RESUMEN

Defective apoptosis might be involved in the pathogenesis of multiple sclerosis (MS). We evaluated apoptosis-related molecules in MS patients before and after autologous haematopoietic stem cell transplantation (AHSCT) using BCNU, Etoposide, AraC and Melphalan (BEAM) or cyclophosphamide (CY)-based conditioning regimens. Patients were followed for clinical and immunological parameters for 2 years after AHSCT. At baseline, MS patients had decreased proapoptotic BAD, BAX and FASL and increased A1 gene expression when compared with healthy counterparts. In the BEAM group, BAK, BIK, BIMEL , FAS, FASL, A1, BCL2, BCLXL , CFLIPL and CIAP2 genes were up-regulated after AHSCT. With the exception of BIK, BIMEL and A1, all genes reached levels similar to controls at day + 720 post-transplantation. Furthermore, in these patients, we observed increased CD8+ Fas+ T cell frequencies after AHSCT when compared to baseline. In the CY group, we observed increased BAX, BCLW, CFLIPL and CIAP1 and decreased BIK and BID gene expressions after transplantation. At day + 720 post-AHSCT, the expression of BAX, FAS, FASL, BCL2, BCLXL and CIAP1 was similar to that of controls. Protein analyses showed increased Bcl-2 expression before transplantation. At 1 year post-AHSCT, expression of Bak, Bim, Bcl-2, Bcl-xL and cFlip-L was decreased when compared to baseline values. In summary, our findings suggest that normalization of apoptosis-related molecules is associated with the early therapeutic effects of AHSCT in MS patients. These mechanisms may be involved in the re-establishment of immune tolerance during the first 2 years post-transplantation.

Asunto(s)

Apoptosis/genética , Proteína 5 Relacionada con la Autofagia/genética , Esclerosis Múltiple/genética , Adulto , Linfocitos T CD8-positivos/efectos de los fármacos , Ciclofosfamida/uso terapéutico , Femenino , Expresión Génica/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo/métodos , Adulto Joven

RESUMEN

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated destruction of pancreatic ß cells, resulting in insulin deficiency and hyperglycaemia. Recent studies have described that apoptosis impairment during central and peripheral tolerance is involved in T1D pathogenesis. In this study, the apoptosis-related gene expression in T1D patients was evaluated before and after treatment with high-dose immunosuppression followed by autologous haematopoietic stem cell transplantation (HDI-AHSCT). We also correlated gene expression results with clinical response to HDI-AHSCT. We observed a decreased expression of bad, bax and fasL pro-apoptotic genes and an increased expression of a1, bcl-x(L) and cIAP-2 anti-apoptotic genes in patients' peripheral blood mononuclear cells (PBMCs) compared to controls. After HDI-AHSCT, we found an up-regulation of fas and fasL and a down-regulation of anti-apoptotic bcl-x(L) genes expression in post-HDI-AHSCT periods compared to pre-transplantation. Additionally, the levels of bad, bax, bok, fasL, bcl-x(L) and cIAP-1 genes expression were found similar to controls 2 years after HDI-AHSCT. Furthermore, over-expression of pro-apoptotic noxa at 540 days post-HDI-AHSCT correlated positively with insulin-free patients and conversely with glutamic acid decarboxylase autoantibodies (GAD65) autoantibody levels. Taken together, the results suggest that apoptosis-related genes deregulation in patients' PBMCs might be involved in breakdown of immune tolerance and consequently contribute to T1D pathogenesis. Furthermore, HDI-AHSCT modulated the expression of some apoptotic genes towards the levels similar to controls. Possibly, the expression of these apoptotic molecules could be applied as biomarkers of clinical remission of T1D patients treated with HDI-AHSCT therapy.

