Polietilenglicoles/química , Quimiocina CCL2/química , Masculino , Terapia por Ultrasonido/métodos , Clorofilidas , Porfirinas/uso terapéutico , Porfirinas/químicaRESUMEN
The nonmyeloablative conditioning regimen comprising total lymphoid irradiation (TLI) and antithymocyte globulin is used for allogeneic hematopoietic stem cell transplant patients. There is a need to safely intensify TLI+antithymocyte globulin to allow for the achievement of sustained mixed chimerism, particularly in cases where pre-existing autoimmunity poses a significant barrier to successful engraftment. We developed a nonmyeloablative immune preconditioning protocol using low-dose total body irradiation (TBI) to increase the level and durability of mixed donor chimerism. Non-obese diabetic mice were preconditioned with a modified protocol comprising TLI, low-dose TBI, and antithymocyte serum before bone marrow (BM) transplantation. The incorporation of low-dose TBI resulted in enhanced lymphodepletion and facilitated successful engraftment of allogeneic BM to create mixed donor chimerism. The establishment of mixed donor chimerism led to a long-term acceptance of transplanted pancreatic islets that were matched to the BM. More importantly, third-party islets from donors that were mismatched to both the recipient and BM donors were also accepted, highlighting the potency of tolerance induction using this preconditioning regimen. These results provide strong support for a rapid clinical evaluation of this modified conditioning regimen in the context of post-transplant tolerance induction.
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Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Islotes Pancreáticos , Irradiación Linfática , Quimera por Trasplante , Acondicionamiento Pretrasplante , Irradiación Corporal Total , Animales , Irradiación Corporal Total/métodos , Quimera por Trasplante/inmunología , Ratones , Acondicionamiento Pretrasplante/métodos , Supervivencia de Injerto/inmunología , Ratones Endogámicos NOD , Donantes de Tejidos , Ratones Endogámicos C57BL , Trasplante Homólogo , Trasplante de Médula Ósea , Rechazo de Injerto/prevención & control , Ratones Endogámicos BALB CRESUMEN
The safety of immunotherapy in patients undergoing transplant remains unclear due to rejection risks. This study assessed the safety and efficacy of programmed death-1 (PD-1) inhibitors in patients with recurrent tumors who had undergone liver transplantation, emphasizing the value of using graft programmed death-ligand 1 expression as a predictor of rejection to guide patient selection. This single-center, open-label, prospective, single-arm study was conducted from July 2019 to May 2024 at Zhongshan Hospital, Fudan University (Shanghai, China). Eligible participants included patients with recurrent or metastatic liver cancer who had undergone liver transplantation and were unresponsive to locoregional or systemic therapies. The primary endpoints were the incidence and clinical outcomes of acute rejection. Secondary endpoints were overall survival and objective response rate. Twenty consecutive patients received PD-1 inhibitor therapy. Of these, 18 had HCC, and 2 had intrahepatic cholangiocarcinoma. Liver graft biopsies confirmed negative programmed death-ligand 1 expression in all participants before PD-1 inhibitor therapy. Three patients (15%) experienced acute rejection, with a 95% CI of 3.2%-37.9%. The 1-year and 2-year survival probabilities after PD-1 inhibitor treatment were 0.55 (95% CI: 0.33-0.77) and 0.24 (95% CI: 0.05-0.43), respectively. The median survival time after tumor recurrence was 24.6 months, exceeding the historically reported median survival time of 16.3 months. These exploratory findings suggest that, in selected recipients of liver transplant, PD-1 inhibitors may be associated with reduced rejection risk and potential survival benefit, although further validation is needed.
