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H G Prentice

Publications and source records attributed to H G Prentice.

At least 73 records · Page 4Linked to original sources
PubMed1998

Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface lymphocyte function-associated antigen-3 (LFA-3) expression and not with the CMV-induced down-regulation of cell surface class I HLA.

CMV and other viruses down-regulate the cell surface expression of class I HLA, and while this allows them to evade CTL, it may make infected cells more susceptible to lysis by NK cells, due to the failure to engage class I inhibitory receptors on the NK cell. We studied CMV infection and found that fibroblasts infected with virus strains Towne, Toledo, Davis, and C1FE were refractory to NK lysis, while those infected with strains AD169, C1F, or R7 were susceptible. All viral strains down-regulated class I HLA to a similar extent, and we concluded that there was no evidence for any correlation between the latter and susceptibility to NK lysis. In contrast, there was a strong correlation between NK killing of CMV-infected cells and cell surface levels of lymphocyte function-associated antigen-3 (LFA-3). Fibroblasts infected with the Towne, Toledo, Davis, and C1FE strains of CMV down-regulated LFA-3 expression and were refractory to lysis, while strains AD169, C1F, and R7 up-regulated LFA-3 and were susceptible to NK killing. U373 MG (malignant glioma) cells expressed constitutively high levels of LFA-3 and were sensitive to NK lysis when infected with any of the above-listed CMV strains. We estimated that a minimum of between 29,000 and 71,000 LFA-3 molecules per target cell were needed for NK susceptibility. The effects on LFA-3 expression were due to immediate early/early viral gene products. We also demonstrated that fibroblasts infected with the strains Towne, Toledo, Davis, and C1FE expressed a ganciclovir-sensitive late CMV gene product, which delivered an inhibitory signal to NK cells.

Antibodies, Blocking↗
PubMed1998

Reconstitution of EBV-specific T cell immunity in solid organ transplant recipients.

EBV-specific autologous CTL were grown in vitro from three adults (two liver transplant recipients and one patient on hemodialysis awaiting kidney retransplant). All CTL lines were TCR alphabeta, CD8 positive cells, EBV specific, and MHC class I restricted. The CTL lines were expanded in vitro and infused in three escalating doses (5 x 10(7), 1 x 10(8), and 2 x 10(8) at monthly intervals. Weekly blood samples were collected following each infusion. EBV-specific CTL precursor cells in peripheral blood were quantitated by limiting dilution analysis, and their effect on EBV load in vivo was assessed by semiquantitative PCR. In all three patients, the numbers of CTL precursor cells increased during the weeks following the infusions and were highest after the third infusion. This level gradually declined but remained above the preinfusion levels for up to 3 mo. EBV genome copy number, on the other hand, dropped following the first infusion and became undetectable thereafter. The EBV DNA level remained lower than the pretransplant level in all patients for up to 3 mo after the last infusion. Our study shows that it is feasible to generate and expand EBV-specific CTL from pretransplant blood samples of solid organ transplant recipients, that these CTL can be stored and infused posttransplant, and that they remain cytotoxic and EBV specific in vivo. The aim of this study is to use these CTL for prevention and treatment of lymphoproliferative disease in solid organ transplant recipients.

Adult↗
PubMed1998

Cataracts after total body irradiation and bone marrow transplantation in patients with acute leukemia in complete remission: a study of the European Group for Blood and Marrow Transplantation.

