RESUMEN
BACKGROUND: Characterization of anti-HLA versus anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immune globulin isotypes in organ transplant recipients after coronavirus disease 2019 (COVID-19) infection has not been reported. We aimed to determine changes in anti-HLA antibodies in renal transplant patients with COVID-19 and compare the immunoglobulin and epitope-binding pattern versus anti-SARS-CoV-2 antibodies. METHODS: This is a cross-sectional study of 46 kidney transplant recipients including 21 with longitudinal sampling. Using a semi-quantitative multiplex assay, we determined immunoglobulin (Ig) M, IgA, IgG, and IgG1-2-3-4 antibodies against Class I and Class II HLA, and 5 SARS-CoV-2 epitopes including the nucleocapsid protein and multiple regions of the spike protein. RESULTS: Fourteen of 46 (30%) patients had donor-specific anti-HLA antibodies (donor-specific antibody [DSA]), 12 (26%) had non-DSA anti-HLA antibodies and 45 (98%) had anti-SARS-CoV-2 antibodies. Most DSAs targeted HLA-DQ (71%), with a dominant IgG isotype and IgG1 subtype prevalence (93%), and/or IgG3 (64%), followed by IgG2 (36%). Comparatively, there was a higher prevalence of IgA (85% versus 14%, P = 0.0001) and IgM (87%, versus 36%, P = 0.001) in the anti-SARS-CoV-2 antibody profile, when compared to DSAs, respectively. Anti-SARS-CoV-2 antibody profile was characterized by increased prevalence of IgM and IgA, when compared to DSAs. The median calculated panel reactive antibody before COVID-19 diagnosis (24%) tended to decrease after COVID-19 diagnosis (10%) but it was not statistically significant ( P = 0.1). CONCLUSIONS: Anti-HLA antibody strength and calculated panel reactive antibody in kidney transplant recipients after COVID-19 do not significantly increase after infection. Although the IgG isotype was the dominant form in both HLA and SARS-CoV-2 antigens, the alloimmune response had a low IgA pattern, whereas anti-SARS-CoV-2 antibodies were high IgA/IgM.
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COVID-19 , Trasplante de Riñón , Aloinjertos , Anticuerpos Antivirales , Prueba de COVID-19 , Estudios Transversales , Epítopos , Antígenos HLA , Antígenos HLA-DQ , Humanos , Inmunoglobulina A , Inmunoglobulina G , Inmunoglobulina M , Trasplante de Riñón/efectos adversos , Proteínas de la Nucleocápside , SARS-CoV-2 , Glicoproteína de la Espiga del CoronavirusRESUMEN
We aimed to investigate the impact of the new kidney allocation system (KAS) on the rate of transplantation of sensitized patients at our center. Pre-KAS and post-KAS intervals were Jan 1st to Dec 3rd 2014 and Jan 1st 2015 to Dec 3rd 2015, respectively. The number of deceased-donor crossmatches performed by flow cytometry increased from 715 pre-KAS to 1188 post-KAS. The percent of crossmatches performed for sensitized patients with calculated panel reactive antibody (cPRA)>0% increased from 19% pre-KAS to 26% post-KAS (p<0.0001). The number of deceased-donor kidney transplants performed at our center increased from 115 pre-KAS to 125 post-KAS (9% increase). There was a significant increase in the percentage of deceased-donor kidney transplants received by sensitized candidates (from 14% to 26% pre- and post-KAS, respectively; p<0.0001). The highest increase was seen in the patients with cPRA>98%, from 0% to 9%, followed by the group with cPRA 50-79%, from 5% to 8%. This increase was balanced by a decrease of 12% in the percentage of non-sensitized recipients, and a modest decrease of 1% in the group with cPRA 1-49%. In conclusion, transplant rate has increased in sensitized patients after KAS. The highest increase was observed among highly sensitized patients (cPRA>98%).