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Antígeno B7-H1 , Rechazo de Injerto , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas , Trasplante de Hígado , Recurrencia Local de Neoplasia , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Femenino , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/inmunología , Estudios Prospectivos , Rechazo de Injerto/epidemiología , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Proyectos Piloto , Antígeno B7-H1/metabolismo , Antígeno B7-H1/análisis , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Adulto , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Aloinjertos/patología , Aloinjertos/inmunología , Anciano , Resultado del Tratamiento , Biomarcadores/metabolismo , Valor Predictivo de las Pruebas , China/epidemiología , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/mortalidad , Hígado/patologíaRESUMEN
Using biomarkers to tailor immunosuppressive therapy after kidney transplantation was proposed to improve clinical care. Timely and individual adaptions of immunosuppression could reduce therapy-related side effects, such as infections, cardiovascular morbidity and malignancy, and further lower the risk of allograft rejection. Despite promising preliminary studies, evidence for implementing such a biomarker in clinical care is insufficient. Prominent candidates for immunologic monitoring after kidney transplantation include donor human leukocyte antigen-specific antibodies, donor-derived cell-free DNA, urinary chemokines and peripheral transcriptomics. In addition, the quantification of Torque Teno virus, a highly prevalent and non-pathogenic virus that was shown to associate with outcomes linked to immunocompetence, has been proposed for immunologic monitoring. This review summarises the prospects and limitations of Torque Teno virus for immunologic risk stratification after kidney transplantation in the context of current state-of-the-art. It will focus on cut-off values of plasma Torque Teno virus load that might be useful to guide immunosuppression in the clinical care of kidney transplant recipients, and highlights recently proposed indications of Torque Teno virus-guided immunosuppression.
Asunto(s)
Infecciones por Virus ADN , Trasplante de Riñón , Torque teno virus , Humanos , Trasplante de Riñón/efectos adversos , Torque teno virus/inmunología , Torque teno virus/aislamiento & purificación , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología , Monitorización Inmunológica/métodos , Medición de Riesgo , Biomarcadores/sangre , Infecciones por Virus ADN/inmunología , Terapia de Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Carga ViralRESUMEN
Donor-specific anti-HLA antibodies (DSA)-induced primary graft failure remains a significant cause of mortality in patients undergoing HLA-mismatched allogeneic hematopoietic stem cell transplantation. In recent years, significant advances have been made in understanding the association between DSA and prognosis following HLA-mismatched transplantation, as well as in the development of DSA desensitization therapies. Based on these advances, the Hematopoietic Stem Cell Application Group, Chinese Society of Hematology, Chinese Medical Association has developed this consensus to better guide the clinical practice of desensitization therapy for DSA-positive, HLA-mismatched transplant candidates.
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Antígenos HLA , Trasplante de Células Madre Hematopoyéticas , Isoanticuerpos , Humanos , Antígenos HLA/inmunología , Donantes de Tejidos , Consenso , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Prueba de HistocompatibilidadRESUMEN
BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality after a kidney transplant (KT). Letermovir (LTV) was approved in high-risk KT recipients, providing an alternative to standard-of-care valganciclovir (VGC) associated with reduced myelosuppression. METHODS: Adult patients receiving a kidney transplant with moderate-risk CMV serostatus between 1/1/2021 and 6/6/2024 were evaluated. Patients were included in VGC or LTV cohort based on de novo prophylaxis regimen. The primary outcomes were efficacy and tolerability. RESULTS: Four hundred and eight KTRs met inclusion criteria: 316 received VGC, 92 received LTV. Cohorts were comparable; the majority received a primary (84.2% vs. 90.2%, p = 0.566) deceased donor (69.6% vs. 68.5%, p = 0.298) transplant with lymphocyte depleting induction (82.3% vs. 90.2%, p = 0.32). Significantly more patients in the VGC cohort required antiviral dose adjustment (61.7% vs. 1.1%, p < 0.0001). Patients in the LTV cohort were significantly more likely to complete antiviral prophylaxis (63.3% vs. 84.8%, p < 0.0001). Patients in the VGC cohort were significantly more likely to experience leukopenia (65.8% vs. 45.7%, p = 0.0006) and neutropenia (30.7% vs. 12.0%, p = 0.0002) during the first-year post-KT. Significantly more patients in the LTV cohort were on the equivalent of >1000 mg mycophenolate/day at 12 months post-KT (59.9% vs. 74.2%, p = 0.0173). Rates of CMV viremia and clinically significant disease through 1-year post-KT were comparable. CONCLUSIONS: De novo LTV in R+ KTRs appears to be safe and effective compared to VGC. This study suggests antiviral prophylaxis is more likely to be successfully completed with LTV and requires less dose titration. Additionally, LTV appears to be associated with less myelosuppression, permitting higher mycophenolate doses at 12 months and avoiding corrective healthcare resource utilization.
