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Biomedical subjects

E Gluckman

Publications and source records attributed to E Gluckman.

At least 91 records · Page 5Linked to original sources
PubMed1999

Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study.

Agnogenic myeloid metaplasia (AMM) is a chronic myeloproliferative disorder in which patients with poor prognostic features, receiving conventional treatments, have a median survival of less than 3 years. In this retrospective multicenter study, we analyze the results and try to define the indications for allogeneic stem cell transplantation in AMM. From January 1979 to November 1997, 55 patients with a median age of 42 years were transplanted from HLA-matched related (n = 49) or alternative (n = 6) donors for AMM. A multivariate analysis was conducted to identify factors associated with posttransplant outcome. The median posttransplant follow-up was 36 months (range, 6 to 223). The 5-year probability of survival was 47% +/- 8% for the overall group, and 54% +/- 8% for patients receiving an unmanipulated HLA-matched related transplant. The 1-year probability of transplant-related mortality was 27% +/- 6%. Hemoglobin level </=100 g/L and osteomyelosclerosis before transplant adversely affected the outcome. The probability of developing grade III-IV acute graft-versus-host disease (GVHD) was 33% +/- 8%. Sixteen of 45 patients developed extensive chronic GVHD. At last follow-up, 22 patients were in complete histohematologic remission. Treatment failure was observed in 13 cases. Age at transplant and karyotype were predictors of treatment failure. Allogeneic stem cell transplantation is an effective treatment leading to cure in a substantial number of patients with AMM. A better characterization of the variables affecting the posttransplant outcome should lead to a decreased transplant-related mortality and an improvement in these results.

Adult↗
PubMed1999

Effective depletion of alloreactive lymphocytes from peripheral blood mononuclear cell preparations.

BACKGROUND: T cells present in an allogeneic bone marrow transplant may produce graft-versus-host disease but also contribute to immune reconstitution and enhance engraftment. Our aim was to separate alloreactive from nonalloreactive T lymphocytes, by performing a mixed lymphocyte culture (MLC) stimulation of donor cells, followed by selective depletion of activated cells expressing the high-affinity interleukin 2 receptor. We then characterized the resulting depleted cell fraction. METHODS: Donor peripheral blood mononuclear cells were cocultured with irradiated peripheral blood mononuclear cells from HLA-nonidentical recipient stimulators in an MLC. After 3 days, CD25+ lymphocytes (alloreactive cells expressing the alpha chain of the interleukin 2 receptor) were removed by immunomagnetic separation. The depleted donor fraction and untreated cells were then rechallenged in a secondary MLC with the original irradiated stimulator cells or a third party to assess relative alloreactivity. RESULTS: Inhibition of the secondary MLC and of host-specific cytotoxic activities was observed as well as a disappearance of interleukin 2 receptor-positive cells. Alloreactivity against unrelated third-party cells was preserved. Limiting dilution analysis of residual alloantigen-reactive T lymphocytes demonstrated a 1.3 log reduction of antihost reactivity. The depletion largely removed host-specific alloreactive CD4+ cells. CONCLUSIONS: This method reduces alloreactivity while retaining reactivity against third-party targets. This approach may allow therapeutic infusion of T cells after HLA-nonidentical allografts with a reduced capacity to produce graft-versus-host disease.

Blood Component Removal↗
PubMed1999

Analysis of the cytokine production by cord and adult blood.

To date, over 400 human umbilical cord blood cord blood (CB) transplants have been reported from different centres world-wide and it is generally agreed that CB represents an encouraging alternative to bone marrow (BM) transplantation. There are a variety of reasons for this which include the wider availability and easier access of CB compared to BM. In addition it has been suggested that there is a reduced graft-versus-host-disease (GvHD) with CB compared to BM transplantation. The explanations for this implied benefit are numerous, but research into this area is only just beginning. Nevertheless, it is clear that both T cells and natural killer (NK) cells have reduced function when isolated from CB compared to adult and both these cell types have been implicated in GvHD pathogenesis. How and why the function is reduced is yet to be determined. Many laboratories have tried to answer these questions and the majority have done this by comparing the function of lymphocytes obtained from adult blood with those compared with CB. Since cytokine production by a cell is an indication of the cells function it is important to determine the differences between adult and CB with respect to production of these soluble factors. Here, we have reviewed the current research regarding these CB and adult cell comparisons with an emphasise on cytokine production. Our aim is to obtain a clearer understanding of the mechanisms which may be involved in causing a reduced GvHD in CB compared to BM transplantation.

