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[This corrects the article DOI: 10.3389/fimmu.2023.1122409.].
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Mast cells (MCs) are innate immune cells with a versatile set of functionalities, enabling them to orchestrate immune responses in various ways. Aside from their known role in allergy, they also partake in both allograft tolerance and rejection through interaction with regulatory T cells, effector T cells, B cells and degranulation of cytokines and other mediators. MC mediators have both pro- and anti-inflammatory actions, but overall lean towards pro-fibrotic pathways. Paradoxically, they are also seen as having potential protective effects in tissue remodeling post-injury. This manuscript elaborates on current knowledge of the functional diversity of mast cells in kidney transplants, combining theory and practice into a MC model stipulating both protective and harmful capabilities in the kidney transplant setting.
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Hipersensibilidad , Trasplante de Riñón , Humanos , Mastocitos , Citocinas/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
The diagnosis of kidney allograft rejection is based on late histological and clinical markers. Early, specific and minimally-invasive biomarkers may improve rejection diagnosis. Endothelial cells (EC) are one of the earliest targets in kidney transplant rejection. We investigated whether circulating EC (cEC) could serve as an earlier and less invasive biomarker for allograft rejection. Blood was collected from a cohort of 51 kidney transplant recipients before and at multiple timepoints after transplantation, including during a for cause biopsy. The number and phenotype of EC was assessed by flow-cytometric analysis. Unbiased selection of EC was done using principal component (PCA) analysis. Paired analysis revealed a transient cEC increase of 2.1-fold on the third day post-transplant, recovering to preoperative levels at seventh day post-transplant and onwards. Analysis of HLA subtype demonstrated that cEC mainly originate from the recipient. cEC levels were not associated with allograft rejection, allograft function or other allograft pathologies. However, cEC in patients with allograft rejection and increased levels of cEC showed elevated levels of KIM-1 (kidney injury marker-1). These findings indicate that cEC numbers and phenotype are affected after kidney transplantation but may not improve rejection diagnosis.
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Células Endoteliales/metabolismo , Citometría de Flujo , Rechazo de Injerto/sangre , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Trasplante de Riñón , Adulto , Aloinjertos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Introduction: The clinical use of tacrolimus is characterized by many side effects which include neurotoxicity. In contrast, tacrolimus has also shown to have neuroregenerative properties. On a molecular level, the mechanisms of action could provide us more insight into understanding the neurobiological effects. The aim of this article is to review current evidence regarding the use of tacrolimus in peripheral nerve injuries.Areas covered: Available data on tacrolimus' indications were summarized and molecular mechanisms were elucidated to possibly understand the conflicting neurotoxic and neuroregenerative effects. The potential clinical applications of tacrolimus, as immunosuppressant and enhancer of nerve regeneration in peripheral nerve injuries, are discussed. Finally, concepts of delivery are explored.Expert opinion: It is unclear what the exact neurobiological effects of tacrolimus are. Besides its known calcineurin inhibiting properties, the mechanism of action of tacrolimus is mediated by its binding to FK506-binding protein-52, resulting in a bimodal dose response. Experimental models found that tacrolimus administration is preferred up to three days prior to or within 10 days post-nerve reconstruction. Moreover, the indication for the use of tacrolimus has been expanding to fields of dermatology, ophthalmology, orthopedic surgery and rheumatology to improve outcomes after various indications.
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Regeneración Nerviosa/efectos de los fármacos , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Tacrolimus/administración & dosificación , Animales , Inhibidores de la Calcineurina/administración & dosificación , Inhibidores de la Calcineurina/efectos adversos , Inhibidores de la Calcineurina/farmacología , Esquema de Medicación , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/farmacología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/fisiopatología , Traumatismos de los Nervios Periféricos/fisiopatología , Tacrolimus/efectos adversos , Tacrolimus/farmacologíaRESUMEN
Cutaneous squamous cell carcinoma (cSCC) is a serious complication after organ transplantation and patients benefit from an early risk assessment. We hypothesized that functional differences in circulating T cells may represent risk factors for post-transplant cSCC development. Here, we analysed genome-wide DNA methylation of circulating T cells of kidney transplant recipients before the clinical onset of cSCC, to identify differences associated with post-transplant cSCC development. This analysis identified higher DNA methylation of SERPINB9, which is an intracellular inhibitor of granzyme B, a protein that induces apoptosis in target cells. High DNA methylation of SERPINB9 in circulating T cells was confirmed in a second patient cohort during recurrent cSCC, indicating that high SERPINB9 methylation represents a persistent risk factor for cSCC development. At the functional level, the inverse correlation between DNA methylation and messenger RNA expression present in non-cSCC patients was absent in the cSCC patients. Also, a significant difference in serpinB9 protein expression between cSCC patients and non-cSCC patients was observed. It was concluded that disturbed regulation of serpinB9 in circulating T cells represents a novel risk factor for post-transplant cSCC in kidney transplant recipients.
