Biomedical subjects

A Ageitos

Publications and source records attributed to A Ageitos.

9 recordsLinked to original sources

PubMed2001

Potential for cytokine and product manipulation to improve the results of autologous stem cell transplantation for rheumatoid arthritis.

The eradication of autoreactive T cells by high dose therapy and stem cell transplantation and the resultant alterations in the immunologic network, thymic reeducation, and peripheral tolerance provide treatment mechanisms for autoimmune and inflammatory diseases. One outcome of autologous stem cell transplantation is a significant decrease in the CD4:CD8 ratio due to a loss in CD4+ cells and a depression in T cell function. Mechanistically, the loss of T cell function is associated with an increased frequency of circulating monocytes, their expression of Fas ligand (FasL), and a high frequency of apoptotic CD4+ T cells. This suggests that activated Fas+ CD4+ lymphocytes interact with FasL+ monocytes. resulting in apoptosis, preferential deletion of CD4+ T cells, an inversion in the CD4:CD8 ratio, and depressed T cell function. These observations suggest the potential for immune regulation using stem cell manipulation or posttransplant cytokine administration as therapeutic strategies for autoimmune/inflammatory diseases.

Apoptosis↗

PubMed2000

Mechanisms of immune dysfunction in stem cell transplantation.

High dose therapy (HDT) and stem cell transplantation (SCT) results in alterations in the immunologic network, thymic re-education and the induction of peripheral tolerance. The changes to the immunoregulatory cascade and tolerance induction associated with autotransplants have been investigated in a series of studies focused on leukocyte reconstitution and function following HDT and autologous SCT. In these studies, we observed a significant decrease in the CD4:CD8 T cell ratio post-transplantation compared to normal peripheral blood (PB) donors due to a decrease in CD4+ cells. In addition, T cell function (phytohemagglutinin (PHA) mitogenesis) was consistently depressed compared to samples obtained from normal PB donors. The loss of T cell function was associated with an increased frequency of circulating monocytes, their expression of Fas ligand (FasL) and a high frequency of apoptotic CD4+ T cells. Indeed, 28-51% of circulating CD4+ T cells were observed to be apoptotic during the first 100 days following HDT and SCT. These studies suggest that 'primed' or activated Fas+ CD4+ lymphocytes interact with FasL+ monocytes, resulting in apoptosis, leading to the preferential deletion of CD4+ T cells, a decrease in the CD4:CD8 T cell ratio and depressed T cell function. Further, as discussed herein, the T cells are activated with a predominantly type 2 phenotype, which may also contribute to the maintenance of the immunosuppressive condition. Therefore, there is the potential to regulate immune recovery by stem cell product manipulation or post-transplantation cytokine administration.

Antineoplastic Agents↗

PubMed2000

Growth factor mobilization and modulation of progenitor cell adhesion to stromal cells: role of VLA-4.

Cellular interactions between hematopoietic progenitor cells and bone marrow (BM) stromal cells are mediated by cell adhesion molecules (CAM). In agreement with previous studies, our flow cytometric analysis of isolated CD34+ cells showed that VLA-4 expression was significantly (p < 0.001) higher on steady-state BM than on CD34+ cells from growth factor-mobilized peripheral stem cell (PSC) products. To determine whether the expression of VLA-4 on progenitor cells plays a role in their adhesion to stromal cells, we examined the binding of isolated CD34+ progenitor cells from BM (n = 14) and PSC (n = 10) products to BM stromal cells in the presence or absence of a neutralizing antibody to VLA-4. In these studies, similar kinetics of BM and PSC CD34+ cell adhesion to BM stromal cells were observed. However, neutralizing antibody to VLA-4 significantly inhibited BM CD34+ but not PSC CD34+ cell adherence to stromal cells, suggesting a role for alternative CAM in cell binding. Further, in long-term co-cultures of BM CD34+ cells with BM stroma, we observed a significantly higher number of colony-forming units granulocyte-macrophage (CFU-GM) released into the media following treatment with neutralizing antibody to VLA-4 than in untreated control cultures. In contrast, no difference in the frequency of nonadherent CFU-GM between antibody-treated and control long-term co-cultures of PSC CD34+ cells with BM stromal cells was observed. This suggests that VLA-4 expression on mobilized PSC versus BM CD34+ cells has biologic relevance for at least 2 weeks based on the long-term BM culture results. In summary, these data suggest that the decreased expression of VLA-4 may have a role in the mobilization of progenitor cells, in part, by regulating their adherence to stromal cells, although additional mediators of adhesion are also involved.