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Acetatos , Antivirales , Infecciones por Citomegalovirus , Citomegalovirus , Rechazo de Injerto , Fallo Renal Crónico , Trasplante de Riñón , Ácido Micofenólico , Complicaciones Posoperatorias , Quinazolinas , Nivel de Atención , Humanos , Trasplante de Riñón/efectos adversos , Femenino , Masculino , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/prevención & control , Persona de Mediana Edad , Antivirales/uso terapéutico , Citomegalovirus/aislamiento & purificación , Citomegalovirus/efectos de los fármacos , Estudios de Seguimiento , Ácido Micofenólico/uso terapéutico , Ácido Micofenólico/efectos adversos , Pronóstico , Supervivencia de Injerto/efectos de los fármacos , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/prevención & control , Estudios Retrospectivos , Factores de Riesgo , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Adulto , Acetatos/uso terapéutico , Quinazolinas/uso terapéutico , Fallo Renal Crónico/cirugía , Complicaciones Posoperatorias/tratamiento farmacológico , Tasa de Filtración GlomerularRESUMEN
Induced pluripotent stem cell (iPSC)-derived pancreatic islets represent a promising therapeutic approach for restoring insulin independence in type 1 diabetes (T1D). However, their clinical success remains critically dependent on overcoming rejection mediated by innate and adaptive immune responses. Current immunosuppressive therapies pose significant long-term risks and only partially control alloimmune and autoimmune reactions. Targeted immunomodulation using monoclonal antibodies is a safer, more precise alternative. Here, we explored the impacts of blocking CD276 (B7-H3) and CD155 (PVR), activating ligands involved in immune recognition and regulation, on the survival and in vivo maturation of iPSC-derived endocrine progenitors (EPs) into functional pancreatic islets. Using a humanized mouse model, we demonstrated that dual blockade of CD276 and CD155 markedly reduced NK cell-mediated graft rejection, prevented CD14+ monocyte activation, and limited overall immune infiltration. In addition, CD155 blockade increased PD-1 levels on activated CD8+ T cells and significantly enhanced regulatory T cell (Treg) expansion and function, thereby promoting graft tolerance. Combined treatment prolonged engraftment and facilitated the maturation of EPs into functional, insulin-secreting cells, as indicated by increased human C-peptide levels and glucose responsiveness 4 weeks post-transplantation. Our findings highlight CD276/CD155 blockade as a novel immunomodulatory strategy to support tolerance and the functional maturation of iPSC-derived pancreatic grafts in T1D.
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Anticuerpos Monoclonales , Tolerancia Inmunológica , Células Madre Pluripotentes Inducidas , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos , Receptores Virales , Animales , Ratones , Trasplante de Islotes Pancreáticos/métodos , Humanos , Células Madre Pluripotentes Inducidas/citología , Anticuerpos Monoclonales/farmacología , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/cirugía , Receptores Virales/antagonistas & inhibidores , Receptores Virales/inmunología , Rechazo de Injerto/prevención & control , Ratones Endogámicos NOD , Células Asesinas Naturales/inmunología , Supervivencia de Injerto , Trasplante Homólogo , Linfocitos T Reguladores/inmunología , Islotes Pancreáticos/citologíaRESUMEN
BACKGROUND: maintenance immunosuppressive therapy, indicated for patients after solid organ transplantation - kidney (R), liver (F), heart (C), lung (P) - and aimed at preventing rejection, involves the intake of at least one Calcineurin (CNI) inhibitor (Cyclosporin - CsA - or Tacrolimus - TAC) in combination with an Antimetabolite (Antim) (Mycophenolate Mofetil or Mycophenolic Acid - MMF - or Azathioprine - AZA) or a proliferation signal inhibitor (mTOR) (Sirolimus - SIR - or Everolimus - EVE) with the possible addition of corticosteroids (in particular Prednisone - PRED). The possibility of comparing prescribing patterns identified through different data sources represents an important methodological challenge and could shed light on the accuracy, advantages, and limitations of different information sources, aspects that must be considered when planning future observational studies. OBJECTIVES: to assess, within a cohort of solid organ transplant patients, the levels of concordance in the definition of post-transplant immunosuppressive therapy between health administrative flows and what is reported by the medical specialist during the patient's periodic follow-up visit. DESIGN: analysis of the level of concordance of information on post-transplant maintenance immunosuppressive therapy collected from two different data sources: the regional health administrative databases (SIS) and the national transplant information system (SIT). This analysis was