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Carcinoma de Células Escamosas/inmunología , Regulación hacia Abajo/inmunología , Trasplante de Riñón/efectos adversos , Serpinas/inmunología , Neoplasias Cutáneas/inmunología , Linfocitos T/inmunología , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/patología , Metilación de ADN/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patología , Linfocitos T/patologíaRESUMEN
BACKGROUND: While conversion from cyclosporine to everolimus is well documented, conversion from tacrolimus has been poorly studied. In this randomised, controlled trial the safety and tolerability of switching from tacrolimus to everolimus with glucocorticoid withdrawal after living-donor kidney transplantation was studied. METHODS: A total of 194 patients were planned to be randomised 1:1 to either continue tacrolimus or to convert to everolimus at month 3 after transplantation. At randomisation, all patients received tacrolimus, mycophenolate mofetil and prednisolone. Everolimus was started in a dose of 1.5 mg twice daily, aiming for predose concentrations of 4-7 ng/ml. Prednisolone was gradually withdrawn in both groups. RESULTS: The trial was stopped prematurely after the inclusion of 60 patients. The interim analysis showed an unacceptably high rejection rate in the everolimus group as compared with the control group: 30.0% vs. 6.7% (95% CI: 0.047-0.420; p = 0.045). An additional 8 patients stopped everolimus because of toxicity. At the end of follow-up (month 12) only 12 (40%) patients assigned to everolimus were still on the study drug. CONCLUSIONS: Conversion from tacrolimus to everolimusbased immunosuppression with withdrawal of prednisolone three months after kidney transplantation results in an unacceptably high risk of acute rejection and causes considerable toxicity. Based on our findings, such a switch strategy cannot be recommended.
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Sustitución de Medicamentos/efectos adversos , Everolimus/administración & dosificación , Glucocorticoides/administración & dosificación , Rechazo de Injerto/inducido químicamente , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Tacrolimus/administración & dosificación , Adulto , Anciano , Femenino , Humanos , Donadores Vivos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Estudios Prospectivos , Resultado del TratamientoRESUMEN
We hypothesize that T cells such as interleukin (IL)-21+ B cell lymphoma 6 (BCL6)+ T follicular helper cells can regulate B cell-mediated immunity within the allograft during acute T cell-mediated rejection; this process may feed chronic allograft rejection in the long term. To investigate this mechanism, we determined the presence and activation status of organized T and B cells in so-called ectopic lymphoid structures (ELSs) in different types of acute renal allograft rejection. Biopsies showing the following primary diagnosis were included: acute/active antibody-mediated rejection, C4d+ (a/aABMR), acute T cell-mediated rejection grade I (aTCMRI) and acute T cell-mediated rejection grade II (aTCMRII). Paraffin sections were stained for T cells (CD3 and CD4), B cells (CD20), follicular dendritic cells (FDCs, CD23), activated B cells (CD79A), immunoglobulin (Ig)D, cell proliferation (Ki67) and double immunofluorescent stainings for IL-21 and BCL6 were performed. Infiltrates of T cells were detected in all biopsies. In aTCMRI, B cells formed aggregates surrounded by T cells. In these aggregates, FDCs, IgD and Ki67 were detected, suggesting the presence of ELSs. In contrast, a/aABMR and aTCMRII showed diffuse infiltrates of T and B cells but no FDCs and IgD. IL-21 was present in all biopsies. However, co-localization with BCL6 was observed mainly in aTCMRI biopsies. In conclusion, ELSs with an activated phenotype are found predominantly in aTCMRI where T cells co-localize with B cells. These findings suggest a direct pathway of B cell alloactivation at the graft site during T cell mediated rejection.