Adult↗
PubMed1999

Allogeneic transplantation from donors other than HLA-identical siblings.

The decade of the 1990s has witnessed impressive advances in the use of alternative donors for allogeneic transplantations. Through funded collaborative, and single-center research efforts, there is great promise that complete and equal access to allogeneic transplantation will be realized. In the next decade, universal donor availability should maximize the patient's chance of overcoming otherwise fatal disease.

Bone Marrow Transplantation↗
PubMed1999

Hepatic veno-occlusive disease.

Hepatic veno-occlusive disease (VOD) after stem cell transplantation is a toxic manifestation of the conditioning regimen most probably emphasized by the allogeneic reaction. Its overall mortality rate is < 4% in adults as well as in children. Recent progress has been achieved in the diagnosis of this complication. However, better methods of both prophylaxis and treatment are needed.

Adult↗
PubMed1999

Human herpes virus 8 (HHV8) serology in allogeneic bone marrow transplant recipients.

Human herpes virus 8 (HHV8) may be sexually transmitted, but transmission via blood cells has not yet been excluded. We used a modified immunofluorescence assay to detect Ab to HHV8 latency-associated nuclear Ag in sera of 200 allogeneic BMT recipients and their related donors. In control subjects, Ab were found in 85% of patients with AIDS-related Kaposi sarcoma (n = 52), 34% of HIV-1 infected subjects without Kaposi sarcoma (n = 56) and 9. 5% of blood donors (n = 42). Among BMT donors, 14.5% were HHV8+, while 10% of recipients were positive before, and 18% after BMT. In the 176 HHV8-negative recipients at BMT, there was no relationship between post-BMT seroconversion, which occurred in 26 cases (15%), and the donor's serological status. Of note, 10 HHV8+ recipients before BMT became negative post-BMT. Outcome of BMT was not influenced by prior HHV8 seropositivity, seroconversion or seroreversion of recipients. That HHV8 seropositivity among blood donors from the Paris area was comparable to that of BMT donors and recipients before BMT indicates that these patients had not been at risk of HHV8 by blood products received before BMT, although post-BMT HHV8 seroconversion probably corresponded to contamination by blood transfusions rather than by the BMT.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Accelerated telomere shortening and telomerase activation in Fanconi's anaemia.

Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure that often evolves towards acute leukaemia. FA also belongs to a group of chromosome instability diseases. Because telomeres are directly involved in chromosomal stability and in cell proliferation capacity, we examined telomere metabolism in peripheral blood mononuclear cells (PBMC). Telomere length was significantly shorter in 54 FA patient samples, compared to 51 controls (P<0.0001). In addition, mean telomere terminal restriction fragment lengths (TRF) in nine heterozygous patient samples did not differ from those of controls. In 14 samples from FA patients with severe aplastic anaemia (SFA), telomere length was significantly shorter than in 22 samples of age-matched FA patients with moderate haematological abnormalities (NSFA) (P<0.001). However, no correlation was found between TRF length and the presence of bone marrow clonal abnormalities in 16 additional, separately analysed, patient samples. Sequential measurement of TRF in six FA patients showed an accelerated rate of telomere shortening. Accordingly, telomere shortening rate was inversely correlated with clinical status. Telomerase, the enzyme that counteracts telomere shortening, was 4.8-fold more active in 25 FA patients than in 15 age-matched healthy controls. A model for the FA disease process is proposed.

Adolescent↗
PubMed1999

Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation.

To determine prognostic factors for survival in bone marrow transplant recipients with invasive aspergillosis (IA), we retrospectively reviewed 27 IA cases observed in our bone marrow transplantation unit between January 1994 and October 1994. On 30 September 1997, six patients were alive and disease-free. The median survival after IA diagnosis was 36 days. Of eight variables found to be related to survival according to the univariate analysis, graft-versus-host disease (GVHD) status at IA diagnosis (P = .0008) and the cumulative prednisolone dose taken during the week preceding IA diagnosis (CPDlw) (P < .0001) were selected by a backward stepwise Cox regression model. A three-stage classification was established: CPD1w of < or =7 mg/kg (3 of 8 patients died; 60-day survival rate, 88%), CPD1w of >7 mg/kg and no GVHD (9 of 10 patients died; 60-day survival rate, 20%), and CPD1w of >7 mg/kg and active acute grade 2 or more or extensive chronic GVHD (9 of 9 patients died; 30-day survival rate, 0) (P < .0001).

