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Biomedical subjects

J C Voltarelli

Publications and source records attributed to J C Voltarelli.

At least 19 recordsLinked to original sources
PubMed2007

Mesenchymal stem cells from patients with chronic myeloid leukemia do not express BCR-ABL and have absence of chimerism after allogeneic bone marrow transplant.

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.

Adolescent↗
PubMed2006

Secondary prevention of type 1 diabetes mellitus: stopping immune destruction and promoting beta-cell regeneration.

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.

Adolescent↗
PubMed2004

Immunological effects of donor lymphocyte infusion in patients with chronic myelogenous leukemia relapsing after bone marrow transplantation.

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.

Adult↗
PubMed2003

Hematopoietic stem cell transplantation for autoimmune diseases in developing countries: current status and future prospectives.

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.

Autoimmune Diseases↗
PubMed2001

Influence of menstrual cycle on NK activity.

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.

Adult↗
PubMed2000

HLA class I and class II profiles of patients presenting with Sydenham's chorea.

Sydenham's chorea (SC) may occur in rheumatic fever (RF) patients without arthritis and carditis. In this study we typed HLA antigens and alleles in patients presenting with the distinct major clinical manifestations of RF, i.e., chorea, carditis, or arthritis, in population and family studies. We evaluated 91 patients with RF for HLA-A, HLA-B, and HLA-DR antigens; of these, 33 had pure chorea, 26 pure carditis, 16 pure arthritis, and 16 carditis plus arthritis. We also typed 24 SC patients and their unaffected siblings for HLA-DRB1 and HLA-DQB1 alleles using molecular methods. HLA-B49 and HLA-DR1 antigens were overrepresented in the total group of patients with RF and in all the subgroups studied, excluding the SC subgroup in which the frequency of HLA-DR1 antigen was not increased. The frequencies of the HLA-DRB1 and HLA-DQB1 alleles in patients with pure chorea were not significantly different from those observed in controls. Similarly, the frequencies of HLA class II alleles in SC patients did not differ significantly from those observed in unaffected siblings. These findings show that immunogenetic susceptibility to RF varies according to the major clinical manifestation presented by the patient.

Adolescent↗
PubMed1998

Association of Alport's syndrome with HLA-DR2 antigen in a group of unrelated patients.

A few family studies have evaluated HLA antigens in Alport's syndrome; however, there are no large population studies. In the present report, we studied 40 unrelated white patients with Alport's syndrome seen at the Unit of Renal Transplantation, Faculty of Medicine of Ribeirão Preto, São Paulo, Brazil. HLA-A, -B, -DR and -DQ antigens were typed using a complement-dependent microlymphocytotoxicity assay. A control white population (N = 403) from the same geographical area was also typed for HLA antigens. Although the frequencies of HLA-A and -B antigens of patients were not statistically different from controls, the frequency of HLA-DR2 antigen observed in patients (65%) was significantly increased in relation to controls (26%; P < 0.001). The relative risk and etiologic fraction for HLA-DR2 antigen were 5.2 and 0.525, respectively. Although few immunological abnormalities have been shown in Alport's syndrome, in this report we emphasize the association of HLA molecules and Alport's syndrome. Besides the well-known inherited molecular defects encoded by type IV collagen genes in Alport's syndrome, the major histocompatibility alleles may be in linkage disequilibrium with these defective collagen genes.

Adolescent↗
PubMed1996

Phenotypic and functional evaluation of natural killer cells in thymectomized children.

The purpose of this study was to determine the effect of thymectomy on the number and activity of NK cells in the peripheral blood of children submitted to thymus removal. Twenty-three children, aged 4 to 48 months at thymectomy, whose thymus was fully removed to permit access to the heart for corrective surgery, were studied. Only children thymectomized during the first year of life had a decreased number of CD2+/CD3+, CD4+/CD16- , and CD8+/CD16- T subsets and an increase in the CD16-/CD56bright+ NK subset. In addition, the CD57-/CD16+ and CD57-/D56+ subsets which are shared by T and NK cells were increased. These findings associated with a tendency to increased NK activity suggest that the human thymus is partially involved in the control of the release of circulating T cells and may negatively modulate some NK subsets, as well as NK activity, during the first year of life but not later.

Adolescent↗
PubMed1996

Regulation of Trypanosoma cruzi infection in mice by gamma interferon and interleukin 10: role of NK cells.

Gamma interferon (IFN-gamma) plays an important role in experimental Trypanosoma cruzi infections, presumably by controlling the early replication of parasites in host macrophages. In this work, we show that NK cells represent an important cell type responsible for the production of most of the IFN-gamma in the early stage of T. cruzi infection and that the in vivo treatment of mice with anti-NK1.1 monoclonal antibody made resistant animals susceptible to the infection. Through in vitro experiments, we demonstrate that normal splenocytes from euthymic or athymic nude mice cultivated for 48 h with live T. cruzi trypomastigotes produced elevated levels of IFN-gamma. In addition, NK-depleted splenocytes show a drastic reduction of IFN-gamma production in response to live T. cruzi trypomastigotes. We also demonstrated that IFN-gamma production is dependent on a factor secreted by adherent cells. Supernatants of spleen cells from athymic nude mice are able to induce IFN-gamma production by normal splenocytes when cultured with trypomastigotes. The addition of anti-interleukin-10 to these cultures resulted in a marked increase in IFN-gamma production. On the other hand, the absence of NK cells led to an increased secretion of interleukin-10 upon in vitro stimulation with T. cruzi. Taken together, these results suggest that NK cells are the major source of IFN-gamma that could be involved in limiting the replication of T. cruzi in host macrophages during the early acute phase of the infection.