performed as part of a retrospective cohort study - the CESIT study - including all patients undergoing single solid organ transplantation (heart, liver, lung, kidney) between 2009 and 2019 in four Italian regions (Lombardy, Lazio, Veneto, Sardinia). The therapeutic combinations of immunosuppressants were identified by means of specific algorithms applied to the SIS data and subsequently compared with the therapeutic patterns recorded by specialist physicians during follow-up visits (FU) and entered electronically in the SIT flow sheets. The analysis focuses mainly on the therapy delivered in the 30 days following hospital discharge (index therapy); it is then extended to comparisons made over longer time windows (at 1, 2, and 3 years from the date of hospital discharge). MAIN OUTCOME MEASURES: the level of agreement between the two data sources in defining the index therapy was assessed using three methods: 1. Cohen's k statistic: this method allowed quantification of the level of agreement at the level of individual active substance; 2. proportion of active ingredients in common: an ordinal categorical variable was calculated for each patient indicating the level of concordance between the sources: null (no active ingredient in common), low (<40 % of ATCs in common), medium (40-59 %), high (>60 %), perfect (identical combinations); 3. Levenshtein distance (LS): considering polypharmacies from a formal point of view as strings, the computational effort that would be required to make them equal was estimated. RESULTS: there were 2,692 solid organ transplant patients for whom index therapy information was available from both SIS and SIT (C: 6.8%; F: 44.9%; P: 5.2%; R: 43.1%). In comparison to CNI immunosuppressants, Cohen's k coefficient showed high levels of concordance for all transplant types (CsA heart: 0.78; CsA liver: 0.96 - TAC heart: 0.74; TAC kidney: 0.92); while for MMF, differential performance by organ type was evident (MMF heart: 0.51; MMF kidney: 0.78). For the Preds, there was greater discordance in particular in R and F. When comparing immunosuppressive therapy as a whole, the 'high/perfect' concordance levels concerned on average 80.1% of the patients (F: 70.1%; R: 91.3%). The results were comparable by applying LS. Finally, the concordance at 1, 2, and 3 years after discharge reported a less good performance than with index therapy, which was, however, stable over the time intervals considered. CONCLUSIONS: the level of concordance between therapeutic combinations for the same patient detected between different sources was generally high: despite this, the level of agreement varied according to the individual active substance, the type of transplant and the time window examined. The results of this work show that SIS are a valuable tool for defining immunosuppressive maintenance therapies and offer useful elements to consider when planning observational studies based on the two data flows.
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Reclamos Administrativos en el Cuidado de la Salud , Rechazo de Injerto , Inmunosupresores , Trasplante de Órganos , Pautas de la Práctica en Medicina , Humanos , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Masculino , Femenino , Pautas de la Práctica en Medicina/estadística & datos numéricos , Rechazo de Injerto/prevención & control , Adulto , Italia , Reclamos Administrativos en el Cuidado de la Salud/estadística & datos numéricos , Estudios Retrospectivos , Estudios de Seguimiento , AncianoRESUMEN
Although a successful auxiliary partial orthotopic liver transplantation (APOLT) demands technical expertise, it provides an opportunity for a post-liver transplant (LT) immunosuppression-free life. With the advent of newer medications and an implicit understanding of the post-LT immunopathophysiology, clinicians have successfully breached the ABO barrier. However, given the time constraints among other factors, the immunological outcomes of this ABO incompatible LT (ABOiLT) remain suboptimal in the setting of an acute liver failure (ALF). Here, we report an urgent ABOi-APOLT in a child with ALF, wherein we combined the benefits of APOLT to tide over the child's acute state (allowing time for native liver regeneration (NLR)) with the apparent immunological disadvantage of ABOiLT (immune injury to the graft) to help further promote this NLR. The child could receive ABOiLT-desensitising medications less than 48 hours prior (ideally 2 weeks) to LT, thereby putting him at a higher risk of rejection and graft loss. He recovered well from the surgery, and on follow-up histopathology and imaging his native liver shows features of regeneration. Moreover, with this NLR the concerns of immune-mediated graft loss associated with ABOiLT have also been mitigated. We present the first report of a case wherein an apparent disadvantage was used to benefit the patient by combining two different LT procedures.