Asunto(s)

Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/cirugía , Proteína Ligando Fas/genética , Expresión Génica , Trasplante de Células Madre Hematopoyéticas , Tolerancia Inmunológica/genética , Leucocitos Mononucleares/efectos de los fármacos , Receptor fas/genética , Adolescente , Adulto , Apoptosis/genética , Autoanticuerpos/metabolismo , Regulación hacia Abajo , Femenino , Estudios de Seguimiento , Glutamato Descarboxilasa/inmunología , Humanos , Inmunosupresores/administración & dosificación , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Masculino , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Trasplante Autólogo , Regulación hacia Arriba , Adulto Joven , Proteína bcl-X/genética , Proteína bcl-X/inmunología , Proteína bcl-X/metabolismo

RESUMEN

Hematopoietic SCT (HSCT) and high-dose chemotherapy are being explored as therapy for various human refractory immune-mediated conditions, including inflammatory bowel diseases (IBD). Nevertheless, the exact immunological mechanisms by which the BM cells (BMCs) or immunosuppression provide remission from these diseases is not yet clear. In this work, we investigated the role of these therapies in the modulation of gut mucosal inflammation in an experimental model of IBD. Colitis was induced in mice by 2,4,6-trinitrobenzenesulfonic acid and after CY was administered (200 mg/kg) alone (CY group) or followed by BMCs infusion (HSCT group). Animals were followed for 60 days. Both HSCT and CY reduced the histopathological features of colitis significantly. Infused cells were localized in the gut, and a marked decrease of CD4(+) leukocytes in the inflammatory infiltrate on days +7 and +14 and of CD8(+) cells on day +7 was found in both treatments allied to impressive reduction of proinflammatory Th1 and Th17 cytokines. Although chemotherapy alone was the best treatment regarding the induction of immunosuppressive molecules, only HSCT resulted in increased survival rates compared with the control group. Our findings indicate that high-dose CY followed by HSCT is effective in the modulation of mucosal immunity and in accelerating immune reconstitution after BMT, thus providing valuable tools to support the development and understanding of novel therapeutic strategies for IBD.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Terapia de Inmunosupresión/métodos , Enfermedades Inflamatorias del Intestino/terapia , Animales , Trasplante de Médula Ósea , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Colitis/tratamiento farmacológico , Colitis/inmunología , Colitis/patología , Colitis/terapia , Terapia Combinada , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Citocinas/metabolismo , Femenino , Inmunidad Mucosa/efectos de los fármacos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Ácido Trinitrobencenosulfónico/toxicidad

RESUMEN

Studies have shown that autologous hematopoietic SCT (HSCT) can be used as an intensive immunosuppressive therapy to treat refractory patients and to prevent the progression of multiple sclerosis (MS). This is a prospective multicentric Brazilian MS trial comparing two conditioning regimens: BEAM/horse ATG and CY/rabbit ATG. Most (80.4%) of the 41 subjects in the study had the secondary progressive MS subtype and the mean age was 42 years. The baseline EDSS score in 58.5% of the subjects was 6.5 and 78% had a score of 6.0 or higher, respectively. The complication rate during the intra-transplantation period was 56% for all patients: 71.4% of the patients in the BEAM/hATG group and 40% in the CY/rATG group (P=0.04). Three subjects (7.5%) died of cardiac toxicity, sepsis and alveolar hemorrhage, all of them in the BEAM/ATG group. EFS was 58.54% for all patients: 47% in the BEAM/hATG group and 70% in the CY/rATG group (P=0.288). In conclusion, the CY/rATG regimen seems to be associated with similar outcome results, but presented less toxicity when compared with the BEAM/hATG regimen. Long-term follow-up would be required to fully assess the differences in therapeutic effectiveness between the two regimens.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas/métodos , Esclerosis Múltiple/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Animales , Suero Antilinfocítico/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carmustina/administración & dosificación , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Rechazo de Injerto/prevención & control , Movilización de Célula Madre Hematopoyética , Caballos , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Calidad de Vida , Conejos

RESUMEN

OBJECTIVES: To evaluate the association of the presence of lymphocytotoxic, anti-beta2-glycoprotein I (anti-beta2-GPI) and anti-ribosomal P (anti-P) antibodies in patients with systemic lupus erythematosus (SLE), presenting or not neuropsychiatric (NP) manifestations, stratified according to the activity of the disease. METHODS: A total of 138 patients with SLE (59 with active NPSLE, 49 with active non-NPSLE, and 30 with inactive disease) and 57 healthy controls were studied. Disease activity was assessed by the SLE Disease Activity Index (SLEDAI). The presence of lymphocytotoxic antibodies was assessed using a complement-dependent lymphocytotoxicity assay. The presence of anti-beta2-GPI and anti-P antibodies was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Lymphocytotoxic antibodies were detected primarily in patients with active disease, that is in 35 out of 59 (59.3%) NPSLE and 23 out of 49 (46.9%) non-NPSLE patients, whereas only four out of 30 (13.3%) inactive SLE patients and none of the healthy controls exhibited the autoantibody. The frequency of lymphocytotoxic antibodies in active SLE patients, considered as a whole or stratified into NPSLE or non-NPSLE, was significantly increased in relation to inactive SLE patients (p<0.001 for each comparison). No significant difference was observed when comparing active NPSLE with non-NPSLE patients. No associations were observed between the presence of anti-beta2-GPI or anti-P antibodies and the activity of SLE or the presence of lymphocytotoxic antibodies. CONCLUSIONS: Lymphocytotoxic antibodies occurred more frequently in patients with active SLE than in patients with inactive disease, irrespective of the presence of NP manifestations, a finding that is similar to classical biomarkers of lupus activity (anti-dsDNA and complement). These results indicate that the assessment of the presence of lymphocytotoxic antibodies may be an additional useful tool for the evaluation of SLE activity.