Adult↗

PubMed1999

Impaired T and NK cell response of bone marrow and peripheral blood stem cell products to interleukin (IL)-2.

The function of steady-state and interleukin (IL)-2-co-cultured mononuclear cells differs significantly between bone marrow (BM) products, growth factor-mobilized peripheral blood stem cell (PSC) products and normal peripheral blood mononuclear cells (PBMC). The natural killer (NK) cell activity and T cell proliferative response of PSC products from non-Hodgkin's lymphoma (NHL) patients are significantly higher than that of BM products and similar to normal PBMC. However, following a five-day co-culture with IL-2 (100 IU/ml), the NK activity of PSC, PBMC, and BM products (lytic units) was increased 176-, 40-, and 14-fold, respectively, compared to that observed prior to IL-2 culture. In contrast, lymphokine activated killer (LAK) cytotoxicity prior to IL-2 culture was low in PSC and BM products and normal PBMC, but was significantly increased in PSC products and PBMC following IL-2 co-culture. The proliferative response of PSC and BM products to the T cell mitogen phytohemagglutinin (PHA) was significantly lower than that observed with normal PBMC; however, PSC had a significantly higher response than cells from BM products. Similar patterns of T cell PHA mitogenic response were observed after IL-2 co-culture. In addition, the IL-2 mitogenic responses of IL-2-co-cultured PSC and BM products were also significantly lower than that observed with PBMC co-cultured with IL-2. The IL-2 mitogenic response of PBMC was also significantly increased compared to prior to IL-2 co-culture; whereas, the IL-2 mitogenic responses from PSC and BM cells were not. In summary, co-culture with IL-2 can increase the NK and LAK cell cytotoxicity of PSC and BM products from NHL patients, but IL-2 co-culture does not improve T cell function within either BM or PSC products.

Adult↗

PubMed1998

Chylopericardium of neoplastic aetiology.

Here we present the case of a 30-year-old man diagnosed with a dysgerminoma with mediastinal involvement, who developed an isolated chylopericardium during treatment. The purpose of this paper is to review the etiology, diagnosis and new approaches to the treatment of chylopericardium.

Adult↗

PubMed1998

Enhancement of adenovirus-mediated gene transfer to human bone marrow cells.

Adenovirus infection of CD34+ hematopoietic stem/progenitor cells is dependent on the multiplicity of infection (MOI), time of incubation, the volume in which the co-incubation occurs and the presence or absence of growth factors. Studies revealed that a brief co-incubation (1-8 hours), resulted in low levels of transgene expression, suggesting that adenovirus infection of CD34+ cells occurs slowly, and optimal transduction requires a 24 hour exposure to adenovirus. Infection by Ad/beta-gal or Ad/p53 at a MOI of 500:1 provided a high transduction efficiency but inhibited hematopoietic function. However, treatment at a MOI of 50-100 resulted in efficient transduction (10.7-15.7% positive) without detectable toxicity. Secondary proof of adenovirus transgene expression was demonstrated by detection of mRNA for p53 in Ad/p53 infected stem cells. We conclude that a 24 hour exposure to recombinant adenovirus encoding p53 or beta-gal, at a MOI of 50-100 is optimal for in vitro gene transfer to BM cells and has no significant effect on hematopoietic function. Adenovirus-mediated transduction of BM cells can also be modulated by growth factors (IL-3, GM-CSF and G-CSF) with improved gene delivery and maintenance of hematopoietic function. In summary, adenovirus vectors can be used to transiently transduce stem cells, and conditions have been defined to maximize expression and limit inhibitory effects on CD34+ cells. These data support continued investigation of this vector for local cytokine delivery and purging of stem cell products.

Adenoviruses, Human↗

PubMed1995

[Expression of latent membrane protein (LMP) in large-cell anaplastic lymphomas].