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Sistema del Grupo Sanguíneo ABO , Incompatibilidad de Grupos Sanguíneos , Fallo Hepático Agudo , Trasplante de Hígado , Humanos , Trasplante de Hígado/métodos , Fallo Hepático Agudo/cirugía , Fallo Hepático Agudo/inmunología , Sistema del Grupo Sanguíneo ABO/inmunología , Masculino , Incompatibilidad de Grupos Sanguíneos/inmunología , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología , Niño , Resultado del TratamientoRESUMEN
BACKGROUND: Modern immunosuppressive regimens have been associated with lower rejection rates after heart transplantation (HTx), yet long-term outcomes have remained limited by drug-related complications. Since 2010, our program has implemented a protocolized corticosteroid withdrawal (CSW) strategy following induction with rabbit anti-thymocyte globulin (RATG) and methylprednisolone. The protocol consists of shifting from a high-dose regimen to a minimization approach with a goal of steroid discontinuation within 12 months. METHODS: We evaluated the impact of this approach on the combined primary endpoint of freedom from allograft rejection ISHLT ≥ 2R, infection, non-cutaneous cancer, or coronary artery vasculopathy (CAV). We conducted a retrospective single-center study including 418 HTx patients. Patients were divided according to era of HTx: Early (1983-1998); Recent (1999-02/2010), and Corticosteroid withdrawal (CSW) (03/2010-06/2018). Multivariate Cox analyses identified predictors of adverse outcomes. RESULTS: Five-year corticosteroid use markedly decreased over eras (Early 61, 4%, Recent 20, 3%, CSW 3, 4% at 5 years; p < 0.001). Freedom from the composite primary endpoint significantly improved with CSW (Early: HR: 3.42; 95% CI: 2.49-4.68; Recent: HR: 2.9; 95% CI: 4.1, both p < 0.0001 compared to CSW.) Only prednisone dose (HR:1.19; 95% CI: 1.09-1.30; p < 0.0001) and era of transplantation (Early vs. CSW: HR:2.70; 95% CI: 1.91-3.81; p < 0.0001; Recent vs. CSW: HR:2.38; 95% CI: 1.68-3.39; p < 0.0001) were independently associated with worse outcomes in the final multivariate Cox model. Notably, death, rejection, infection, and CAV were less frequent in the CSW era. CONCLUSION: Protocolized CSW within 1 year after HTx was associated with improved long-term outcomes, including death, fewer rejection episodes, infections, and CAV. These findings support rapid steroid tapering as a safe and effective strategy in contemporary HTx.
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Corticoesteroides , Rechazo de Injerto , Trasplante de Corazón , Inmunosupresores , Complicaciones Posoperatorias , Privación de Tratamiento , Humanos , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/mortalidad , Masculino , Estudios Retrospectivos , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/prevención & control , Rechazo de Injerto/mortalidad , Femenino , Persona de Mediana Edad , Supervivencia de Injerto/efectos de los fármacos , Estudios de Seguimiento , Pronóstico , Corticoesteroides/administración & dosificación , Complicaciones Posoperatorias/patología , Complicaciones Posoperatorias/etiología , Inmunosupresores/uso terapéutico , Factores de Riesgo , Adulto , Tasa de SupervivenciaRESUMEN
BACKGROUND: Tacrolimus is the maintenance immunosuppression of choice in pediatric liver transplant (LT) recipients. However, in selective cases, sirolimus is used as an alternative immunosuppressive treatment. We aimed to review a single centre's experience of using sirolimus as an alternative to tacrolimus in pediatric LT recipients. METHODS: Single centre retrospective study of pediatric LT recipients who were started on sirolimus as an alternative immunosuppressant to tacrolimus. Children (< 16 years) who were started on sirolimus between May 2000 and May 2024 were included in the study. RESULTS: A total of 19 children were started on sirolimus following LT and followed up for a median of 4 years (range 0.4-12.8). Post-transplant lymphoproliferative disorder (PTLD) was the most common reason for tacrolimus discontinuation and conversion to sirolimus (n = 14), followed by tacrolimus-related adverse effects (n = 4) and disease recurrence (n = 1). There were no cases of PTLD recurrence or biopsy-confirmed rejection whilst on sirolimus. Proteinuria and hyperlipidaemia were the most common sirolimus side effects observed. Eighteen children remain on sirolimus to date, and none required discontinuation from side effects. In those with PTLD, 4 episodes of rejection occurred between the period of tacrolimus discontinuation and starting sirolimus (median immunosuppression-free time of 5 months), with one child requiring regrafting due to chronic rejection. CONCLUSION: The experience from our centre demonstrates sirolimus to be a safe and effective alternative to tacrolimus in a selected population of pediatric LT recipients. Further research with a larger sample size is required to confirm these findings and evaluate the long-term safety of sirolimus in this population.