Asunto(s)

Suero Antilinfocítico/inmunología , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Autoanticuerpos/inmunología , Proteínas del Sistema Complemento/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Humanos , Lupus Eritematoso Sistémico/sangre , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Masculino , Persona de Mediana Edad , Proteínas Ribosómicas/inmunología , Índice de Severidad de la Enfermedad , beta 2 Glicoproteína I/inmunología

RESUMEN

Autoimmune diseases constitute a heterogeneous group of conditions commonly treated with anti-inflammatory, immunosuppressant and immunomodulating drugs, with satisfactory results in most cases. Nevertheless, some patients become resistant to conventional therapy. The use of high doses of drugs in such cases results in the need for bone marrow reconstitution, a situation which has stimulated research into the use of hematopoietic stem cells in autoimmune disease therapy. Stem cell transplantation in such diseases aims to destroy the self-reacting immune cells and produce a new functional immune system, as well as substitute cells for tissue damaged in the course of the disease. Significant results, such as the reestablishment of tolerance and a decrease in the recurrence of autoimmune disease, have been reported following stem cell transplantation in patients with autoimmune disease in Brazil and throughout the world. These results suggest that stem cell transplantation has the potential to become an important therapeutic approach to the treatment of various autoimmune diseases including rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, Crohn's disease, autoimmune blood cytopenias, and type I diabetes mellitus.

Asunto(s)

Humanos , Enfermedades Autoinmunes/terapia , Trasplante de Células Madre , Trasplante de Células Madre Hematopoyéticas

RESUMEN

We report here the first six cases of leprosy associated with HLA-identical allogeneic SCT in different phases and with different findings and outcomes. Skin and peripheral nerves may be sites of leprosy associated with SCT, stressing the importance of differential diagnosis between leprosy and GVHD or drug reactions. Clinical manifestations of leprosy before or after transplantation did not influence the outcome of SCT in our cases.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas/efectos adversos , Lepra/etiología , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Lepra/diagnóstico , Lepra/patología , Masculino , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/etiología , Trasplante Homólogo , Resultado del Tratamiento

RESUMEN

Autoimmune diseases constitute a heterogeneous group of conditions commonly treated with anti-inflammatory, immunosuppressant and immunomodulating drugs, with satisfactory results in most cases. Nevertheless, some patients become resistant to conventional therapy. The use of high doses of drugs in such cases results in the need for bone marrow reconstitution, a situation which has stimulated research into the use of hematopoietic stem cells in autoimmune disease therapy. Stem cell transplantation in such diseases aims to destroy the self-reacting immune cells and produce a new functional immune system, as well as substitute cells for tissue damaged in the course of the disease. Significant results, such as the reestablishment of tolerance and a decrease in the recurrence of autoimmune disease, have been reported following stem cell transplantation in patients with autoimmune disease in Brazil and throughout the world. These results suggest that stem cell transplantation has the potential to become an important therapeutic approach to the treatment of various autoimmune diseases including rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, Crohn's disease, autoimmune blood cytopenias, and type I diabetes mellitus.