Asunto(s)
Trasplante de Riñón , Donantes de Tejidos/estadística & datos numéricos , Obtención de Tejidos y Órganos/estadística & datos numéricos , Receptores de Trasplantes/estadística & datos numéricos , Adulto , Anciano , Femenino , Supervivencia de Injerto , Antígenos HLA/genética , Antígenos HLA/inmunología , Prueba de Histocompatibilidad/métodos , Humanos , Isoanticuerpos/inmunología , Masculino , Persona de Mediana Edad , Factores de Tiempo , Obtención de Tejidos y Órganos/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The diagnosis of AML with monocytic differentiation is limited by the lack of highly sensitive and specific monocytic markers. Immunoglobulin-like transcript 3 (ILT3) is an immune inhibitory receptor expressed by myelomonocytic cells and at high levels by tolerogenic dendritic cells. METHODS: Using flow cytometry, we analyzed the expression of ILT3 in 37 patients with AML and 20 patients with no detectable disease. RESULTS: We showed that ILT3 was expressed in all cases of AML displaying monocytic differentiation (FAB M4/M5; N = 18), but not in AML M1/M2 and M3 (N = 19; P < 0.0001). Co-expression of ILT3 and immature cell markers, such as CD34 and CD117, was observed in monoblastic leukemia. ILT3 expression was preserved after treatment in M4/M5 patients with refractory or relapsed disease. ILT3 expression was associated with the presence of cytogenetic abnormalities linked to an intermediate prognosis (P = 0.001). Rare CD45dimCD34+CD117+ILT3+ cells were identified in noninvolved bone marrow, suggesting that ILT3 expression is acquired at an early stage by normal myelomonocytic precursors. CONCLUSIONS: ILT3 is a highly sensitive and specific marker which distinguishes AML with monocytic differentiation from other types of AML. Testing of ILT3 expression should be incorporated into the initial diagnostic work-up and monitoring of patients with AML.
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Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Receptores de Superficie Celular/metabolismo , Adulto , Antígenos CD34/metabolismo , Diferenciación Celular , Células Dendríticas/metabolismo , Femenino , Citometría de Flujo , Humanos , Leucemia Monocítica Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Masculino , Glicoproteínas de Membrana , Persona de Mediana Edad , Monocitos , Pronóstico , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptores InmunológicosRESUMEN
B lymphoblastic leukaemia (B-ALL) cells are characterized by the expression of various B-cell antigens. Expression of T/Natural Killer-cell antigens, however, has rarely been reported in B-ALL (TAg+ B-ALL), and the significance of this aberrant antigen expression is unclear. We thus analysed the frequency of TAg+ B-ALL at our institution and investigated its significance in the context of immunophenotypes, cytogenetic/molecular findings, and prognosis. We reviewed 134 consecutive cases of B-ALL and found 18 cases (13·4%) of TAg+ B-ALL. The most common aberrant T-cell antigens expressed were CD2, CD5, and CD7 at equivalent rates (each in six cases), CD4 (two cases), and CD56 (three cases). Adverse cytogenetic abnormalities were seen in a significantly larger proportion of the TAg+ cases (72·2%) than the TAg- cases (32·2%; P = 0·003). Multivariate Cox-regression analysis showed that the risk of relapse over time was higher in the TAg+ cases, independent of high risk status (based on age and white blood cell count) and the presence of adverse cytogenetic abnormalities (hazard ratio = 2·256, P = 0·065). These findings suggest that T-cell antigen expression in B-ALL may be an independent predictor of poor prognosis, and a useful marker to identify patients at increased risk for relapse and for harbouring adverse cytogenetic abnormalities.
