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1.
Leukemia ; 29(10): 2039-49, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25975191

RESUMEN

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.


Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Sinergismo Farmacológico , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Monoclonales/administración & dosificación , Citotoxicidad Celular Dependiente de Anticuerpos , Apoptosis/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Proliferación Celular/efectos de los fármacos , Citotoxicidad Inmunológica , Proteínas de Unión al ADN/fisiología , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Citometría de Flujo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/patología , Terapia Recuperativa , Tretinoina/administración & dosificación , Células Tumorales Cultivadas
2.
J Cell Mol Med ; 16(8): 1827-39, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21973026

RESUMEN

Although mesenchymal stromal cells (MSCs) have been applied clinically to treat cardiac diseases, it is unclear how and to which extent transplanted MSCs exert their beneficial effects. To address these questions, pre-clinical MSC administrations are needed for which pigs appear to be the species of choice. This requires the use of porcine cells to prevent immune rejection. However, it is currently unknown to what extent porcine MSCs (pMSCs) resemble human MSCs (hMSCs). Aim of this study was to compare MSC from porcine bone marrow (BM) with human cells for phenotype, multi-lineage differentiation potential, immune-modulatory capacity and the effect on cardiac function after transplantation in a mouse model of myocardial infarction. Flow cytometric analysis revealed that pMSC expressed surface antigens also found on hMSC, including CD90, MSCA-1 (TNAP/W8B2 antigen), CD44, CD29 and SLA class I. Clonogenic outgrowth was significantly enriched following selection of CD271+ cells from BM of human and pig (129 ± 29 and 1961 ± 485 fold, respectively). hMSC and pMSC differentiated comparably into the adipogenic, osteogenic or chondrogenic lineages, although pMSC formed fat much faster than hMSC. Immuno-modulation, an important feature of hMSC, was clearly demonstrated for pMSC when co-cultured with porcine peripheral blood cells stimulated with PMA and pIL-2. Finally, pMSC transplantation after myocardial infarction attenuated adverse remodelling to a similar extent as hMSC when compared to control saline injection. These findings demonstrate that pMSCs have comparable characteristics and functionality with hMSCs, making reliable extrapolation of pre-clinical pMSC studies into a clinical setting very well possible.


Asunto(s)
Diferenciación Celular , Inmunomodulación/inmunología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Miocardio/patología , Adipocitos/citología , Adipocitos/metabolismo , Adipogénesis , Animales , Antígenos CD/metabolismo , Células de la Médula Ósea/citología , Proliferación Celular , Separación Celular , Condrogénesis , Citometría de Flujo , Pruebas de Función Cardíaca , Humanos , Inmunofenotipificación , Masculino , Ratones , Ratones SCID , Osteoblastos/citología , Osteoblastos/metabolismo , Osteogénesis , Fenotipo , Sus scrofa , Linfocitos T/citología , Linfocitos T/metabolismo
3.
J Cell Mol Med ; 14(5): 1064-70, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20465578

RESUMEN

Patients suffering from heart failure as a result of myocardial infarction are in need of heart transplantation. Unfortunately the number of donor hearts is very low and therefore new therapies are subject of investigation. Cell transplantation therapy upon myocardial infarction is a very promising strategy to replace the dead myocardium with viable cardiomyocytes, smooth muscle cells and endothelial cells, thereby reducing scarring and improving cardiac performance. Despite promising results, resulting in reduced infarct size and improved cardiac function on short term, only a few cells survive the ischemic milieu and are retained in the heart, thereby minimizing long-term effects. Although new capillaries and cardiomyocytes are formed around the infarcted area, only a small percentage of the transplanted cells can be detected months after myocardial infarction. This suggests the stimulation of an endogenous regenerative capacity of the heart upon cell transplantation, resulting from release of growth factor, cytokine and other paracrine molecules by the progenitor cells--the so-called paracrine hypothesis. Here, we focus on a relative new component of paracrine signalling, i.e. exosomes. We are interested in the release and function of exosomes derived from cardiac progenitor cells and studied their effects on the migratory capacity of endothelial cells.