Asunto(s)

Enfermedades Autoinmunes/terapia , Trasplante de Células Madre , Trasplante de Células Madre Hematopoyéticas , Humanos

RESUMEN

The natural history and pathogenic processes of infection by the human immunodeficiency virus type 1 (HIV-1) are complex, variable, and dependent upon a multitude of viral and host factors and their interactions. The CCR5-Delta32 allele remains the most important genetic factor known to be associated with host resistance to the HIV-1 infection. However, other mutations in the CCR5, CCR2, CX(3)CR1, CXCL12 (SDF1), and CCL5 (RANTES) genes have been identified and associated with host resistance and/or susceptibility to HIV-1 infection and disease progression. Some studies have also suggested that chemokine receptor gene polymorphisms may affect response to potent antiretroviral therapy. This article reviews the polymorphisms already described in the mutant chemokine receptors or ligands and their impact on the host susceptibility to HIV-1 infection and on the clinical course of the disease, as well as the development of new anti-HIV therapies that takes into account these potential targets in the host. These genetic polymorphisms could be used as genetic markers to detect individuals at higher risk of developing either a faster disease progression or therapeutic failure. Once these individuals are identified, therapeutic strategies based on either different, more aggressive drugs or combinations of drugs can be used, either alone or in combination with shorter intervals for therapeutic monitoring. Pharmacogenetics is very likely to underlie future therapies for HIV-1 infection, and current patients with multi-resistance to the existing antiretroviral agents could also benefit from this approach. These developments also underscore the importance of continuing the investigation of new therapies targeted to the host in order to inhibit the HIV-1 entry into the host cells.

Asunto(s)

Antirretrovirales/uso terapéutico , Quimiocinas/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Receptores de Quimiocina/genética , Receptor 1 de Quimiocinas CX3C , Quimiocina CCL5/genética , Quimiocina CXCL12 , Quimiocinas CC/genética , Quimiocinas CXC/genética , Sobrevivientes de VIH a Largo Plazo , Humanos , Polimorfismo Genético , Receptores CCR2 , Receptores CCR5/genética , Receptores de Quimiocina/antagonistas & inhibidores

RESUMEN

Bone marrow is a heterogeneous cell population which includes hematopoietic and mesenchymal progenitor cells. Dysregulated hematopoiesis occurs in chronic myelogenous leukemia (CML), being caused at least in part by abnormalities in the hematopoietic progenitors. However, the role of mesenchymal stem cells (MSCs) in CML has not been well characterized. The objectives of the present study were to observe the biological characteristics of MSCs from CML patients and to determine if MSCs originate in part from donors in CML patients after bone marrow transplantation (BMT). We analyzed MSCs from 5 untreated patients and from 3 CML patients after sex-mismatched allogeneic BMT. Flow cytometry analysis revealed the typical MSC phenotype and in vitro assays showed ability to differentiate into adipocytes and osteoblasts. Moreover, although some RT-PCR data were contradictory, combined fluorescence in situ hybridization analysis showed that MSCs from CML patients do not express the bcr-abl gene. Regarding MSCs of donor origin, although it is possible to detect Y target sequence by nested PCR, the low frequency (0.14 and 0.34%) of XY cells in 2 MSC CML patients by fluorescence in situ hybridization analysis suggests the presence of contaminant hematopoietic cells and the absence of host-derived MSCs in CML patients. Therefore, we conclude that MSCs from CML patients express the typical MSC phenotype, can differentiate into osteogenic and adipogenic lineages and do not express the bcr-abl gene. MSCs cannot be found in recipients 12 to 20 months after BMT. The influence of MSCs on the dysregulation of hematopoiesis in CML patients deserves further investigation.

Asunto(s)

Trasplante de Médula Ósea , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Mesenquimatosas/química , Acondicionamiento Pretrasplante , Adolescente , Adulto , Quimera , Femenino , Proteínas de Fusión bcr-abl/análisis , Hematopoyesis , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Células Madre Mesenquimatosas/fisiología , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo

RESUMEN

Bone marrow is a heterogeneous cell population which includes hematopoietic and mesenchymal progenitor cells. Dysregulated hematopoiesis occurs in chronic myelogenous leukemia (CML), being caused at least in part by abnormalities in the hematopoietic progenitors. However, the role of mesenchymal stem cells (MSCs) in CML has not been well characterized. The objectives of the present study were to observe the biological characteristics of MSCs from CML patients and to determine if MSCs originate in part from donors in CML patients after bone marrow transplantation (BMT). We analyzed MSCs from 5 untreated patients and from 3 CML patients after sex-mismatched allogeneic BMT. Flow cytometry analysis revealed the typical MSC phenotype and in vitro assays showed ability to differentiate into adipocytes and osteoblasts. Moreover, although some RT-PCR data were contradictory, combined fluorescence in situ hybridization analysis showed that MSCs from CML patients do not express the bcr-abl gene. Regarding MSCs of donor origin, although it is possible to detect Y target sequence by nested PCR, the low frequency (0.14 and 0.34 percent) of XY cells in 2 MSC CML patients by fluorescence in situ hybridization analysis suggests the presence of contaminant hematopoietic cells and the absence of host-derived MSCs in CML patients. Therefore, we conclude that MSCs from CML patients express the typical MSC phenotype, can differentiate into osteogenic and adipogenic lineages and do not express the bcr-abl gene. MSCs cannot be found in recipients 12 to 20 months after BMT. The influence of MSCs on the dysregulation of hematopoiesis in CML patients deserves further investigation.

Asunto(s)

Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Trasplante de Médula Ósea , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/cirugía , Células Madre Mesenquimatosas , Acondicionamiento Pretrasplante , Quimera , Proteínas de Fusión bcr-abl/análisis , Hematopoyesis , Hibridación Fluorescente in Situ , Células Madre Mesenquimatosas , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo

RESUMEN

Type 1 diabetes mellitus results from a cell-mediated autoimmune attack against pancreatic ß-cells. Traditional treatments involve numerous daily insulin dosages/injections and rigorous glucose control. Many efforts toward the identification of ß-cell precursors have been made not only with the aim of understanding the physiology of islet regeneration, but also as an alternative way to produce ß-cells to be used in protocols of islet transplantation. In this review, we summarize the most recent studies related to precursor cells implicated in the regeneration process. These include embryonic stem cells, pancreas-derived multipotent precursors, pancreatic ductal cells, hematopoietic stem cells, mesenchymal stem cells, hepatic oval cells, and mature ß-cells. There is controversial evidence of the potential of these cell sources to regenerate ß-cell mass in diabetic patients. However, clinical trials using embryonic stem cells, umbilical cord blood or adult bone marrow stem cells are under way. The results of various immunosuppressive regimens aiming at blocking autoimmunity against pancreatic ß-cells and promoting ß-cell preservation are also analyzed. Most of these regimens provide transient and partial effect on insulin requirements, but new regimens are beginning to be tested. Our own clinical trial combines a high dose immunosuppression with mobilized peripheral blood hematopoietic stem cell transplantation in early-onset type 1 diabetes mellitus.

Asunto(s)

Humanos , Niño , Adolescente , Adulto , Diabetes Mellitus Tipo 1/terapia , Trasplante de Islotes Pancreáticos/inmunología , Islotes Pancreáticos/fisiología , Regeneración/inmunología , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 1/inmunología , Inmunosupresores/uso terapéutico , Islotes Pancreáticos/inmunología , Trasplante de Células Madre/métodos

RESUMEN

Type 1 diabetes mellitus results from a cell-mediated autoimmune attack against pancreatic beta-cells. Traditional treatments involve numerous daily insulin dosages/injections and rigorous glucose control. Many efforts toward the identification of beta-cell precursors have been made not only with the aim of understanding the physiology of islet regeneration, but also as an alternative way to produce beta-cells to be used in protocols of islet transplantation. In this review, we summarize the most recent studies related to precursor cells implicated in the regeneration process. These include embryonic stem cells, pancreas-derived multipotent precursors, pancreatic ductal cells, hematopoietic stem cells, mesenchymal stem cells, hepatic oval cells, and mature beta-cells. There is controversial evidence of the potential of these cell sources to regenerate beta-cell mass in diabetic patients. However, clinical trials using embryonic stem cells, umbilical cord blood or adult bone marrow stem cells are under way. The results of various immunosuppressive regimens aiming at blocking autoimmunity against pancreatic beta-cells and promoting beta-cell preservation are also analyzed. Most of these regimens provide transient and partial effect on insulin requirements, but new regimens are beginning to be tested. Our own clinical trial combines a high dose immunosuppression with mobilized peripheral blood hematopoietic stem cell transplantation in early-onset type 1 diabetes mellitus.