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Linfocitos B/inmunología , Rechazo de Injerto/inmunología , Trasplante de Riñón , Linfocitos T Colaboradores-Inductores/inmunología , Estructuras Linfoides Terciarias/inmunología , Adulto , Anciano , Biopsia , Células Dendríticas Foliculares/inmunología , Femenino , Humanos , Interleucinas/metabolismo , Antígeno Ki-67/análisis , Riñón/patología , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
Blockade of the CD80/86-CD28 pathway by belatacept after kidney transplantation is associated with an increased risk of rejection compared with standard, calcineurin inhibitor (CNI)-based therapy. CD28- T cells, which express CD57, are not susceptible to belatacept treatment. High numbers of CD4+ CD57+ programmed death 1 (PD-1)- T cells pretransplantation have been associated with a higher chance of rejection, although conflicting data have been reported. To investigate the working mechanism behind this possible higher chance of rejection, we studied the expression of co-inhibitory molecules (CD223, CD244 and PD-1), proliferative capacity and cytotoxic potential of fluorescence activated cell sorted (FACS) CD4+ CD57+ PD-1- and CD8+ CD57+ PD-1- T cells, and their CD57- control populations, after alloantigen stimulation. The effect of belatacept on the cytotoxic capacity of pretransplantation peripheral blood mononuclear cells from 20 patients who received belatacept post-transplantation was also tested. Expression of co-inhibitory molecule CD223 increased by approximately 10-fold after allogeneic stimulation in all four T cell subsets. Proliferation and up-regulation of CD244 and PD-1 was observed for CD4+ CD57- PD-1- T cells after allogeneic stimulation, but no up-regulation of these markers occurred on CD8+ T cells or CD4+ CD57+ PD-1- T cells. However, CD4+ CD57+ PD-1- T cells and, to a lesser extent, CD8+ CD57+ PD-1- T cells displayed higher cytotoxicity as indicated by granzyme B expression. Belatacept inhibited the cytotoxic potential of CD4+ CD57+ PD-1- T cells (median of inhibition 31%, P < 0·01) and CD8+ CD57+ PD-1- T cells (median of inhibition 10%, P < 0·05). In conclusion, alloantigen-activated CD4+ CD57+ PD-1- T cells exhibited a less proliferative but more cytotoxic profile than their CD57- counterparts. Their cytotoxic capacity can be inhibited partly by belatacept and was not associated with development of rejection after kidney transplantation.
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Abatacept/uso terapéutico , Rechazo de Injerto/inmunología , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/inmunología , Trasplante de Riñón , Linfocitos T Citotóxicos/inmunología , Adulto , Anciano , Antígenos CD/metabolismo , Antígenos CD57/metabolismo , Proliferación Celular , Células Cultivadas , Citotoxicidad Inmunológica , Femenino , Rechazo de Injerto/tratamiento farmacológico , Humanos , Isoantígenos/inmunología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Países Bajos , Receptor de Muerte Celular Programada 1/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
Proinflammatory, cytotoxic CD4+ CD28null T cells can be substantially expanded in patients with end-stage renal disease. These cells have been associated with the risk for rejection, but their alloreactive potential is unknown. CD4+ CD28null T cells were stimulated with HLA-mismatched antigen presenting cells in the absence/presence of exogenous cytokines. Alloreactive potential was evaluated based on proliferation, degranulation, cytotoxicity, and cytokine production. Further, their suppressive capacity was assessed by measuring inhibition of proliferating alloreactive CD28+ T cells. CD4+ CD28null T cells contained alloreactive (CD137+ ) T cells but did not proliferate in response to allogeneic stimulation, unless interleukin (IL)-15 was added. However, they could proliferate on stimulation with cytomegalovirus antigen without exogenous cytokines. IL-15 increased the frequency of proliferating alloreactive CD4+ CD28null T cells to 30.5% without inducing CD28 expression (P < .05). After allogeneic stimulation together with IL-15 and IL-21, frequency of degranulating CD107a+ CD4+ CD28null T cells increased significantly from 0.6% to 5.8% (P < .001). Granzyme B and perforin positivity remained similar, but production of interferon-γ and tumor necrosis factor-α increased by the combination of IL-15 and IL-21 (P < .001 and P < .05, respectively). Finally, CD4+ CD28null T cells did not show significant suppression. Thus, CD4+ CD28null T cells represent a population with absent alloreactivity unless IL-15 is present.