PURPOSE: Advances in bone marrow transplantation (BMT) have consistently improved long-term survival. Therefore, evaluation of late complications such as cataracts is of paramount importance. METHODS AND MATERIALS: We analyzed data of 2149 patients from the EBMT registry. A cohort of 1063 patients were evaluable for survival and ophthalmologic status after transplant for acute leukemia (AL) in first or second complete remission. Conditioning therapy included either single-dose total body irradiation (STBI) or fractionated TBI (FTBI) grouped in different dose rates (low: LDR < or = 0.04 Gy/min; high: HDR > 0.04 Gy/min). RESULTS: The overall 10-year estimated cataract incidence (ECI) was 50%. It was 60% in the STBI group, 43% in the FTBI group < or = 6 fractions, and 7% in the FTBI group > 6 fractions (p < 10(-4)). It was significantly lower (30%) in the LDR than in the HDR groups (59%;p < 10(-4)). Patients receiving heparin for veno-occlusive disease prophylaxis had fewer cataracts than those who did not (10-year ECI: 33% vs. 53%, respectively;p = 0.04). The 10-year ECI was 65% in the allogeneic vs. 46% in the autologous BMT patients (p = 0.0018). Factors independently associated with an increased risk of cataract were an older age (> 23 years), higher dose rate (> 0.04 Gy/min), allogeneic BMT, and steroid administration (> 100 days). The use of FTBI was associated with a decreased risk of cataract. Heparin administration was a protective factor in patients receiving STBI. In terms of cataract surgery, the unfavorable factors for requiring surgery were: age > 23 yr, STBI, dose rate > 0.04 Gy/min, chronic graft-vs.-host disease (cGvHD), and absence of heparin administration. Among the patients who required cataract surgery (111 out of 257), secondary posterior capsular opacification was observed in 15.7%. CONCLUSION: High dose rate and STBI are the main risk factors for cataract development and the need for surgery, and the administration of heparin has a protective role in cataractogenesis.

Adolescent↗
PubMed1998

RP59500 (Quinupristin/dalfopristin): three case reports of its use in infection due to Enterococcus faecium.

We describe three cases of Enterococcus faecium sepsis arising in immunocompromised patients, severely ill with other conditions, who were treated with the new injectable streptogramin RP59500. There are still few reports of clinical experience with this drug. All had bacteriological resolution, with one patient recovering fully. Although two of the three patients died, this was due to underlying disease in one case and a gram-negative superinfection in another. Quinupristin/dalfopristin therapy was not associated with significant adverse effects in any of the patients.

Adolescent↗
PubMed1998

Use of intravenous immune globulin in addition to antiviral therapy in the treatment of CMV gastrointestinal disease in allogeneic bone marrow transplant patients: a report from the European Group for Blood and Marrow Transplantation (EBMT). Infectious Diseases Working Party of the EBMT.

The best treatment of CMV gastrointestinal disease has been controversial, with some centers adding intravenous (i.v.) Ig to antiviral chemotherapy. The aim of this retrospective survey was to compare the outcome of antiviral chemotherapy with or without i.v. Ig. A questionnaire was sent to centers belonging to the EBMT. Thirty-three patients with CMV gastrointestinal disease were reported, 22 patients were given antiviral chemotherapy alone and 11 patients a combination of antiviral chemotherapy and i.v. Ig. Eighteen of 33 (55%) patients responded to therapy, 13 of those treated with antiviral chemotherapy alone and five (45%) of those treated with the combination (P = NS). Patients with acute GVHD of grades II-IV had significantly worse outcomes than patients with acute GVHD grades 0-I. In a Cox proportional hazards model corrected for acute GVHD there was no difference in outcome of CMV gastrointestinal disease with or without addition of Ig. Survival at 100 days after diagnosis of CMV gastrointestinal disease was 64%. There was no difference in survival in patients treated with or without i.v. Ig. The results of this retrospective survey indicate that addition of i.v. Ig to antiviral chemotherapy might not improve outcome in patients with biopsy-proven CMV gastrointestinal disease.

Adolescent↗
PubMed1998

Longitudinal fluctuations in cytomegalovirus load in bone marrow transplant patients: relationship between peak virus load, donor/recipient serostatus, acute GVHD and CMV disease.

Quantitative competitive PCR was used to monitor the quantity of cytomegalovirus (HCMV) in 1647 blood samples from 110 BMT recipients. DNAemia was detected in 49/110 (45%) of the patients, of whom 15/49 experienced HCMV disease. Peak virus load during surveillance was elevated in symptomatic (median 4.5 log10 genomes/ml) vs asymptomatic patients (median 3.6 log10 genomes/ml, P=0.002) and was also significantly elevated in HCMV seropositive recipients of seronegative marrow, (R+D-, median 5.0 log10), compared to those in the R-D- and R+D+ groups (P < 0.01 and <0.005). Odds ratios for disease per 0.25 log10 increase in viral load, recipient seropositivity and aGVHD were 1.43 (P=0.004), 6.60 (P=0.05) and 3.17 (P=0.08), respectively. In multivariate logistic regression analysis only elevated viral load remained a significant risk factor for HCMV disease. The computed disease probability viral load curve showed a rapid increase in disease risk at viral loads between 3.8 and 5.5 log10 genomes/ml in blood, and odds ratios for disease were determined for different threshold viral loads. These data demonstrate the central role of viral load in the pathogenesis of HCMV in BMT recipients and provide an additional marker for targeting and monitoring therapy.