Asunto(s)

Diabetes Mellitus Tipo 1/terapia , Trasplante de Islotes Pancreáticos/inmunología , Islotes Pancreáticos/fisiología , Regeneración/inmunología , Adolescente , Adulto , Niño , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 1/inmunología , Humanos , Inmunosupresores/uso terapéutico , Islotes Pancreáticos/inmunología , Trasplante de Células Madre/métodos

RESUMEN

Allogeneic bone marrow transplantation (alloBMT) is the only curative therapy for chronic myelogenous leukemia (CML). This success is explained by the delivery of high doses of antineoplastic agents followed by the rescue of marrow function and the induction of graft-versus-leukemia reaction mediated by allogeneic lymphocytes against host tumor cells. This reaction can also be induced by donor lymphocyte infusion (DLI) producing remission in most patients with CML who relapse after alloBMT. The immunological mechanisms involved in DLI therapy are poorly understood. We studied five CML patients in the chronic phase, who received DLI after relapsing from an HLA-identical BMT. Using flow cytometry we evaluated cellular activation and apoptosis, NK cytotoxicity, lymphocytes producing cytokines (IL-2, IL-4 and IFN-gamma), and unstimulated (in vivo) lymphocyte proliferation. In three CML patients who achieved hematological and/or cytogenetic remission after DLI we observed an increase of the percent of activation markers on T and NK cells (CD3/DR, CD3/CD25 and CD56/DR), of lymphocytes producing IL-2 and IFN-gamma, of NK activity, and of in vivo lymphocyte proliferation. These changes were not observed consistently in two of the five patients who did not achieve complete remission with DLI. The percent of apoptotic markers (Fas, FasL and Bcl-2) on lymphocytes and CD34-positive cells did not change after DLI throughout the different study periods. Taken together, these preliminary results suggest that the therapeutic effect of DLI in the chronic phase of CML is mediated by classic cytotoxic and proliferative events involving T and NK cells but not by the Fas pathway of apoptosis.

Asunto(s)

Trasplante de Médula Ósea/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/cirugía , Transfusión de Linfocitos , Adulto , Trasplante de Médula Ósea/inmunología , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Masculino , Recurrencia Local de Neoplasia/inmunología , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Quimera por Trasplante/inmunología , Resultado del Tratamiento

RESUMEN

Allogeneic bone marrow transplantation (alloBMT) is the only curative therapy for chronic myelogenous leukemia (CML). This success is explained by the delivery of high doses of antineoplastic agents followed by the rescue of marrow function and the induction of graft-versus-leukemia reaction mediated by allogeneic lymphocytes against host tumor cells. This reaction can also be induced by donor lymphocyte infusion (DLI) producing remission in most patients with CML who relapse after alloBMT. The immunological mechanisms involved in DLI therapy are poorly understood. We studied five CML patients in the chronic phase, who received DLI after relapsing from an HLA-identical BMT. Using flow cytometry we evaluated cellular activation and apoptosis, NK cytotoxicity, lymphocytes producing cytokines (IL-2, IL-4 and IFN-gamma), and unstimulated (in vivo) lymphocyte proliferation. In three CML patients who achieved hematological and/or cytogenetic remission after DLI we observed an increase of the percent of activation markers on T and NK cells (CD3/DR, CD3/CD25 and CD56/DR), of lymphocytes producing IL-2 and IFN-gamma, of NK activity, and of in vivo lymphocyte proliferation. These changes were not observed consistently in two of the five patients who did not achieve complete remission with DLI. The percent of apoptotic markers (Fas, FasL and Bcl-2) on lymphocytes and CD34-positive cells did not change after DLI throughout the different study periods. Taken together, these preliminary results suggest that the therapeutic effect of DLI in the chronic phase of CML is mediated by classic cytotoxic and proliferative events involving T and NK cells but not by the Fas pathway of apoptosis.

Asunto(s)

Humanos , Masculino , Femenino , Adulto , Trasplante de Médula Ósea , Leucemia Mielógena Crónica BCR-ABL Positiva , Transfusión de Linfocitos , Trasplante de Médula Ósea , Estudios de Seguimiento , Enfermedad Injerto contra Huésped , Leucemia Mielógena Crónica BCR-ABL Positiva , Recurrencia Local de Neoplasia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Quimera por Trasplante , Resultado del Tratamiento

RESUMEN

In this paper we present preliminary results of hematopoietic stem cell transplantation for autoimmune diseases in Brazil and China. Chinese experience transplanting lupus is significant and the Brazilian experience with several autoimmune diseases is growing. We discuss peculiar conditions in developing countries which could affect the results, and future prospectives for the organization of phase III randomized trials in those countries.