Asunto(s)
Movimiento Celular , Células Endoteliales/citología , Exosomas/metabolismo , Miocitos Cardíacos/citología , Células Madre/metabolismo , Basigina/metabolismo , Movimiento Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Exosomas/efectos de los fármacos , Humanos , Metaloproteinasas de la Matriz/metabolismo , Modelos Biológicos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Transducción de Señal/efectos de los fármacos , Trasplante de Células Madre , Células Madre/citología , Células Madre/efectos de los fármacos
4.
Panminerva Med ; 52(1): 27-40, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20228724

RESUMEN

Following myocardial infarction, damage due to ischemia potentially leads to heart failure. Stem cell transplantation has emerged as a potential treatment to repair the injured heart, due to the inherent characteristics of stem cells such as self-renewal, unlimited capacity for proliferation and ability to differentiate to various cell lineages. Most promising results have been reported thus far on mesenchymal stem cells (MSC). Following transplantation in the heart, stem cells are expected to 1) reduce the damage; 2) activate the endogenous regenerative potential of the heart; and 3) participate in the regeneration of the tissue. Until now, the results of intervention with stem cells in animals were promising, but clinical studies have failed to live up to those expectations. Current problems limiting the efficacy of cellular therapy are: 1) limited knowledge on the time and mode of administration; 2) loss of homing receptors on culture-expanded cells as a consequence of the culture conditions; 3) massive cell death in the transplanted graft in the damaged heart, due to the hostile environment, 4) lack of knowledge on MSC behaviour in the heart. Since generally only 1-5% of delivered cells were found to actually engraft within the infarct zone, there is an urgent need for improvement. In animal models, strategies to precondition MSC before transplantation to survive in the damaged heart were applied successfully. These include exposure of cells to physical treatments (hypoxia and heat shock), pharmacological agents, "priming" of cells with growth factors, and genetic modification by over-expression of anti-apoptotic proteins, growth factors or pro-survival genes. To develop the strategy with maximal engraftment, survival and function of cells in the heart is the ultimate challenge for years to come.


Asunto(s)
Enfermedades Cardiovasculares/terapia , Células Madre Mesenquimatosas/citología , Células del Estroma/citología , Diferenciación Celular , Trasplante de Células , Humanos , Medicina Regenerativa , Tasa de Supervivencia
5.
Curr Opin Organ Transplant ; 14(5): 560-5, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19623073

RESUMEN

PURPOSE OF REVIEW: For heart failure patients, the urgent need for heart transplantation exceeds the availability of donor hearts. Therefore, cell transplantation has emerged as an interesting and potential solution. This review will focus on the capability of different types of stem cells to regenerate the heart. Moreover, the mechanism for success will be addressed, focusing on the specific (and indispensable?) role of the cells. RECENT FINDINGS: In recent years, many types of stem cells have been described as a possible source for cell transplantation in failing hearts, with mixed outcomes. Cell transplantation is hampered by suboptimal delivery techniques, limited survival of cells, and reduced proliferation and differentiation rates in vivo. Interestingly, the number of injected cells that engrafted the heart successfully cannot explain the observed beneficial effects and, therefore, paracrine effects are suggested for the success in cell therapy. SUMMARY: This review summarizes the current types of stem or progenitor cells used in cardiac cell therapy and beneficial effects on heart function and morphology in preclinical studies. Currently, the observed effects suggest that paracrine effects might be responsible, thereby triggering mobilization and activation of resident (stem) cells, which challenges the classical concept and true regenerative capacity of cell therapy at this point.