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Células Presentadoras de Antígenos/inmunología , Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/inmunología , Interleucina-15/metabolismo , Fallo Renal Crónico/cirugía , Activación de Linfocitos/inmunología , Linfocitos T Citotóxicos/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Interleucinas/metabolismo , Trasplante de Riñón , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Acute rejection is one of the major immunological determinants of kidney graft function and survival. Early biomarkers to predict rejection are lacking. Emerging evidence reveals a crucial role for the monocyte/macrophage lineage cells in the pathogenesis of rejection. We hypothesized that higher pretransplant numbers of proinflammatory CD16+ monocytes can predict rejection. The study cohort consisted of 104 kidney transplant recipients (58 with no rejection and 46 with biopsy-proven rejection) and 33 healthy persons. Posttransplant median follow-up time was 14.7 mo (interquartile range 0.3-34 mo). Pretransplantation blood samples were analyzed by flow cytometry for monocyte immunophenotypes. Groups were compared by Cox regression models for the occurrence of acute rejection. We documented a significantly increased absolute number of pretransplant CD16+ monocytes in patients who developed biopsy-proven rejection after transplantation compared with those with no rejection (hazard ratio [HR] 1.60, 95% CI 1.28-2.00, p < 0.001) and healthy persons (HR 1.47, 95% CI 1.18-1.82, p < 0.001). In parallel, significantly fewer absolute numbers of CD16- monocytes were observed at pretransplant time points in rejectors versus nonrejectors (HR 0.74, 95% CI 0.58-0.94, p < 0,014). A higher pretransplant number of CD16+ monocytes is significantly associated with a higher risk of acute rejection after kidney transplantation.
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Biomarcadores/sangre , Rechazo de Injerto , Trasplante de Riñón , Monocitos/inmunología , Receptores de IgG/inmunología , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Proteínas Ligadas a GPI/inmunología , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
Ageing is associated with changes in the peripheral T cell immune system, which can be influenced significantly by latent cytomegalovirus (CMV) infection. To what extent changes in circulating T cell populations correlate with T cell composition of the lymph node (LN) is unclear, but is crucial for a comprehensive understanding of the T cell system. T cells from peripheral blood (PB) and LN of end-stage renal disease patients were analysed for frequency of recent thymic emigrants using CD31 expression and T cell receptor excision circle content, relative telomere length and expression of differentiation markers. Compared with PB, LN contained relatively more CD4+ than CD8+ T cells (P < 0·001). The percentage of naive and central memory CD4+ and CD8+ T cells and thymic output parameters showed a strong linear correlation between PB and LN. Highly differentiated CD28null T cells, being CD27- , CD57+ or programmed death 1 (PD-1+ ), were found almost exclusively in the circulation but not in LN. An age-related decline in naive CD4+ and CD8+ T cell frequency was observed (P = 0·035 and P = 0·002, respectively) within LN, concomitant with an increase in central memory CD8+ T cells (P = 0·033). Latent CMV infection increased dramatically the frequency of circulating terminally differentiated T cells, but did not alter T cell composition and ageing parameters of LN significantly. Overall T cell composition and measures of thymic function in PB and LN are correlated strongly. However, highly differentiated CD28null T cells, which may comprise a large part of circulating T cells in CMV-seropositive individuals, are found almost exclusively within the circulation.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Fallo Renal Crónico/inmunología , Ganglios Linfáticos/inmunología , Anciano , Envejecimiento/inmunología , Antígenos de Diferenciación de Linfocitos T/análisis , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Infecciones por Citomegalovirus/inmunología , Femenino , Humanos , Memoria Inmunológica , Ganglios Linfáticos/citología , Activación de Linfocitos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Latencia del VirusRESUMEN
The number of elderly patients with end-stage renal disease (ESRD) has increased significantly during the last decade. Elderly ESRD patients are vulnerable to infectious complications because of an aged immune system. Additional immunological ageing effects may be derived from the uraemic environment and cytomegalovirus (CMV) latency. Elderly patients may be affected by these factors in particular, but data in this age group are limited. To assess the degree of immunological ageing and proliferative capacity of T lymphocytes, 49 elderly ESRD patients (defined as aged ≥ 65 years) on the renal transplantation waiting list were recruited and compared to 44 elderly healthy individuals (HI), matched for age and CMV serostatus. CMV latency was associated with more highly differentiated CD4+ and CD8+ T cells in both elderly HI and patients. Elderly CMV seropositive ESRD patients showed a substantial reduction in the number of naive CD4+ and CD8+ T cells compared with age- and CMV serostatus-matched HI. Elderly ESRD patients also showed significantly decreased numbers of central memory CD4+ and CD8+ T cells compared with HI, independently of CMV serostatus. In addition, thymic output and relative telomere length of both CD4+ and CD8+ T cells were decreased in CMV seropositive ESRD patients compared with HI. The proliferative capacity of T cells was similar for patients and HI. Elderly ESRD patients have an advanced aged T cell compartment when compared to age-matched healthy controls, which is driven mainly by CMV latency.