Adolescent↗
PubMed1999

Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of the haemopoietic stem cells for which the only curative treatment is bone marrow transplantation. There are few reports on the use of allogeneic transplantation for PNH, and nearly all of them include only a few patients. Between September 1978 and December 1997, 16 patients underwent marrow transplantation for PNH at the Hospital Saint Louis. The 5-year survival rate for the 16 patients was 58 +/- 13%. Two factors, an absolute neutrophil count >1.0 x 109/l and haemoglobin level >9 g/dl at transplant, were found to be statistically associated with a better outcome.

Adolescent↗
PubMed1999

Allogeneic hematopoietic stem cell transplantation: current issues and future prospects.

Major developments have occurred in the field of hematopoietic stem cell transplantation since the first successful transplants from HLA-identical siblings in the late 60's. The formally experimental procedure has become established therapy for a number of congenital or acquired disorders of the hematopoietic system and for chemotherapy-sensitive malignancies. Reduced transplant-related mortality has led to a widening of indications. The present review summarizes current issues and future prospects in allogeneic stem cell transplantation. These issues and prospects will include; stem cell sources, alternative donors, graft-versus-host disease, indications and long-term survival following allogeneic stem cell transplantation.

Acute Disease↗
PubMed1998

Graft-versus-host disease and graft-versus-leukemia effect in mice grafted with peripheral newborn blood.

We previously used peripheral newborn blood (NBB) as a possible in vivo experimental model for cord blood (CB) transplantation and showed that B10.D2 NBB cells successfully reconstituted adult (DBA/2 x B10.D2)F1 mice without causing graft-versus-host disease (GVHD), probably because of their phenotypic and functional immaturity. Here we investigated the influence of T-cell maturation occurring in NBB cells during the early postbirth period on the degree of engraftment, the incidence of GVHD, and the graft-versus-leukemia (GVL) potential. These parameters were compared in recipients grafted with bone marrow (BM) cells. We observed an increased percentage of CD4(+) mature T cells accompanied by the acquisition of proliferative responses to phytohemagglutinin (PHA) and to allogeneic cells of day-5 NBB cells. The capacity of day-2 NBB to engraft was moderately reduced and recipients developing GVHD were occasionally observed after the graft of day-5 NBB cells. No GVL effect was evidenced regardless of the time of postbirth blood collection. However, the GVL effect can be obtained by the delayed infusion of donor mature T cells to recipients grafted with day-0 NBB, without causing GVHD. In contrast, the same protocol applied to mice grafted with BM cells induced GVHD mortality of all recipients. Interleukin (IL)-10 but not IL-2 messenger RNA was expressed in NBB cells as opposed to BM cells. These findings suggest that, in terms of GVHD incidence, delayed infusion of mature T cells as post-transplant tumor immunotherapy would be more effective when applied after CB than after BM transplantation.

Animals↗
PubMed1998

Squamous cell carcinomas after allogeneic bone marrow transplantation for aplastic anemia: further evidence of a multistep process.

BACKGROUND: Secondary solid tumors are rare events occurring in patients who underwent allogeneic marrow transplantation for aplastic anemia and Fanconi's anemia. Human herpes virus 8 (HHV8), Epstein-Barr virus (EBV), and human papillomaviruses (HPV) sequences have been found in squamous cell carcinoma (SCC) occurring in organ transplant recipients. The tumor suppressor gene p53 has been strongly linked to the occurrence of SCC in the nonimmunocompromised population. PATIENTS AND METHODS: In eight patients with SCC, we searched for HHV8, EBV, varicella zoster virus, adenovirus, and HPV sequences from DNA extracted from selected areas of SCC. We also looked for p53 expression in those specimens as well as the presence of anti-p53 antibodies in the serum of these patients at the onset of SCC. RESULTS: In one patient, we found the presence of both HHV8 and EBV sequences, and in another patient we found HPV16 sequences. All five tumors that could be studied disclosed evidence of p53 accumulation, but none of the eight patients had anti-p53 antibodies in the sera. CONCLUSION: SCC developing in marrow transplant recipients seems to occur via a multistep process. Genetic predisposition may be present, as in patients with Fanconi's anemia. Transplantation-related factors, such as irradiation and chronic graft-versus-host disease, also have a role. In this article, we add two more potent risk factors: p53 alteration(s) and in some cases the presence of oncogenic viruses.

Anemia, Aplastic↗
PubMed1998

Hodgkin's disease of donor origin after allogeneic bone marrow transplantation for myelogeneous chronic leukemia.