Asunto(s)
Insuficiencia Cardíaca/cirugía , Trasplante de Células Madre/métodos , Humanos , Resultado del Tratamiento
6.
J Thromb Haemost ; 7(1): 217-26, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18983508

RESUMEN

BACKGROUND: Blood outgrowth endothelial cells (BOEC) are good candidates for vascular (re-) generating cell therapy. Although cord blood (CB) BOEC have been reported as more proliferative than peripheral blood (PB) BOEC, not much is known about their functional properties. OBJECTIVES: We have studied the following determinants in BOEC expanded from CB and PB: endothelial phenotype, in vitro adhesion, migration, proliferation, and angiogenic tube forming capacity. METHODS/RESULTS: Endothelial phenotype of BOEC was evaluated by fluorescence activated cell sorting (FACS) analysis and confirmed the presence of endothelial markers including CD31, CD105, CD144, CD146, KDR/VEGFR-2, Tie-2, and TNF-alpha-induced VCAM-1 and ICAM-1. Evaluation of cell proliferation revealed a higher basal proliferation of CB-BOEC, which increased after exposure to bFGF but not VEGF. The lower basal proliferation of PB-BOEC increased with VEGF or bFGF addition. Array analysis of angiogenic genes showed many comparable expressions in both BOEC, and a slightly more pronounced pro-angiogenic profile in CB-BOEC than PB-BOEC. Both BOEC were able to form tubular structures in a three-dimensional fibrin matrix. Tube formation in CB-BOEC was markedly induced by TNF-alpha only and inhibited by anti-urokinase antibodies. It was comparable to that induced by combined addition of TNF-alpha and VEGF or bFGF, while maximal tube formation in PB-BOEC required simultaneous exposure to TNF-alpha/VEGF or TNF-alpha/bFGF. CONCLUSIONS: The endothelial phenotype and characteristics for homing, adhesion, migration, inflammation, and angiogenic tube formation are almost equal for BOEC from CB and PB. A slightly more angiogenic phenotype favors CB-BOEC. However, addition of VEGF to PB-BOEC induces equal proliferation and tube formation.


Asunto(s)
Sangre , Células Endoteliales/fisiología , Neovascularización Fisiológica , Adhesión Celular , Movimiento Celular , Proliferación Celular , Células Cultivadas , Células Endoteliales/citología , Sangre Fetal , Humanos , Inmunofenotipificación , Factor A de Crecimiento Endotelial Vascular/farmacología
7.
Vox Sang ; 88(1): 1-9, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15663716

RESUMEN

An increase in the number of circulating endothelial cells (CEC) and of bone marrow-derived endothelial progenitor cells (EPC) in the peripheral blood is associated with vascular injury, repair and neovascularization. The phenotype and number of CEC may serve as diagnostic or prognostic parameters of vascular injury and tumour growth. An increase in the number of EPC may reflect repair of ischaemic vascular injury, a finding which has resulted in the initiation of clinical cardiovascular pilot trials using cell therapy. However, there is no consensus on the exact phenotype of the EPC and haematopoietic stem cells (HSC) and therefore the best candidate cell for transplant has not been established. Although the use of peripheral blood stem cells following mobilization, or of ex vivo-expanded cells, may improve EPC-mediated vascular graft endothelialization or tissue vascularization, sustained EPC-induced neovascularization still needs to be proven. Flow cytometric characterization, in combination with functional assays, will further elucidate the phenotype of the CEC and EPC, thereby providing reliable detection to appreciate their role in vascular diseases and cancer and to evaluate and, if possible, improve their therapeutic potential.


Asunto(s)
Células Endoteliales/fisiología , Endotelio Vascular/patología , Células Madre/fisiología , Células Sanguíneas , Movimiento Celular , Células Endoteliales/citología , Humanos , Neovascularización Fisiológica , Fenotipo , Células Madre/citología
8.
Haematologica ; 86(10): 1021-8, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11602407