Acyclovir↗
PubMed1998

The effect of T cell depletion with Campath-1M on immune reconstitution after chemotherapy and allogeneic bone marrow transplant as treatment for leukaemia.

The prophylactic use of T cell depletion (TCD) strategies for the prevention of graft-versus-host disease (GVHD) following allogeneic stem cell transplantation remains widespread. Initial reports of high incidence of graft rejection after TCD BMT led to a move away from this approach but improved conditioning regimens have reduced this risk substantially. The use of TCD has also been associated with higher relapse risk post-BMT although the success of donor leukocyte infusion (DLI) as treatment for relapse has reduced this problem, especially in chronic myeloid leukaemia (CML). Currently the use of TCD BMT is increasing particularly due to the relative increase in BMT from non-related donors for whom TCD is the optimal GVHD prophylaxis. However, doubts remain over the long-term effect on the reconstituted immune system of recipients of TCD BMT, particularly in adult recipients. In this study we have undertaken a detailed sequential analysis in 23 patients who received allo-grafts from HLA-identical sibling donors after high-dose chemo/radiotherapy for acute or chronic leukaemia. Of these patients, 11 received non-manipulated grafts, five received 'partially TCD' (PTCD) and a further seven received 'fully TCD' (FTCD) bone marrow. T cell depletion was performed ex vivo by Campath-1M plus autologous serum as a source of complement. Partial TCD describes grafts with a T cell reduction of 1-2 log. Full TCD refers to grafts with a reduction of >2.5 log. The decision regarding the optimal degree of TCD was clinical and was based upon the perceived relative risk of relapse based upon the disease and remission status. All patients were monitored for up to 12 months post-BMT with regard to reconstitution of T and NK cell subsets. T cell depletion at either level was associated with a slower recovery of CD4 cells. This was most marked in the FTCD recipients and lasted throughout the period of study. CD8 cell recovery was also slower in the TCD recipients but this normalised throughout the 12 months post-BMT. The ratio of CD45RA+:CD45RO+ increased in all recipients after month 3. This suggests that a degree of extra-thymic T cell maturation can occur in recipients of allogeneic BMT. NK cell recovery was more rapid in the TCD recipients and these differences were maintained throughout the first year.

Adult↗
PubMed1998

Acute skin GVHD following syngeneic BMT for CLL.

A 41-year-old woman received a syngeneic BMT for CLL and subsequently developed acute skin GVHD. Transfusion-related allogeneic GVHD was excluded on the basis of an unchanged HLA type in circulating lymphocytes. Short tandem repeat PCR was used to confirm syngeneicity between donor and recipient. The patient had a personal and family history of autoimmune disease which may have made her particularly susceptible to development of syngeneic GVHD. The distinction between allogeneic and syngeneic or autologous GVHD is important because of therapeutic implications.

Acute Disease↗
PubMed1998

FLAG-idarubicin and allogeneic stem cell transplantation for Ph-positive ALL beyond first remission.

We describe a single centre experience of eight consecutive patients with relapsed or refractory Ph+ ALL treated with the FLAG/idarubicin regimen followed by BMT or PBSCT. Following FLAG/idarubicin, one achieved a partial response and seven CR. All patients subsequently received allogeneic transplants: one sibling BMT, three matched unrelated (MUD) BMT and four sibling PBSCT. Two patients received second transplants with PBSC from their original BM donors following FLA/Ida with no further conditioning. Three patients are alive in CR 9, 24 and 32 months after transplant. Seven of eight patients had a cytogenetic response following FLAG/Ida induction and one of seven became bcr-abl negative. All eight patients had a complete cytogenetic response following transplant. Four of five assessable patients became p190 bcr-abl negative after transplant; three of these subsequently relapsed. Both patients with the p210 bcr-abl transcript remained bcr-abl positive in CR after transplant. FLAG/Ida was well tolerated and appears to be effective in inducing remission in relapsed Ph+ ALL. The use of FDR-containing chemotherapy without further conditioning prior to PBSCT deserves further study in heavily pre-treated patients and, in patients with relapsed ALL following BMT, may be a safer option than DLI (donor lymphocyte infusion) by avoiding the associated risk of aplasia.