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Antígenos CD/biosíntesis , Leucemia de Células B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Linfocitos T/inmunología , Enfermedad Aguda , Adolescente , Adulto , Antígenos CD/inmunología , Antígenos Virales de Tumores/biosíntesis , Antígenos Virales de Tumores/inmunología , Niño , Preescolar , Femenino , Humanos , Inmunofenotipificación , Lactante , Masculino , Adulto JovenRESUMEN
Past studies have shown decreased hematogones in the bone marrow of patients with myelodysplastic syndromes and acquired aplastic anemia. In this study, we examined the bone marrow of patients with chronic myeloid leukemia (n = 33, mean age 49 years, age range 2-83 years) for the presence of hematogones and compared their frequency with that of age-matched controls (n = 50). We found that the percentages of total and stage I hematogones were decreased in chronic myeloid leukemia at diagnosis (n = 25) and at follow-up post therapy (n = 8) when compared to age-matched controls (diagnosis, total: 0.29% vs. 0.87%, p = 0.001; diagnosis, stage I: 0.06% vs. 0.20%, p = 0.008; follow-up, total: 0.17% vs. 0.87%, p < 0.001; follow-up, stage I: 0.04 vs. 0.20, p = 0.003). We also found a significant decrease in the number of natural killer cells in patients with chronic myeloid leukemia at diagnosis. Further studies are warranted to elucidate the mechanism of hematogone decrease in chronic myeloid leukemia and whether this finding also applies to other myeloproliferative neoplasms.
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Citometría de Flujo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Precursoras de Linfocitos B/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD19/metabolismo , Antígenos CD34/metabolismo , Células de la Médula Ósea/metabolismo , Niño , Preescolar , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Neprilisina/metabolismo , Adulto JovenRESUMEN
The involvement of humoral response in allograft rejection has been suggested by both immunologic and histochemistry studies. In the present study, we explored the role of alloantibodies in a large cohort of heart allograft recipients followed for 15 years. Sequential samples of sera were obtained from 950 recipients of heart allografts before and after transplantation at the time when protocol endomyocardial biopsies were performed. The presence of anti-human leukocyte antigen (HLA) antibodies was investigated using complement mediated cytotoxicity and solid phase assay (SPA). Our data reveal an inverse correlation between the development of alloantibodies after transplantation and heart allograft survival. The 15-year graft survival was highest in patients who never developed alloantibodies (70%) or who displayed them only before transplantation (71%); graft survival in recipients who showed antibodies both before and after transplantation (56%), or only after transplantation (47%), was lower. The deleterious effect of antibodies on graft survival started 8 years after transplantation, suggesting that the production of de novo antibodies may have been triggered by some later event. We found that patients with de novo antibodies appearing more than 1 year after transplantation had the poorest survival. Furthermore, the development of de novo antibodies was preceded in 76% of these patients by cellular rejection grade 3 or higher, according to the International Society for Heart Transplantation (ISHT) grading criteria. Development of antibody-mediated rejection (AMR) had a significant negative impact on graft survival (16% in AMR(+) vs 63% in AMR(-) patients, p = 0.0008). Of the 23 patients with AMR, 21 displayed cytotoxic donor-specific antibodies (DSA) at the time of diagnosis, and in 18 of these cases SPA showed that they were directed against the donors' HLA. The data demonstrate that the detection of alloantibodies permits a better definition of AMR in heart allograft recipients. Identification of patients at risk for developing AMR is of great importance for early treatment of rejection episodes.
Asunto(s)
Supervivencia de Injerto/inmunología , Trasplante de Corazón/inmunología , Inmunización , Isoanticuerpos/sangre , Isoanticuerpos/inmunología , Adolescente , Adulto , Anciano , Femenino , Rechazo de Injerto/inmunología , Trasplante de Corazón/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Periodo Preoperatorio , Trasplante Homólogo/inmunología , Trasplante Homólogo/mortalidad , Adulto JovenRESUMEN
Hematopoietic stem cell (HSC) transplantation is an important therapeutic option for patients with hematologic malignancies. To explore the immunomodulatory effects of HSC mobilization agents, we studied the function and phenotype of CD4(+) T cells from 16 adult patients with hematologic malignancies undergoing HSC mobilization treatment for autologous transplantation. Immune cell function was determined using the Immuknow (Cylex) assay by measuring the amount of adenosine triphosphate (ATP) produced by CD4(+) cells from whole blood. ATP activity measured in G-CSF-treated patients was significantly higher than that measured in healthy individuals or "nonmobilized" patients. In patients treated with G-CSF, CD4(+) T cells were predominantly CD25(low)FOXP3(low), consistent with an activated phenotype. However, T-cell depletion did not abrogate ATP production in blood samples from G-CSF-treated patients, indicating that CD4(+) myeloid cells contributed to the increased ATP levels observed in these patients. There was a significant correlation between ATP activity and patient survival, suggesting that efficient activation of CD4(+) cells during mobilization treatment predicts a low risk of disease relapse. Monitoring immune cell reactivity using the Immuknow assay may assist in the clinical management of patients with hematologic malignancies and optimization of HSC mobilization protocols.