RESUMEN

BACKGROUND AND OBJECTIVES: We hypothesized that qualitative or quantitative differences in hematopoietic stem cells from fetal liver (FL) and fetal bone marrow (FBM) may be the cause of their organ specificity. DESIGN AND METHODS: To analyze possible differences in vivo, we compared the engraftment potential of equal numbers of CD34+ cells isolated from human FL or FBM into immunodeficient NOD/SCID mice. RESULTS: Mice showing engraftment following transplantation of CD34+ cells from FL demonstrated 14% (range 2-76%) CD45+ cells of human origin in the bone marrow compared to significantly lower levels of engraftment (4%, range 2-20%, p < 0.04) of FBM CD34+ cells. Likewise, the percentage of CD34+ CD38- cells in FBM was 4 times lower than the percentage in FL (1.4+/-0.9% and 5.6+/-0.7%, respectively). Similar organ distribution of engrafted human cells was found. Subset analysis of human cells in bone marrow of engrafted mice revealed identical distribution of the lymphoid, myeloid and erythroid lineages after transplantation of CD34+ cells from FL or FBM. INTERPRETATION AND CONCLUSIONS: The FL CD34+ cells showed a four-fold higher content of the CD34+ CD38- subset coinciding with a four-fold higher engraftment of CD34+ cells into NOD/SCID mice. Since the organ distribution and differentiation potential of the cells engrafted were similar, we concluded that CD34+ hematopoietic cells derived from FL and FBM have quantitatively different, but qualitatively the same potential for engraftment into NOD/SCID mice.


Asunto(s)
Antígenos CD34 , Células de la Médula Ósea/citología , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas , Hígado/citología , Trasplante Heterólogo , Animales , Femenino , Feto/citología , Humanos , Hígado/embriología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Especificidad de Órganos , Embarazo
9.
Bone Marrow Transplant ; 28(2): 163-71, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11509934

RESUMEN

Umbilical cord blood (UCB), bone marrow (BM) and mobilized peripheral blood (mPB) are used as sources of hematopoietic stem cells for transplantation. The NOD/SCID mouse model was used to compare the lineage-specific repopulating potential of CD34(+) cells derived from these sources. Six to 8 weeks after transplantation, blood, BM, spleen, liver and thymus, were harvested, and analyzed by flow cytometry using CD34, CD45, myeloid, and lymphoid lineage-specific antibodies. Fifty percent engraftment of human cells in bone marrow of mice was estimated to be reached with 0.55 x 10(6) CD34(+) UCB cells or with 7.9 x 10(6) CD34(+) cells from adult sources, illustrating a 10-fold superiority of UCB CD34(+) cells to engraft NOD/SCID mice. Lineage-specific characterization of engrafted human cells showed that the high engraftment potential of CD34(+) cells from UCB was due to a preferential B cell development (2-81%). In contrast, comparable percentages of myeloid cells were found following transplantation of CD34(+) cells from UCB, BM and mPB (1-38%), and occurred at significant levels only at relatively high doses. Since the CD34 content of UCB transplants is usually at least one log lower than of transplant from adult sources, these results correspond to the clinical findings with UCB transplantation showing a relatively high overall engraftment, but delayed myeloid recovery.


Asunto(s)
Sangre Fetal/citología , Trasplante de Células Madre Hematopoyéticas , Trasplante Heterólogo/fisiología , Adulto , Animales , Antígenos CD/sangre , Antígenos CD34/sangre , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Citometría de Flujo , Humanos , Recién Nacido , Hígado/citología , Hígado/inmunología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Bazo/citología , Bazo/inmunología , Timo/citología , Timo/inmunología
10.
Ann N Y Acad Sci ; 938: 9-17, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11458530

RESUMEN

For more than 10 years umbilical cord blood (UCB) has been used as an alternative source of hematopoietic stem cells for allogeneic transplantation. Although the clinical results are encouraging, UCB is associated with delayed engraftment. To address these issues we have used the NOD/SCID mouse model to study the engraftment potential of cord blood cells in more detail, to assess the engraftment potential of expanded megakaryocytic progenitor cells, and to study the effect of co-transplantation of mesenchymal stem cells on engraftment.