Adolescent↗
PubMed1998

The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA compared: a report from the MRC Paediatric and Adult Working Parties.

The purpose of the study was to examine the influence of age on outcome in a large cohort of children and adults with lymphoblastic leukaemia who were treated on two similar trials. Factors influencing outcome were examined in 2204 patients aged over 1 year treated between 1985 and 1992 on the parallel Medical Research Council Trials UKALL X and XA, for children and adults, respectively. There was a progressive worsening in survival with increasing age from 85% (95% CI 83-87) at 5 years for children aged 1-9 to 24% (CI 17-31) for patients over 40. Induction failures, deaths in remission and bone marrow relapses increased significantly with age. Analysis of clinical and biological features showed dominance of early B-ALL in childhood and increasing incidence of the Ph' chromosome with age. Over 80% of eligible children, but a much lower proportion of adults especially those over 40, was entered. Compliance was stricter in the paediatric trial but most deviations in adults involved giving more treatment. Analysis of results in a proportional hazards model confirmed the overwhelming independent influence of age; with all other factors equal a 10 year old had half the risk of treatment failure of a 20 year old and a 44 year old double the risk. Selective entry to therapeutic trials and increased treatment-related toxicity are features of adult ALL but age itself remains a dominant prognostic factor. While improved supportive care and refinements of conventional therapy may have some effect on prognosis, new understandings and treatment approaches to adult ALL are needed.

Adolescent↗
PubMed1998

Impact of previous aspergillosis on the outcome of bone marrow transplantation.

A retrospective analysis of 48 patients with documented or probable invasive aspergillosis (IA) prior to bone marrow transplantation (BMT) was conducted in 16 centers. Treatment of primary IA was medical in all 48 patients and surgical in 20; clinicoradiological resolution of IA occurred in 30 of 48 patients. Pretransplantation risk factors for relapse IA, total mortality, and IA-related mortality were analyzed by multivariate logistic regression with the following dichotomous risk factors: surgery as part of the initial treatment, resolution of IA by the time of BMT, donor type, conditioning regiment, total-body irradiation, T cell depletion, immunosuppressive therapy, type of antifungal prophylaxis, and growth factor prophylaxis. Conditioning with busulfan/cyclophosphamide was associated with a beneficial outcome for total survival and reduced IA-related mortality. Posttransplantation risk factors such as the development of graft-vs.-host disease (GVHD), therapy for GVHD, and the duration of neutropenia did not have a significant effect on relapse IA, IA-related mortality, or total mortality. The overall incidence of relapse IA was lower than expected (33% [16 of 48 patients]), but the mortality rate among relapsed patients was 88% (14 of 16). Patients receiving prophylaxis with absorbable or intravenous antifungals had less relapses of IA than did those not receiving prophylaxis (12 of 41 vs. four of seven, respectively). This finding reflects the need for better prophylaxis and new antifungal treatments for patients undergoing BMT who have a history of IA.

Amphotericin B↗
PubMed1997

Temporal dynamics of CD69 expression on lymphoid cells.

Lymphocyte activation remains an area of intense interest to immunologists and cell biologists and the dynamics of expression of surface molecules during the process are widely studied. The CD69 C-type lectin is reportedly the earliest activation antigen on lymphocytes and can be detected within hours of mitogenic stimulation. Recently reports have described differential activation dynamics with respect to different antigenic or mitogenic stimuli. This study has investigated the dynamics of CD69 expression over time after mitogenic, allogeneic, cytokine and target cell mediated activation of T-cell and NK cell subsets. It is apparent that the dynamics of CD69 expression differ with respect to the cell type and the method of stimulation. Mitogenic stimulation resulted in the most rapid expression of CD69 on both T- and NK cells while alloantigen stimulation induced a far slower response. Target cell stimulation of NK cells gave paradoxical results in that the CD69 + ve subset increased as a proportion of the total NK cells but did not increase in number. This was due to the selective binding of CD69 - ve NK cells to the target cells and their subsequent loss from the lymphoid gate. We confirmed this by showing that CD69 + ve NK cells do not lyse K562 target cells. This observation demonstrates the caution needed in the analysis of flow cytometric data based solely upon relative proportions of cells within discrete subsets.