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Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Citomegalovirus/fisiología , Fallo Renal Crónico/etiología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Latencia del Virus/inmunología , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/inmunología , Estudios de Casos y Controles , Diferenciación Celular , Senescencia Celular/inmunología , Femenino , Humanos , Recuento de Linfocitos , Masculino , Fenotipo , Subgrupos de Linfocitos T/citologíaRESUMEN
Patients with end-stage renal disease have prematurely aged T cell systems. We tested whether T cell aging parameters were associated with the risk of infections after renal transplantation (RTx). We studied 188 patients over 1 year. Peripheral T cells were analyzed before and at 3 and 6 mo after RTx for frequency of recent thymic emigrants, relative telomere length and differentiation status. These parameters were related to the occurrence of opportunistic and serious infections. Overall, 84 patients developed an infection. In this group, 50 developed an opportunistic infection and 53 developed a serious infection. T cell aging parameters assessed before RTx were not associated with infection risk. The memory T cells showed a decrease within the first 3 mo in both groups (p < 0.001). The CD4(+) memory T cells increased between 3 and 6 mo within the infection group (p = 0.015). The number of CD8(+) memory T cells increased in both groups (p < 0.001) but reached baseline levels only in the infection group. In the infection group, the CD8(+) CD28(null) T cell percentage increased between 3 and 6 mo (p = 0.024), tending to be higher than at baseline (p = 0.061). These differences in post-RTx dynamics resulted from infections. Parameters of uremia-associated premature aging of peripheral T cells do not predict posttransplant infections.
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Senescencia Celular/inmunología , Rechazo de Injerto/etiología , Trasplante de Riñón/efectos adversos , Infecciones Oportunistas/etiología , Complicaciones Posoperatorias , Linfocitos T/patología , Uremia/fisiopatología , Adulto , Anciano , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/patología , Supervivencia de Injerto , Humanos , Fallo Renal Crónico/cirugía , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/patología , Pronóstico , Factores de Riesgo , Linfocitos T/inmunologíaRESUMEN
Regulatory T cell (Treg)-based therapy is a promising approach to treat many immune-mediated disorders such as autoimmune diseases, organ transplant rejection, and graft-versus-host disease (GVHD). Challenges to successful clinical implementation of adoptive Treg therapy include difficulties isolating homogeneous cell populations and developing expansion protocols that result in adequate numbers of cells that remain stable, even under inflammatory conditions. We investigated the potential of discarded human thymuses, routinely removed during pediatric cardiac surgery, to be used as a novel source of therapeutic Tregs. Here, we show that large numbers of FOXP3(+) Tregs can be isolated and expanded from a single thymus. Expanded thymic Tregs had stable FOXP3 expression and long telomeres, and suppressed proliferation and cytokine production of activated allogeneic T cells in vitro. Moreover, expanded thymic Tregs delayed development of xenogeneic GVHD in vivo more effectively than expanded Tregs isolated based on CD25 expression from peripheral blood. Importantly, in contrast to expanded blood Tregs, expanded thymic Tregs remained stable under inflammatory conditions. Our results demonstrate that discarded pediatric thymuses are an excellent source of therapeutic Tregs, having the potential to overcome limitations currently hindering the use of Tregs derived from peripheral or cord blood.