Asunto(s)
Sangre Fetal/citología , Trasplante de Células Madre Hematopoyéticas , Animales , Antígenos CD34/análisis , Células Sanguíneas/trasplante , Trasplante de Médula Ósea , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Células Cultivadas/trasplante , Trasplante de Tejido Fetal , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/tendencias , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Pulmón/citología , Pulmón/embriología , Megacariocitos/citología , Mesodermo/citología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Especificidad de Órganos , Poliploidía , Quimera por Radiación , Inmunodeficiencia Combinada Grave/terapia , Trombopoyetina/farmacología , Trasplante Heterólogo
11.
Blood ; 96(6): 2100-7, 2000 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-10979954

RESUMEN

It was hypothesized that during mammalian development, the extensive need for hematopoietic cells requires equal contribution to blood cell production from both quiescent and cycling hematopoietic stem cells (HSCs) while maintaining the stem cell pool. To investigate this hypothesis, the engraftment potential of umbilical cord blood (UCB) CD34(+) cells residing in either G(0) (G(0)CD34(+) cells) or G(1) (G(1)CD34(+) cells) phases of the cell cycle was assessed in nonobese diabetic/severe combined immune-deficient (NOD/SCID) mice. Whereas the level of chimerism in mice transplanted with UCB G(0)CD34(+) cells was 69.9% +/- 24.0%, mice receiving equal numbers of G(1)CD34(+) cells harbored 46.7% +/- 21.3% human cells 8 weeks posttransplantation. Both groups of cells sustained multilineage differentiation and the production of CD34(+) cells in recipient animals. The relationship between the number of transplanted G(0)CD34(+) or G(1)CD34(+) cells and the level of chimerism was analyzed by a general linear models procedure. Although the initial level of chimerism following transplantation of G(0)CD34(+) cells was higher than that sustained by G(1)CD34(+) cells, the increment in the degree of chimerism obtained with each additional 10(3) cells of either phenotype was identical, suggesting that the reconstitution potential of these 2 types of cells was similar. Of interest is that human cells recovered from primary recipients of both G(0)CD34(+) and G(1)CD34(+) cells engrafted in secondary NOD/SCID recipients, albeit at a substantially lower level, confirming the primitive nature of UCB CD34(+) cells residing in G(1).


Asunto(s)
Hematopoyesis , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Animales , Antígenos CD34 , Recuento de Células Sanguíneas , Diferenciación Celular , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mitosis
12.
Bone Marrow Transplant ; 22 Suppl 1: S58-60, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9715891

RESUMEN

The repopulating ability and homing potential of CD34+ cells isolated from either bone marrow (BM) or umbilical cord blood (UCB) was compared in NOD/SCID mice. Mice were sublethally irradiated (3.5 Gy) and within 24 h transplanted i.v. with 10(5)-10(6) CD34+ cells. Four weeks post-transplantation blood was collected from the tail vein for detection of human cells and after 6-7 weeks the mice were sacrificed and blood, BM, thymus, lymph nodes, spleen, liver, lung and kidney were harvested and single cells suspensions were made. Human cells were detected by flow cytometry, and staining was performed for CD34, CD45, and markers of the myeloid, and lymphoid lineages. CD34+ cells from UCB successfully engrafted into the NOD/SCID mice. Eighty-five percent of cells in BM of the mice were of human origin, depending on the dose of cells injected. In all other organs these percentages were always lower, and maximally 63, 13, 3 and 2% in spleen, liver, lung and kidney, respectively. Transplantation of CD34+ cells isolated from human BM, on the other hand, resulted in a very low percentage of human cells after 6-7 weeks of transplantation, not exceeding 3% of the cell suspension. Whether this difference in repopulating ability can be explained by an intrinsic qualitative difference or by differences in quantity of stem cells within the CD34+ compartment from UCB or BM remains to be determined.