Asunto(s)
Adenosina Trifosfato/biosíntesis , Linfocitos T CD4-Positivos/metabolismo , Factores Estimulantes de Colonias/uso terapéutico , Neoplasias Hematológicas/terapia , Movilización de Célula Madre Hematopoyética , Linfocitos T CD4-Positivos/efectos de los fármacos , Factores Estimulantes de Colonias/farmacología , Femenino , Factores de Transcripción Forkhead/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/metabolismo , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Estimación de Kaplan-Meier , Recuento de Leucocitos , Activación de Linfocitos/efectos de los fármacos , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Fitohemaglutininas/farmacología , Curva ROC , Caracteres Sexuales , Células Madre/citologíaRESUMEN
The tolerogenic phenotype of human dendritic cells is characterized by high cell surface expression of the inhibitory receptor ILT3. ILT3 signals both intracellularly inhibiting tyrosine phosphorylation, NF-kappaB and MAPK p38 activity, transcription of certain co-stimulatory molecules, secretion of cytokines and chemokines, and extracellularly into the T cells with which the dendritic cells interact. Both ILT3(high) tolerogenic dendritic cells and soluble ILT3 induce CD4 Th anergy and differentiation of antigen specific CD8 T suppressor cells. Recombinant ILT3-Fc protein has important immunotherapeutic potential acting directly on activated T cells and promoting the induction of immunological tolerance.
Asunto(s)
Células Dendríticas/inmunología , Tolerancia Inmunológica , Receptores de Superficie Celular/inmunología , Membrana Celular/metabolismo , Citocinas/fisiología , Humanos , Glicoproteínas de Membrana , Receptores Inmunológicos , Transducción de SeñalRESUMEN
Our knowledge regarding the nature and function of 'hematogones' has evolved considerably, since the initial description more than 70 years ago. Once considered the 'mystery cells' of the bone marrow, major advances in immunology and flow cytometry have enabled us to better characterize these cells and recognize them as physiologic precursors of B-cells. In this review, we describe the morphologic and phenotypic characteristics and clinical relevance of hematogones, and report recent advances in our understanding and knowledge of these cells as they relate to physiologic and different pathologic conditions.
Asunto(s)
Linfocitos B/citología , Células de la Médula Ósea/citología , Células Madre/citología , Animales , Antígenos CD/análisis , Diferenciación Celular , Linaje de la Célula , Femenino , Citometría de Flujo/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , FenotipoRESUMEN
Acquired aplastic anemia (AA) and myelodysplastic syndromes (MDS) are bone marrow (BM) failure syndromes with overlapping clinical features, and at least a subset appears to share common pathophysiologic mechanisms. Recent studies of MDS have shown down-regulation of genes involved in B-cell development and decreased B-cell precursors (hematogones). We explored the possibility that AA, similar to MDS, might also be associated with defects in development of lymphoid cells, especially B-cells, by using flow cytometry to assess the presence of hematogones and mature lymphocytes in BM samples from 25 children with AA and 41 age-matched controls. We observed that the percentage of total and early (stage I) hematogones were significantly decreased in AA compared to controls, and they returned to normal numbers after hematopoietic stem-cell transplant. This demonstrates early B-cell lineage involvement in AA, similar to recent findings in MDS. Our findings suggest dysfunction of an early multilineage progenitor in the pathogenesis of AA.