Secondary malignancies (lymphomas, leukemias, and solid tumors) occurring after bone marrow transplantation are now more frequently reported, as the patients surviving the early phase of the graft and remaining free of their original disease are more numerous. Besides early Epstein-Barr virus-associated B-cell lymphoproliferative diseases, which are the most common type and most often of donor origin, few late-occurring lymphomas have been described that might represent a distinct entity. We report here a case of Hodgkin's disease developing 8 years after allogeneic bone marrow transplantation for chronic myelogeneous leukemia. Only two Hodgkin's diseases after allogeneic bone marrow transplantation have been reported in the literature so far. The case we report is of interest because of its donor origin and its association with Epstein-Barr virus infection.

Adult↗
PubMed1998

The umbilical cord blood alphabeta T-cell repertoire: characteristics of a polyclonal and naive but completely formed repertoire.

Umbilical cord blood (CB) constitutes a promising alternative to bone marrow for allogeneic transplantation and is increasingly used because of the reduced severity of graft-versus-host disease after CB transplantation. We have compared the T-cell receptor beta chain (TCRB) diversity of CB lymphocytes with that of adult lymphocytes by analyzing the complementarity determining region 3 (CDR3) size heterogeneity. In marked contrast to adult samples, we observed bell-shaped profiles in all of the 22 functional beta-chain variable (BV) subfamilies that reflect the lack of prior antigenic stimulation in CB samples. However, the mean CDR3 size and BV usage were comparable between CB and adult samples. BJ2 (65%) segments were used preferentially to BJ1 (35%), especially BJ2S7, BJ2S5, BJ2S3, and BJ2S1, in both CB and in adult lymphocytes. We therefore conclude that although naive as reflected by the heterogeneity of the CDR3 size, the TCRBV repertoire appears fully constituted at birth. The ability to expand TCRB subfamilies was confirmed by stimulation with staphylococcal superantigens toxic shock syndrome toxin-1 and staphylococcal enterotoxin A. This study provides the basis for future analysis of the T-cell repertoire reconstitution following umbilical CB transplantation.

Adult↗
PubMed1998

Allogeneic bone marrow transplantation vs filgrastim-mobilised peripheral blood progenitor cell transplantation in patients with early leukaemia: first results of a randomised multicentre trial of the European Group for Blood and Marrow Transplantation.

In a multicentre trial involving 20 transplant centres from 10 countries haematopoietic stem cells were obtained either from the bone marrow of 33 sibling donors or from the peripheral blood of 33 such donors after administration of filgrastim (10 microg/kg/day). The haematopoietic stem cells were infused into their HLA-identical recipients suffering from acute leukaemias in remission or chronic myeloid leukaemia in chronic phase. PBPC donors tolerated filgrastim administration and leukapheresis well with the most frequent side-effects being musculoskeletal pain, headache, and mild increases of LDH, AP, Gamma-GT or SGPT. Pain and haematoma at the harvest site and mild anaemia were the most frequent complaints of BM donors. Severe or life-threatening complications were not seen with any type of harvest procedure. Time to platelet recovery greater than 20 x 10(9)/l was 15 days (95% confidence interval (CI) 13-16 days) in the PBPCT group and 19 days (CI 16-25) in the BMT group. Time to neutrophil recovery greater than 0.5 x 10(9)/l was 14 days (CI 12-15 days) in the PBPCT group as compared to 15 days (CI 15-16 days) in the BMT group. The numbers of platelet transfusions administered to PBPCT and BMT patients were 12 (range: 1-28) and 10 (range: 3-39), respectively. Sixteen patients (48%) transplanted with bone marrow and 18 patients (54%) transplanted with PBPC developed acute GVHD of grades II-IV; acute GVHD of grades III or IV developed in six (18%) and seven (21%) patients, respectively. Kaplan-Meier plots for transplant-related mortality until day 100 and leukaemia-free survival at a median of 400 days after BMT or PBPCT showed no significant differences. Administration of filgrastim and leukapheresis in normal donors were feasible and well tolerated. The number of days with restricted activity and of nights spent in hospital was lower in donors of PBPC. Transplantation of PBPC to HLA-identical siblings with early leukaemia resulted in earlier platelet engraftment. The incidence of moderate to severe acute GVHD, transplant-related mortality, and leukaemia-free survival did not show striking differences. Further investigation of allogeneic PBPCT as a substitute for allogeneic BMT is warranted.

Adolescent↗