Asunto(s)
Células de la Médula Ósea/citología , Sangre Fetal/citología , Células Madre Hematopoyéticas/citología , Animales , Antígenos CD34/análisis , Células de la Médula Ósea/química , División Celular , Células Cultivadas , Sangre Fetal/química , Células Madre Hematopoyéticas/química , Humanos , Antígenos Comunes de Leucocito/análisis , Ratones , Ratones Endogámicos NOD , Ratones SCID
13.
Transpl Immunol ; 4(3): 198-202, 1996 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-8893449

RESUMEN

Analysis of T cell subsets in the spleen during graft-versus-host (GVH) reactions in a fully allogeneic mouse strain combination demonstrated that first CD4+ T cells become activated, and initiate the GVH reaction. Subsequently, CD8+ T cells become involved. Here we show that anti-CD8 treatment on day +3 resulted in a significant increase in survival, while early treatment (day -1 or day +1) did not. Acute GVH reactions were induced (day 0) in lethally irradiated (C57BL/6 x CBA/J)F1 (H-2b/k) mice by intravenous injection of BALB/c (H-2d) spleen and lymph node cells (3.6 x 10(7)) within 24 h after irradiation. Mice were treated intraperitoneally with a single optimally depleting dose of rat anti-CD8 (YTS 169.4) or untreated. Symptoms of GVHD became obvious 6 days after reconstitution, and mortality started at day 8. The mutual influence of CD4+ and CD8+ T cells in the development of GVHD becomes apparent from our data, and demonstrates that GVHD lethality can be caused by CD8+ T cells as well as by CD4+ T cells.


Asunto(s)
Anticuerpos/uso terapéutico , Antígenos CD8/inmunología , Reacción Injerto-Huésped/efectos de los fármacos , Animales , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD4/inmunología , Citometría de Flujo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Bazo/citología , Subgrupos de Linfocitos T , Factores de Tiempo
15.
Fertil Steril ; 62(6): 1217-20, 1994 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7957987

RESUMEN

OBJECTIVE: To determine prostanoid levels (prostaglandin E2, prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2 [TXB2]) in embryo culture medium containing inactivated maternal serum and their correlation with the clinical outcome of IVF-ET. DESIGN: Prostanoid levels were measured in blank control medium and in medium containing an embryo or nonfertilized oocyte with a high-pressure liquid chromatography (HPLC-RIA) method. Comparisons of HPLC-RIA, Seppak C18-RIA, and RIA directly in the medium demonstrated identical results for TXB2, allowing the use of direct RIA in the large investigation of 129 media. SETTING: Leiden University Hospital, The Netherlands. PATIENTS: Patients with (n = 12) and without (n = 15) an ongoing pregnancy after IVF-ET. MAIN OUTCOME MEASURES: Prostanoid levels in embryo culture medium and relationship between prostanoid levels and successful implantation. RESULTS: Thromboxane B2 is the only prostanoid consistently found in these media. In both groups there was no difference in TXB2 levels between control media, media containing a nonfertilized oocyte, and media containing an embryo. There was no difference in TXB2 levels between media that had harbored the beginning of a successful pregnancy and those that had not produced a pregnancy. CONCLUSION: Thromboxane B2 in the embryo culture medium originates from maternal serum and bears no relationship with the likelihood of fertilization and implantation.


Asunto(s)
Medios de Cultivo/metabolismo , Implantación del Embrión , Fertilización In Vitro , Prostaglandinas/metabolismo , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Proyectos Piloto , Radioinmunoensayo , Tromboxano B2/metabolismo
16.
Bone Marrow Transplant ; 14(4): 535-43, 1994 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-7858528