Asunto(s)
Anemia Aplásica/patología , Linfocitos B/patología , Células de la Médula Ósea/patología , Células Madre Hematopoyéticas/patología , Adolescente , Anemia Aplásica/sangre , Anemia Aplásica/cirugía , Antígenos CD19/análisis , Antígenos CD34/análisis , Linfocitos B/metabolismo , Células de la Médula Ósea/metabolismo , Niño , Preescolar , Femenino , Citometría de Flujo/métodos , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Humanos , Hibridación Fluorescente in Situ , Antígenos Comunes de Leucocito/análisis , Masculino , Neprilisina/análisis , Resultado del TratamientoRESUMEN
Monitoring of immune status in transplant recipients is essential for predicting the risk of rejection or infection. In this study, we assessed the significance of immune cell function in 76 renal allograft recipients after Thymoglobulin induction and initiation of maintenance immunosuppression. Using the Immuknow (Cylex Inc) assay, the amount of adenosine triphosphate (ATP) produced by CD4+ cells in response to phytohemagglutinin (PHA) was measured in patients whole blood. In parallel, the frequency and phenotype of CD4+ T cells were determined by flow cytometry. The Immuknow assay yielded paradoxically high ATP values during the first 3 months post-transplantation, despite very low CD4+ T cell counts. High ATP values were caused by peripheral blood myeloid cells, did not predict rejection, and occurred primarily in transplant recipients who received darbepoietin (p = 0.017). CD4+ T cells displayed predominantly an activated/memory phenotype and comprised a subpopulation of CD25+FOXP3+ cells. Over the first 5 months post-transplantation, mean ATP activity gradually decreased, whereas CD4+ T cell counts slowly increased. Low ATP values were predictive of infection (p = 0.002). Thus Immuknow results need to be interpreted with caution in patients receiving Thymoglobulin induction therapy. Although low ATP levels identify patients at increased risk for infection, high ATP values fail to correlate with rejection and do not justify increased immunosuppression.
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Anticuerpos Monoclonales/inmunología , Linfocitos T CD4-Positivos/inmunología , Terapia de Inmunosupresión , Trasplante de Riñón , Adenosina Trifosfato/biosíntesis , Suero Antilinfocítico , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Femenino , Rechazo de Injerto , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Trasplante HomólogoRESUMEN
The presence of complement fixing anti-human leukocyte antigen (HLA) antibodies in the circulation of organ transplant recipients may result in heart allograft rejection. Here, we assessed the clinical impact of pre- and post-transplantation allosensitization on long-term survival of heart allografts. Sequential samples of sera from heart allograft recipients were screened pretransplantation for panel reactive antibodies using the complement-dependent cytotoxicity test. Patients were monitored post-transplantation for donor specific anti-HLA class I and class II antibodies. Kaplan-Meier graft survival plots were generated to analyze the effect of anti-HLA antibodies on transplantation outcomes. Statistical analysis showed that the post-transplantation development of alloantibodies was a significant risk factor that was associated with low long-term survival rates; in contrast, recipients' gender, age, previous transplantations, and degree of HLA matching with the donor had no effect on long-term survival. The presence in pretransplantation sera of antibodies against more than 10% of the HLA reference panel (PRA >10%) was associated with AMR and with a relatively lower rate of graft survival after 1 year but did not affect 10-year survival. The present data underline the importance of monitoring the development of anti-HLA antibodies as a tool for early diagnosis and treatment of AMR.