PURPOSE: The presence of Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP) was investigated in 40 cases of lymphoproliferative diseases which include Hodgkin's disease (HD), anaplastic large cell lymphoma (ALCL) and non-Hodgkin's lymphoma (NHL) of B and T-cell nature. MATERIAL AND METHODS: All cases were immunophenotyped in paraffin-embedded lymph node tissues, with a complete panel of monoclonal antibodies against B-cells, T-cells, histiocytes, activation and proliferation markers and classified as: 24 anaplastic large cell lymphoma (ALCL, 8 classical type and 16 ALCL-HD related), 10 lymphocyte predominant HD (LP, 5 classical type and 5 with ALCL areas), 4 NHL (two T-Cell type and 2 T-cell rich B-cell NHL). Immunohistochemistry techniques were performed ABC-complex and phosphatase alkaline anti-phosphatase alkaline (APAAP). RESULTS: LMP was detected in 35% (14/40) of total cases. In LP group one third of cases were LMP+. In ALCL-HD related cases 44% were LMP+ versus 13% in ALCL group. All LMP cases were CD30+ except one NHL-T and a T-cell rich B-cell NHL. The predominant immunophenotype was LMP+/CD20+ (57%) versus LMP+/CD20-. Most cases were of B-cell (36%) lineage. Null ALCL cases were LMP-. CONCLUSIONS: LMP, the most oncogenic EBV protein could play a pathogenic role in lymphoproliferative processes. It is not exclusive of HD and appears in other NHL preferentially of B-cell nature, above all in ALCL cases relating the two neoplasias HD and ALCL, both CD30 positive.

Herpesvirus 4, Human↗

PubMed1995

[Large-cell anaplastic lymphomas: a genetic and immunophenotypic study].

PURPOSE: To characterize from a genetic point of view a group of non-Hodgkin's anaplastic large-cell lymphomas (ALCL) by Southern blot and PCR methods with different probes (molecular study) and with direct or post 24-78 hours cultures with GTC banding techniques (cytogenetic). To correlate the results to the immunophenotype performed with a complete panel of monoclonal antibodies (MoAb) according to avidin-biotine and alkaline phosphatase (APAAP) methods. MATERIAL AND METHODS: Sixty cases of ALCL were reviewed and only 19 selected (with frozen or fresh material) because a complete immunohistologic and genotypic correlation had been done. According to CD15 expression two groups were considered, CD15+ (the so-called Hodgkin's related or Hodgkin's like) and CD15- or classical type. RESULTS: Only 26.5% of cases showed immuno -genotypic correlation. Immunohistochemistry is an accurate method for activation, proliferation and B-cell nature, but T-cell cases were not stained because T-cell paraffin markers are not completely specific. CD15 group had only 30% rearranged cases with scarce cytogenetic abnormalities, as it occurs in Hodgkin's disease (HD). ALCL classical type showed 66% rearranged cases, and one of the T-cell cases showed an incomplete t (2:5) translocation or polyploid cell lines. CONCLUSIONS: Both groups have different genetic and immunophenotypic behaviour which resembles HD or NHL. CD15 positive cases or ALCL HD-related constitute a borderline entity which has to be recognized because of the different therapy and clinical behaviour.

Hodgkin Disease↗

PubMed1995

[T-cell-rich B-cell lymphoma: multifactorial study of 4 cases].

PURPOSE: With the correlational study of four cases in several areas (clinic, morphoimmunologycal, ultrastructural and genetic) we try to valorate the still controversial entity known as T-cell rich B-cell lymphoma (TRBL), and stablish some useful clues in order to settle down the differential diagnosis between TRBL, Hodgkin's disease (HD), and T-cell non-Hodgkin's lymphomas (TNHL). PATIENTS AND METHODS: Cases proceeded from Oncology Department, and had been firstly misdiagnosed either as HD (3 cases) or as TNHL (1 case). Biopsies were processed and stained in routine way, H&E, Giemsa and Wilder. Immunohystological study, using monoclonal antibodies against B-cells, T-cells, histiocytes, activation and proliferation markers, was also performed with avidin biotine peroxidase (ABC) method. Ultrastructural study was performed in three of the cases; two patients were studied by PCR and Southern blot. RESULTS: All of the cases showed a diffuse hystological pattern, with variable fibrosis, and proliferation of venules and capillaries. Small lymphoid cells, being positive for CD3, were dominant. Large blastic cells, positive for CD20, some of them with a Sternberg-like appearance, could be found, in a spitty pattern. Histiocytes were abundant and positive to CD68. Proliferation index (Ki-67) ranged between 13 and 24.5% being the stain mainly positive for B-cells and in a certain extent, also for T-cells. Ultrastructural features were closer to those of the NHL than to the ones found in HD. Molecular study failed to prove any rearrangement. CONCLUSIONS: TRBL is a rare entity between B-cell NHL group. Diagnosis and differential diagnosis (mostly with HD and T-cell NHL) have to be properly made, because of the very distinct prognosis and therapy.

Adult↗