RESUMEN

The effects of rat anti-CD3 and anti-CD4 moAb, of the IgG2a as well as of the IgG2b subclass, on the development of lethal graft-versus-host disease (GVHD) in a fully allogeneic mouse strain combination were compared in vivo. After treatment with these moAb, mice recovered from an initial loss of body weight. Moreover, their survival significantly improved. A single dose of 200 micrograms moAb resulted in a complete and long-term survival, which was not the case after treatment with anti-CD4 IgG2a moAb. A dose of at least 1 mg anti-CD4 IgG2a was necessary to induce a tolerant state. Mice effectively treated were fully repopulated with donor-type cells. Flow cytometric analysis of the recipient spleen cells demonstrated that the moAb caused depletion, modulation or coating of T cells or a combination of these. The moAb with the highest depleting capacity appeared to be anti-CD4 IgG2b moAb. Anti-CD3 IgG2a as well as IgG2b treatment resulted in a strong modulation of CD3 surface proteins, which was found on all days examined. Modulation of CD4 surface antigens did not occur in the case of anti-CD4 IgG2a moAb treatment. Anti-CD4 IgG2b moAb treatment, on the other hand, not only caused some CD4 modulation, but also, quite unexpectedly, a significant modulation of the CD3 molecule. Coating was only observed after treatment with anti-CD4 IgG2a moAb and lasted at least 1 week.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Complejo CD3/inmunología , Antígenos CD4/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Inmunoglobulina G/uso terapéutico , Isotipos de Inmunoglobulinas/uso terapéutico , Linfocitos T/inmunología , Animales , Peso Corporal , Quimera , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos CBA
17.
Bone Marrow Transplant ; 13(3): 293-301, 1994 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8199571

RESUMEN

Lethal GVHD in the fully allogeneic BALB/c (donor)-(C57BL x CBA)F1 (recipient) mouse strain combination could be prevented by a single dose of IgG2b monoclonal antibodies (moAb) directed to T cells. The influence of the time of administration of this moAb after GVHD induction and the effect of anti-T cell subset moAb on the development of GVHD was investigated in this study. Moreover, the state of tolerance in the mice that had become long-term chimeras was examined. Anti-Thy-1 treatment of the recipients 1 day before, 2 h before or 1 day after reconstitution almost completely prevented lethal GVHD. A single dose of 100 micrograms of anti-Thy-1 was as effective as four daily doses of 25 micrograms each. Treatment with a single dose of 25 micrograms or with intervals of 4 days between doses of 25 micrograms was statistically significantly less effective. We injected the recipients with moAb directed to the CD4+ or CD8+ T cells subsets. Using a dose of 100 micrograms moAb, anti-CD4 treatment appeared to be less effective than anti-Thy-1 treatment whereas anti-CD8 treatment was not effective at all. A double dose of anti-CD4 was equally effective as anti-Thy-1 treatment. All mice that became long term survivors remained free of signs of GVHD and were > 99% repopulated with donor type cells. Injection of spleen cells from these BALB/c into (C57BL x CBA)F1 chimeric mice was used to reconstitute lethally irradiated BALB/c, BALB.K and (C57BL x CBA)F1 recipients. Lethal GVHD developed in the BALB.K and (C57BL x CBA)F1 recipients but not in the BALB/c recipients.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Terapia de Inmunosupresión , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Antígenos CD4/análisis , Antígenos CD4/inmunología , Antígenos CD8/análisis , Antígenos CD8/inmunología , Quimera , Relación Dosis-Respuesta a Droga , Femenino , Técnica del Anticuerpo Fluorescente , Enfermedad Injerto contra Huésped/inmunología , Tolerancia Inmunológica , Isoanticuerpos/inmunología , Isoanticuerpos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Bazo/citología , Factores de Tiempo
18.
Prostaglandins ; 43(6): 567-72, 1992 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-1410521

RESUMEN

The effects of treatment with the synthetic long-acting somatostatin analogue SMS-201-995 were studied in a patient with a fluid and electrolyte secreting villous adenoma of the rectum. The effects of SMS-201-995 on rectal fluid volume and electrolyte loss, and local and general prostanoid production were compared with those of treatment with indomethacin. During treatment with the somatostatin analogue iso-osmolar rectal fluid production increased about 25%; the quantity of prostaglandin E2 in the rectal fluid rose almost 20-fold. Prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha and 13,14-dihydro-15-keto-prostaglandin F2 alpha output showed similar, though less impressive increments during somatostatin treatment. The somatostatin analogue did not affect urinary prostanoid excretion except for levels of 2,3-dinor-thromboxane B2, which doubled. With indomethacin treatment diurnal rectal fluid production dropped by about 50% and all prostanoids measured in urine and rectal fluid decreased below control values. It appears that the somatostatin analogue SMS-201-995 has a marked stimulatory effect on the in vivo prostanoid production by the villous adenoma. Perhaps this stimulation is not confined to the tumor only, but also affects thromboxane synthesis.