Asunto(s)
Rechazo de Injerto/diagnóstico , Antígenos HLA/inmunología , Trasplante de Corazón/inmunología , Isoanticuerpos/sangre , Anciano , Femenino , Rechazo de Injerto/mortalidad , Rechazo de Injerto/terapia , Supervivencia de Injerto/inmunología , Antígenos HLA/sangre , Trasplante de Corazón/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Monitorización InmunológicaRESUMEN
Allogeneic hematopoietic cell transplantation represents an important therapy for certain malignant and nonmalignant diseases. However, graft-versus-host disease (GVHD) is a major cause of mortality and morbidity. The search for agents that can efficiently suppress GVHD has been going on for more than half a century. GVHD is particularly strong in xenogeneic donor-recipient combinations, given the unlimited number of potentially immunogenic antigens donor lymphocytes encounter in the host. Using a hu-nonobese diabetic/severe combined immunodeficiency (hu-NOD/SCID) gamma-null model of xenogeneic GVHD, we have demonstrated that treatment with recombinant immunoglobulin-like transcript 3-Fc protein induces the differentiation of CD8(+) T suppressor cells and blocks the cellular and humoral arm of the GVH reaction.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inmunoterapia , Receptores de Superficie Celular/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Animales , Anticuerpos Heterófilos/inmunología , Antígenos Heterófilos/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Diferenciación Celular/genética , Progresión de la Enfermedad , Femenino , Ingeniería Genética , Enfermedad Injerto contra Huésped/fisiopatología , Enfermedad Injerto contra Huésped/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Inmunosupresores/inmunología , Inmunosupresores/metabolismo , Glicoproteínas de Membrana , Ratones , Ratones Endogámicos NOD , Ratones SCID , Quimera por Radiación , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Receptores Inmunológicos , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patologíaRESUMEN
Presensitizing alloantibodies may represent a grave danger in organ transplantation, increasing the risk of antibody-mediated rejection (AMR) and graft loss. However, not all antibodies are harmful to the graft. In our study of a cohort of 325 deceased-donor renal allograft recipients, the patients were determined eligible to receive an allograft based on a negative complement-dependent cytotoxicity (CDC) crossmatch (XM). Yet at the time of transplantation, many candidates displayed donor-specific antibodies (DSA) by more sensitive methods, such as solid-phase assays (SPA, Luminex) or flow cytometry crossmatch (FCXM). The majority of the patients who were DSA positive by either SPA (67%) or FCXM (66%) presented an AMR-free clinical course posttransplantation. Among the patients who developed AMR (N = 29), 76% proved clinically manageable and did not lose the graft. Analysis of the DSA mean fluorescence intensities (MFI) of Luminex indicated no statistically significant difference between patients who experienced AMR episodes and those who did not. Importantly, many of the patients with AMR did not test positive for DSA by SPA (20/29) or FCXM (14/29). Despite false-positive and false-negative results, the detection of DSA by SPA or FCXM was positively associated with AMR, but not with actuarial graft survival. The field of organ transplantation has always struggled to reconcile two opposing goals: improving transplantation outcome while increasing access to transplantation. SPA and FCXM appear to be oversensitive and defining patients as "sensitized" according to these methods would block access to transplantation for many candidates who would otherwise benefit greatly from receiving the allograft. Nevertheless, SPA and FCXM are invaluable tools, assisting clinicians in gauging AMR risk and tailoring immunosuppression of the posttransplantation immunological monitoring accordingly.
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Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Antígenos HLA/inmunología , Técnicas de Inmunoadsorción , Isoanticuerpos/inmunología , Trasplante de Riñón , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Formación de Anticuerpos , Cadáver , Errores Diagnósticos , Femenino , Citometría de Flujo , Rechazo de Injerto/sangre , Rechazo de Injerto/prevención & control , Humanos , Isoanticuerpos/sangre , Masculino , Microesferas , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Pruebas Serológicas , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Primary effusion lymphoma (PEL) is a rare type of B-cell non-Hodgkin lymphoma (NHL), which predominantly occurs in HIV-infected individuals, and is pathogenetically linked with Kaposi sarcoma (KS)-associated herpes virus/human herpes virus-8 (KSHV/HHV-8) infection with or without evidence of Epstein-Barr virus (EBV) co-infection. Although uncommon, PELs have been reported in immunocompetent patients and recipients of solid organ allografts. Rare cases of KSHV(-) EBV(+) post-transplant effusion lymphomas resembling PEL have also been described, as have KSHV(-) EBV(-) effusion lymphomas, the latter including those arising in individuals with chronic liver disease. We report a unique KSHV(-) EBV(-) post-transplant effusion lymphoma associated with serum paraproteins, occurring in an HIV(-) individual, which had cytologic features and phenotype similar to PEL, and displayed a complex karyotype including isochromosome 12p and translocation t(8;22), resulting in rearrangement of c-MYC.