Animals↗
PubMed1995

NK and LAK functions in human chronic Chagas disease.

Natural killer (NK) and lymphokine activated killer (LAK) functions were measured in 40 patients with chronic Chagas disease divided into asymptomatic/indeterminate (18) and symptomatic forms (22) and in 24 healthy controls. A chromium release assay was used employing K562 or P815 cell lines as targets. There was no difference in either NK or LAK activity between the three groups. A small number of patients in each group showed results above or below the normal range for controls. However, there was no correlation between NK and LAK values in the same individual. In conclusion, NK immunosuppression associated with human chronic Chagas disease.

Cell Line↗
PubMed1994

Expansion of a subset of TCR gamma/delta human lymphocytes from various lymphoid organs cultured with recombinant IL-2.

1. TCR1 cells are a minor component of CD3+ lymphocytes which bear the gamma/delta T-cell receptor. There are limited data concerning the activation of TCR1 cells or TCR1 cell subsets in human lymphoid organs. We analyzed a subset of TCR1 cells (delta TCS1+) in peripheral blood (PBL), spleen (SPL), lymph nodes (LN), bone marrow (BM), and thymus (THY) after activation with IL-2. Lymphoid cells from these organs were cultured with 1500 U/ml IL-2 for 14 days and analyzed at periodic intervals for delta TCS1+ cells. 2. We found increased numbers of delta TCS1+ cells in 6- and 14-day cultures from SPL (20.8 +/- 11.8% positive cells after 14 days of culture), LN, BM and THY but not in peripheral blood (1.8 +/- 0.9%). These delta TCS1+ cells coexpressed CD2, CD3, CD8 and CD56, but were negative for TCR alpha/beta and CD4. We also detected an expansion of TCR1+ cells in IL-2-stimulated PBL employing the pan-gamma/delta marker TCR delta 1; however, in contrast to solid organs, these TCR1+ cells were delta TCS1 negative. 3. Sorting experiments demonstrated directly that delta TCS1 cells from spleen cultures mediate high cytotoxic activity against K562 cell targets (39.4% median specific cytotoxicity) and low activity against Daudi (9.6%), COLO (2.7%) and an antibody-sensitized human B-cell line (17%). 4. These results show expansion and cytotoxic activation by IL-2 of a subset of human TCR1 cells in solid lymphoid organs.

Cells, Cultured↗
PubMed1993

Adhesion of CD16+ K cells to antibody-coated targets is mediated by CD2 and CD18 receptors.

In order to investigate the function of CD2 and CD18 receptors in antibody-dependent cellular cytotoxicity (ADCC), Fab' fragments of the monoclonal antibodies 9.6 (anti-CD2) and 60.3 (anti-CD18) were preincubated with the human natural killer (NK) clone EB4.19 and tested for conjugate formation and cytotoxic function against the human B-cell line KMS and the mouse thymoma line SL-2. We concluded that: (1) the FcR CD16 does not participate in conjugate formation; (2) adhesion between target and effector cells mediated by CD2 and CD18 is a prerequisite for subsequent activation of the lytic programme through the CD16 receptor.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1993

Adrenal response to adrenocorticotropin hormone and HLA typing of subjects with different degrees of 21-hydroxylase deficiency.

1. To evaluate different degrees of 21-hydroxylase (21-OH) deficiency we studied the 17-hydroxyprogesterone (17-OHP) and cortisol response to the adrenocorticotropin hormone (ACTH) stimulation test. In a study of 13 families we characterized the relatives of patients with classical 21-OH deficiency using HLA antigen typing and the ACTH test. The subjects were divided into five groups: 12 patients with the classical form, 11 patients with the nonclassical form, 38 heterozygotes, 6 normal homozygotes and 33 controls. 2. The 17-hydroxyprogesterone response to ACTH (mean +/- SD) varied as follows according to the degree of 21-OH deficiency: 25442 +/- 15718 ng/dl for the classical group, 4198 +/- 1637 ng/dl for the nonclassical group, 348 +/- 267 ng/dl for the heterozygotes, 127 +/- 81 ng/dl for normal homozygotes, and 164 +/- 120 ng/dl for the controls. Basal plasma cortisol did not differ among the five groups. The cortisol response to ACTH was not different among controls (30 +/- 8 micrograms/dl), normal homozygotes (28 +/- 7 micrograms/dl) and heterozygotes (26.5 +/- 7 micrograms/dl). The cortisol response was decreased in the patient groups and was lower in the classical (14 +/- 10 micrograms/dl) than in the nonclassical group (20 +/- 4 micrograms/dl). 3. In most families (11/13), HLA typing was informative in identifying the 21-OH deficiency containing haplotype, which correlated with the hormonal profile. In two families there was no correlation between the HLA genotype and the clinical expression of 21-OH activity for two HLA identical pairs of siblings.

Adolescent↗
PubMed1992

Malignant T gamma/delta lymphoproliferative disease with natural killer lytic activity.

A 17-year-old girl presented with a lymphoproliferative disease involving the bone marrow, peripheral blood, and liver associated with reactive hyperplasia of the spleen. Neoplastic cells were atypical medium-sized lymphoblasts with convoluted nuclei and nucleoli without features of large granular lymphocytes (LGL). The phenotype was CD3+ CD4- CD8-, TCR alpha/beta-, TCR gamma/delta+, delta TCS1-, and CD16+, and these cells exhibited spontaneous natural killer (NK) activity. DNA analysis showed rearrangement of the TCR gamma gene but not of TCR beta or of Ig mu genes. This unusual lymphoproliferative disease may represent the neoplastic expansion of a minor subset of normal T gamma/delta cells with NK activity.

Adolescent↗