Asunto(s)
Adenoma/complicaciones , Diarrea/tratamiento farmacológico , Indometacina/uso terapéutico , Octreótido/uso terapéutico , Neoplasias del Recto/complicaciones , Adenoma/metabolismo , Anciano , Líquidos Corporales/metabolismo , Diarrea/etiología , Electrólitos/metabolismo , Humanos , Masculino , Prostaglandinas/biosíntesis , Prostaglandinas/orina , Neoplasias del Recto/metabolismo
19.
Prostaglandins ; 42(2): 137-50, 1991 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-1775636

RESUMEN

We have recently demonstrated that corticotropin releasing hormone (CRH) potentiates the contractile response to oxytocin of human gestational myometrium, using a high flow microsuperfusion system and electrical field stimulation. We now report this potentiation to be equivalent to that of 1 nM prostaglandin F2 alpha (PGF2 alpha), while 10 nM PGF2 alpha did not potentiate the response to oxytocin. Prostaglandin E2 (PGE2) also showed no augmentation of the contraction force of the myometrium in response to oxytocin. The CRH potentiated response was inhibited by the lipoxygenase and cyclooxygenase inhibitor BW755C (1 microM) and by indomethacin (0.1 microM), but not by the lipoxygenase inhibitor BW4C (1 microM). Measurements of prostaglandins in the superfusate showed no significant trends. It is concluded that the potentiation of contraction force to oxytocin by CRH is dependent on prostaglandins, probably PGF2 alpha and that leukotrienes, generated via the lipoxygenase pathway are not involved.


Asunto(s)
Bencenoacetamidas , Hormona Liberadora de Corticotropina/farmacología , Dinoprost/farmacología , Leucotrienos/fisiología , Miometrio/efectos de los fármacos , Oxitocina/farmacología , Contracción Uterina/efectos de los fármacos , 4,5-dihidro-1-(3-(trifluorometil)fenil)-1H-pirazol-3-amina/farmacología , Dinoprostona/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Humanos , Ácidos Hidroxámicos/farmacología , Indometacina/farmacología , Inhibidores de la Lipooxigenasa/farmacología , Miometrio/citología , Embarazo
20.
Eur J Obstet Gynecol Reprod Biol ; 35(1): 15-21, 1990 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-2107105

RESUMEN

Urinary TXB2 and 6-keto-PGF1 alpha were measured by high pressure liquid chromatography combined with radioimmunoassay, in order to determine whether or not urinary excretion of 6-keto-PGF1 alpha and TXB2 followed a same pattern in pregnancy and labor. The excretion of 6-keto-PGF1 alpha was higher than that of TXB2 in both non-pregnant and pregnant women, but the ratio between them increased in pregnancy. The urinary excretion of both 6-keto-PGF1 alpha and TXB2 excretion was significantly increased (p less than 0.001) in pregnancy. Labor was associated with a much wider inter-individual variation in the excretion of 6-keto-PGF1 alpha and TXB2 than observed in pregnancy and in non-pregnant women. Also, the ratio between the two compounds varied more in labor than in pregnancy. The data indicate that the urinary levels of these two compounds do not follow a single well-determined pattern in pregnancy and labor.


Asunto(s)
Epoprostenol/orina , Trabajo de Parto/orina , Embarazo/orina , Tromboxanos/orina , 6-Cetoprostaglandina F1 alfa/orina , Adulto , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Radioinmunoensayo , Tromboxano B2/orina
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