Asunto(s)
Linfoma de Efusión Primaria/patología , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 8/aislamiento & purificación , Humanos , Inmunofenotipificación , Trasplante de Hígado , Linfoma de Efusión Primaria/genética , Linfoma de Efusión Primaria/virología , Masculino , Persona de Mediana Edad , Células Plasmáticas/patología , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/patología , Sarcoma de Kaposi/virologíaRESUMEN
Dendritic cells (DC) are key components of the immune system, which actively participate in innate and adaptive immune responses. They are traditionally viewed as the immunologic centerpiece that is able to prime CD4(+) helper and CD8(+) cytotoxic T-cell effector populations. However, accumulated evidence highlights the functional plasticity of DC, which are shown to also be able to display a tolerogenic function eliciting the differentiation of T suppressor (Ts) and regulatory (Treg) cells. This tolerogenic state of DC is characterized by low costimulatory potential and high expression of inhibitory receptors. Conspicuously among the latter is the immunoglobulin-like transcript 3 (ILT3), which independently prevents the activation of both DC and T cells. DC overexpressing ILT3 display lower phosphorylation levels of NF-kappaB and fail to stimulate the full program of Th proliferation and maturation eliciting instead the differentiation of CD8(+) T(S) and CD4(+) Treg. In contrast, ILT3-knockdown DC have robust cytokine and chemokine production, and are able to trigger stronger T-cell responses to viral antigens or alloantigens. Understanding and manipulating the functional immunogenic/tolerogenic dichotomy of DC has important clinical applications for achieving tolerance in organ transplantation, stemming autoimmune diseases or, conversely, generating efficient immunogenic vaccines for immunotherapy in cancer and chronic viral diseases.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Receptores de Superficie Celular/inmunología , Linfocitos T Reguladores/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/metabolismo , Humanos , Activación de Linfocitos/inmunología , Glicoproteínas de Membrana , FN-kappa B/inmunología , FN-kappa B/metabolismo , Neoplasias/inmunología , Neoplasias/metabolismo , Trasplante de Órganos , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores Inmunológicos , Linfocitos T Reguladores/metabolismoRESUMEN
Cytogenetic abnormalities of chromosome 12p involving the TEL/ETV6 gene are observed in a variety of hematopoietic neoplasms including acute leukemias, myelodysplastic syndromes, and myeloproliferative disorders. Karyotypic aberrations, including rearrangements, deletions, and amplifications of chromosome 12p, have been documented in B-cell non-Hodgkin lymphoma; however, rearrangements targeting TEL have rarely been reported. Here we describe a diffuse large B-cell lymphoma that had a complex karyotype including t(9;12)(q22;p13), which was confirmed by fluorescence in situ hybridization to represent rearrangement of TEL. Additional cytogenetic abnormalities included t(3;14)(q27;q32) involving the variant, alternative breakpoint region of the BCL6 gene and del(6)(q13q23), resulting in the loss of 1 allele of BLIMP1. This case reiterates the importance of correlating morphologic and phenotypic findings with the results of cytogenetic analysis to avoid errors in diagnosing hematologic neoplasms and highlights the rare association of B-cell non-Hodgkin lymphoma with aberrations of TEL.
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Linfoma de Células B Grandes Difuso/genética , Neoplasias Primarias Secundarias/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Adulto , Aberraciones Cromosómicas , Femenino , Citometría de Flujo , Reordenamiento Génico de Linfocito B , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/terapia , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/patología , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/terapia , Translocación Genética , Proteína ETS de Variante de Translocación 6RESUMEN
The G6b-B gene encodes a novel cell surface receptor of the immunoglobulin superfamily that activates inhibitory signaling pathways by triggering SHP-1/SHP-2 via immunoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic domain. We previously identified decreased G6b-B expression in peripheral blood mononuclear cells (PBMC) during acute cellular cardiac allograft rejection. We studied the expression of G6b-B in different human mononuclear cell populations and its regulation. Real-time polymerase chain reaction (PCR) revealed that G6b-B mRNA is higher in CD4+ T cells or monocytes, but is not different between CD25+ CD4+ T cells and CD25- CD4+ T cells. G6b-B mRNA was increased in CD4+ T cells in presence of interleukin-4 in dose- and time-dependent manners. To understand the regulatory mechanism, we analyzed a 1.9-kb 5'-flanking region of the G6b-B translation start site and found a putative cis-acting element for Signal Transducer and Activator of Transcription (STAT)-6. Luciferase-reporter-gene-assay and electrophoretic mobility shift assays identified the STAT6 site as necessary for the induction of G6b-B by IL-4. Our study demonstrates that G6b-B expression is highly restricted to peripheral CD4+ T cells and up-regulated by the IL-4-induced STAT6 pathway, strongly suggesting that G6b-B is involved in regulation of the immune response by CD4+ T cell-mediated and IL-4 induced regulatory mechanisms.