Asunto(s)

Enfermedades Autoinmunes/terapia , Países en Desarrollo , Trasplante de Células Madre Hematopoyéticas/métodos , Brasil , China , Ensayos Clínicos como Asunto , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Humanos , Resultado del Tratamiento

Asunto(s)

Antígenos HLA-DR/inmunología , Trasplante de Riñón/inmunología , Brasil , Cartilla de ADN , Etnicidad , Antígenos HLA-DR/genética , Prueba de Histocompatibilidad/métodos , Humanos , Fallo Renal Crónico/cirugía , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Conformacional Retorcido-Simple , Resultado del Tratamiento

RESUMEN

We report two cases of refractory chronic graft-versus-host disease after donor lymphocyte infusions in which the skin lesions improved dramatically with the use of intravenous pulses of lidocaine. This form of therapy has been used successfully for the cutaneous involvement of scleroderma and may have vasodilator and anti-inflammatory effects.

Asunto(s)

Enfermedad Injerto contra Huésped/patología , Lidocaína/administración & dosificación , Transfusión de Linfocitos/efectos adversos , Enfermedades de la Piel/tratamiento farmacológico , Adulto , Trasplante de Médula Ósea , Niño , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Humanos , Inyecciones Intravenosas , Leucemia/complicaciones , Leucemia/terapia , Masculino , Recurrencia , Esclerodermia Localizada/tratamiento farmacológico , Esclerodermia Localizada/etiología , Esclerodermia Localizada/patología , Enfermedades de la Piel/etiología , Enfermedades de la Piel/patología , Trasplante Homólogo

RESUMEN

Natural killer (NK) cells are CD3- CD56+ and/or CD16+ cytotoxic lymphocytes that mediate first-line defense against various types of target cells without prior immunization. To assess the effect of the menstrual cycle and gender on NK activity we evaluated 30 healthy women (mean age 28.1 years, range 21-39) in follicular and luteal phases, 29 postmenopausal women (mean age 58.8 years, range 42-72) and 48 healthy men (mean age 31.6 years, range 21-40). In a flow cytometric test of NK activity, peripheral blood mononuclear effector cells were mixed with K562 targets cells labeled with DiO (3,3'-dioctadecyloxacarbocyanine perchlorate) at effector:target cell ratios of 40, 20, 10 and 5:1. Dead cells were stained with propidium iodide and results were expressed as lytic units per 10(7) cells. In addition, progesterone levels were determined in the luteal phase of the menstrual cycle of healthy women by a chemiluminescence assay. Our results showed that (1) NK cytotoxicity was higher in the follicular than in the luteal phase of the menstrual cycle (P < 0.0001); (2) postmenopausal women and men showed NK activity similar to women in the follicular phase but higher than women in the luteal phase of the menstrual cycle (P < 0.05); and (3) there was no correlation between NK activity and levels of progesterone. The data suggest that progesterone does not influence NK activity directly and that other factors may explain the reduction of NK activity in the luteal phase of the menstrual cycle.

Asunto(s)

Células Asesinas Naturales/inmunología , Ciclo Menstrual/inmunología , Adulto , Anciano , Citotoxicidad Inmunológica , Femenino , Fase Folicular/inmunología , Humanos , Técnicas In Vitro , Células K562 , Fase Luteínica/sangre , Fase Luteínica/inmunología , Masculino , Menopausia/inmunología , Persona de Mediana Edad , Progesterona/sangre , Caracteres Sexuales

RESUMEN

Applications of flow cytometry to clinical and experimental hematopoietic stem cell transplantation (HSCT) are discussed in this review covering the following topics: diagnosis and classification of lymphohematologic disorders, quantitation of hematopoietic progenitors in the graft, lymphohematopoietic reconstitution following HSCT and animal models of human HSCT. At the end, the utilization of flow cytometry in clinical HSCT by Brazilian transplant centers is briefly reviewed.

Asunto(s)

Citometría de Flujo/métodos , Trasplante de Células Madre Hematopoyéticas , Animales , Recuento de Células/métodos , Modelos Animales de Enfermedad , Enfermedades Hematológicas/clasificación , Enfermedades Hematológicas/diagnóstico , Células Madre Hematopoyéticas , Humanos , Enfermedades Linfáticas/clasificación , Enfermedades Linfáticas/diagnóstico