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Factores de Transcripción Forkhead/metabolismo , Enfermedad Injerto contra Huésped/terapia , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Linfocitos T Reguladores/inmunología , Timo/citología , Adulto , Animales , Células Cultivadas , Niño , Femenino , Citometría de Flujo , Enfermedad Injerto contra Huésped/inmunología , Humanos , Activación de Linfocitos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Homeostasis del Telómero , Timo/inmunología , Timo/metabolismoRESUMEN
Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with nonexpressers. This randomized-controlled study investigated whether adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady-state. Two hundred forty living-donor, renal transplant recipients were assigned to either receive a standard, body-weight-based or a CYP3A5 genotype-based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard-dose and genotype-based groups: 37.4% versus 35.6%, respectively; p = 0.79. The proportion of patients with a subtherapeutic (i.e. <10 ng/mL) or a supratherapeutic (i.e. >15 ng/mL) Tac predose concentration in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population.
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Peso Corporal , Citocromo P-450 CYP3A/genética , Rechazo de Injerto/genética , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Donadores Vivos , Tacrolimus/uso terapéutico , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Genotipo , Tasa de Filtración Glomerular , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/epidemiología , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/genética , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Polimorfismo de Nucleótido Simple , Complicaciones Posoperatorias , Prevalencia , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Cytomegalovirus (CMV) infection profoundly affects the T cell compartment and is associated with alterations in T cell aging parameters and generation of cytotoxic CD4(+) CD28null T cells. Hence, the effect of a primary CMV infection post-kidney transplantation (KT) on the peripheral T cell compartment was examined. As aging parameters, we determined the T cell differentiation status, T cell receptor excision circle (TREC) content, CD31(+) naïve T cell numbers and relative telomere length (RTL) pre-KT and 12 months post-KT. CMV-seronegative KT recipients, receiving a kidney from a CMV-seropositive donor (D+/R-) were compared to D+/R+ KT recipients. Eleven out of the 22 D+/R- KT recipients had CMV viremia post-KT. They developed CMV-specific CD4(+) and CD8(+) T cells and their T cell compartment shifted towards a more differentiated memory phenotype with expansion of CD4(+) CD28null and CD8(+) CD28null cells. One year post-KT, the CD8(+) T cell count was almost doubled compared to nonviremic D+/R- and D+/R+ KT recipients. In addition, the RTL of the CD8(+) T cell was significantly lower and both the TREC content and CD31(+) naïve T cell numbers significantly decreased. Moreover, primary CMV infection was associated with a negative impact on glomerular filtration rate. In conclusion, primary CMV infection has a substantial impact on the number and phenotype of peripheral T cells and may negatively affect renal allograft function.
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Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Rechazo de Injerto/inmunología , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias , Linfocitos T/inmunología , Infecciones por Citomegalovirus/virología , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Supervivencia de Injerto , Humanos , Fallo Renal Crónico/virología , Pruebas de Función Renal , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Inmunología del Trasplante , Replicación Viral/inmunologíaRESUMEN
Memory B cells play a pivotal role in alloreactivity in kidney transplantation. Follicular T helper (Tfh) cells play an important role in the differentiation of B cells into immunoglobulin-producing plasmablasts [through interleukin (IL)-21]. It is unclear to what extent this T cell subset regulates humoral alloreactivity in kidney transplant patients, therefore we investigated the absolute numbers and function of peripheral Tfh cells (CD4(POS) CXCR5(POS) T cells) in patients before and after transplantation. In addition, we studied their relationship with the presence of donor-specific anti-human leucocyte antigen (HLA) antibodies (DSA), and the presence of Tfh cells in rejection biopsies. After transplantation peripheral Tfh cell numbers remained stable, while their IL-21-producing capacity decreased under immunosuppression. When isolated after transplantation, peripheral Tfh cells still had the capacity to induce B cell differentiation and immunoglobulin production, which could be inhibited by an IL-21-receptor-antagonist. After transplantation the quantity of Tfh cells was the highest in patients with pre-existent DSA. In kidney biopsies taken during rejection, Tfh cells co-localized with B cells and immunoglobulins in follicular-like structures. Our data on Tfh cells in kidney transplantation demonstrate that Tfh cells may mediate humoral alloreactivity, which is also seen in the immunosuppressed milieu.