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Linfocitos T CD4-Positivos/inmunología , Interleucina-4/metabolismo , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Factor de Transcripción STAT6/metabolismo , Células Cultivadas , Humanos , Interleucina-4/inmunología , Redes y Vías Metabólicas , Factor de Transcripción STAT6/inmunologíaRESUMEN
Attempts to enhance patients' immune responses to malignancies have been largely unsuccessful. We now describe an immune-escape mechanism mediated by the inhibitory receptor Ig-like transcript 3 (ILT3) that may be responsible for such failures. Using a humanized SCID mouse model, we demonstrate that soluble and membrane ILT3 induce CD8(+) T suppressor cells and prevent rejection of allogeneic tumor transplants. Furthermore, we found that patients with melanoma, and carcinomas of the colon, rectum, and pancreas produce the soluble ILT3 protein, which induces the differentiation of CD8(+) T suppressor cells and impairs T cell responses in MLC. These responses are restored by anti-ILT3 mAb or by depletion of soluble ILT3 from the serum. Immunohistochemical staining of biopsies from the tumors and metastatic lymph nodes suggests that CD68(+) tumor-associated macrophages represent the major source of soluble ILT3. Alternative splicing, resulting in the loss of the ILT3 transmembrane domain, may contribute to the release of ILT3 in the circulation. These data suggest that ILT3 depletion or blockade is crucial to the success of immunotherapy in cancer. In contrast, the inhibitory activity of soluble ILT3 on T cell alloreactivity in vitro and in vivo suggests the potential usefulness of rILT3 for immunosuppressive treatment of allograft recipients or patients with autoimmune diseases.
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Adenocarcinoma/inmunología , Neoplasias Colorrectales/inmunología , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Melanoma/inmunología , Neoplasias Pancreáticas/inmunología , Receptores de Superficie Celular/fisiología , Linfocitos T Reguladores/inmunología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Empalme Alternativo , Animales , Diferenciación Celular/inmunología , Línea Celular Tumoral , Anergia Clonal , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Femenino , Rechazo de Injerto/patología , Humanos , Melanoma/metabolismo , Melanoma/patología , Glicoproteínas de Membrana , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/sangre , Receptores de Superficie Celular/genética , Receptores Inmunológicos , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/patología , Escape del TumorRESUMEN
T cell responses against leukemia-associated antigens have been reported in chronic lymphocytic leukemia (CLL). However, the relentless accumulation of CLL B cells in some patients indicates that anti-tumor immune responses are inefficient. Inhibitory receptors from the Ig-like transcript (ILT) family, such as ILT3 and ILT4, are crucial to the tolerogenic activity of antigen presenting cells. In this study, we examined the expression of ILT3 on CD5+ B cells obtained from 47 patients with CLL. Using flow cytometry and RT-PCR, we found that B CLL cells from 23 of 47 patients expressed ILT3 protein and mature ILT3 mRNA. ILT3 protein and mRNA were not found in normal B cells obtained from donors without CLL. Expression of ILT4 in normal and B CLL cells showed a pattern similar to ILT3. The frequency of ILT3 positive CLL B cells was higher in patients with lymphoid tissue involvement, suggesting that ILT3 may have prognostic value in CLL. Our findings indicate that expression of ILT3 and ILT4 on CLL B cells represents a phenotypic abnormality that may play a role in tolerization of tumor-specific T cells.