Asunto(s)
Linfocitos B/inmunología , Rechazo de Injerto/inmunología , Inmunidad Humoral , Memoria Inmunológica , Trasplante de Riñón , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Anciano , Linfocitos B/fisiología , Línea Celular , Femenino , Rechazo de Injerto/patología , Rechazo de Injerto/prevención & control , Humanos , Terapia de Inmunosupresión/métodos , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T Colaboradores-Inductores/patologíaRESUMEN
Mesenchymal or stromal stem cells (MSC) interact with cells of the immune system in multiple ways. Modulation of the immune system by MSC is believed to be a therapeutic option for autoimmune disease and transplant rejection. In recent years, B cells have moved into the focus of the attention as targets for the treatment of immune disorders. Current B-cell targeting treatment is based on the indiscriminate depletion of B cells. The aim of this study was to examine whether human adipose tissue-derived MSC (ASC) interact with B cells to affect their proliferation, differentiation, and immune function. ASC supported the survival of quiescent B cells predominantly via contact-dependent mechanisms. Coculture of B cells with activated T helper cells led to proliferation and differentiation of B cells into CD19(+) CD27(high) CD38(high) antibody-producing plasmablasts. ASC inhibited the proliferation of B cells and this effect was dependent on the presence of T cells. In contrast, ASC directly targeted B-cell differentiation, independently of T cells. In the presence of ASC, plasmablast formation was reduced and IL-10-producing CD19(+) CD24(high) CD38(high) B cells, known as regulatory B cells, were induced. These results demonstrate that ASC affect B cell biology in vitro, suggesting that they can be a tool for the modulation of the B-cell response in immune disease.
Asunto(s)
Tejido Adiposo/citología , Linfocitos B Reguladores/citología , Comunicación Celular/inmunología , Células Madre Mesenquimatosas/citología , Células Plasmáticas/citología , Linfocitos T Colaboradores-Inductores/citología , Tejido Adiposo/inmunología , Apoptosis/inmunología , Linfocitos B Reguladores/inmunología , Diferenciación Celular/inmunología , Procesos de Crecimiento Celular/inmunología , Supervivencia Celular/inmunología , Técnicas de Cocultivo , Humanos , Células Madre Mesenquimatosas/inmunología , Tonsila Palatina/citología , Tonsila Palatina/inmunología , Células Plasmáticas/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Renal tubular epithelial cells (TECs) are one of the main targets of alloreactive T cells during acute rejection. We hypothesize that TECs modulate the outcome of alloimmunity by executing immunosuppressive effects in order to dampen the local inflammation. We studied whether TECs possess immunosuppressive capacities and if indoleamine 2,3-dioxygenase (IDO) might play a role in suppressing T cell alloreactivity. Next, we studied the role of programmed death ligand 1 (PD-L1) and intercellular adhesion molecule-1 (ICAM-1 with regard to TEC-related immunomodulatory effects. CD3/CD28 and alloactivated peripheral blood mononuclear cells were co-cultured with activated TECs. We analysed CD4(+) and CD8(+) T cell proliferation and apoptosis in the absence or presence of IDO inhibitor 1-methyl-L-tryptophan (1-L-MT), anti-PD-L1 and anti-ICAM-1. Further, we examined whether inhibition of T cell proliferation was cell-cell contact-dependent. We found that TECs dose-dependently inhibited CD4(+) and CD8(+) T cell proliferation (P<0.05). Activated TECs showed significantly increased IDO activity and up-regulated PD-L1 and ICAM-1 expression. Suppressed CD4(+) and CD8(+) T cell proliferation was only partially restored or failed to restore using 1-L-MT. Activated TECs increased early and late apoptosis of proliferating CD4(+) and CD8(+) T cells; only CD4(+) T cell apoptosis was statistically affected by 1-L-MT. Transwell experiments revealed that TEC-mediated immunosuppression is cell-cell contact-dependent. We found that anti-ICAM-1 affected only CD4(+) T cell apoptosis and not T cell proliferation. Our data show that TECs suppress both CD4(+) and CD8(+) T cell proliferation contact dependently. Interestingly, inhibition of proliferation and enhancement of apoptosis of T cell subsets is differentially regulated by indoleamine 2,3-dioxygenase and ICAM-1, with no evidence for the involvement of PD-L1 in our system.