Antigens, CD↗
PubMed1997

Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation study. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

The presentation cytogenetic result was correlated with outcome for 999 patients with acute myeloblastic leukemia (AML) having bone marrow transplantation (BMT) in first complete remission (CR1). The karyotype at diagnosis was classified according to the modified Chicago classification. Allogeneic BMT (AlloBMT) was performed in 500 patients and autologous BMT (ABMT) in 499 patients. For both groups, an abnormal chromosome (abn) 5 and/or 7 or a hypodiploid karyotype had a poor outcome, whereas t(15;17), pseudodiploidy, hyperdiploidy and diploidy were associated with a standard prognosis. Abn (16) and t(8;21) were also of standard prognosis for ABMT, but favorable for AlloBMT. When comparing AlloBMT and ABMT in patients with favorable or standard cytogenetics, AlloBMT was of benefit for remission duration and leukemia-free survival (LFS). Patients with an unfavorable karyotype had a similar outcome, regardless of type of BMT. By multivariate analysis, cytogenetics at diagnosis had the strongest prognostic value for relapse, LFS, and survival in AlloBMT. In ABMT, cytogenetics influenced relapse and LFS. We concluded that the karyotype at diagnosis had important prognostic implication in AML grafted in CR1.

Adolescent↗
PubMed1997

Construction and biological characterization of an interleukin-12 fusion protein (Flexi-12): delivery to acute myeloid leukemic blasts using adeno-associated virus.

Interleukin-12 (IL-12) is a cytokine that exhibits pleiotropic effects on lymphocytes and natural killer cells and has been shown to have promise for the immunotherapy of cancer. The combination of the immune costimulatory molecule B7.1 and IL-12 has been shown to be synergistic for T cell activation. By transfecting tumor cells with both IL-12 and B7.1 cDNAs, it may be possible to use these modified targets as vaccines. A major obstacle in designing a vector to deliver these genes results from the structure of IL-12. Functional IL-12 is a heterodimer composed of two distinct subunits that are encoded by separate genes on different chromosomes. Production of functional IL-12 requires the coordinated expression of both genes. This presents several problems in vectors, particularly those in which additional genes, either a co-stimulatory gene or a selectable marker, are inserted. Therefore, we have constructed a single cDNA that encodes a single-chain protein, called Flexi-12, which retains all of the biological characteristics of recombinant IL-12 (rIL-12). The monomeric polypeptide Flexi-12 is able to induce the proliferation of phytohemagglutinin (PHA) blasts, induce PHA blasts to secrete interferon-gamma (IFN-gamma) and additionally, by preincubation, enhance the killing of K562 targets by PBLs. These phenomena are in a dose-dependent manner comparable to that seen with rIL-12. We have also shown that tyrosine phosphorylation of the STAT 4 transcription factor, which has been shown to be unique to the IL-12 signaling pathway, occurs with Flexi-12 at levels similar to those seen with rIL-12. We have packaged Flexi-12 into a recombinant adeno-associated virus (AAV) and used this vector to infect acute myeloid leukemic (AML) blasts. Infected AML blasts produced between 2 and 6 ng of IL-12/10(6) cells per ml per 48 hr. These studies also confirm that AAV is an efficient delivery vehicle for cytokines to leukemic cells. Direct analysis of these modified cells acting as tumor vaccines is underway.

Amino Acid Sequence↗
PubMed1997

Long-term survival in allogeneic bone marrow transplant recipients following acyclovir prophylaxis for CMV infection. The European Acyclovir for CMV Prophylaxis Study Group.

Recipients of HLA-matched, related or unrelated allogeneic BMT who were CMV seropositive or those receiving unmanipulated marrow from a seropositive donor were randomised to receive one of three treatment regimens, i.v. acyclovir 500 mg/m2 three times a day from 5 days before transplant to 30 days after transplant followed by oral acyclovir 800 mg four times a day for a further 6 months, i.v. acyclovir followed by placebo, or 400 mg oral acyclovir four times a day followed by placebo (control). This paper reports the 1 year data on the same cohort of patients which was previously reported. Intravenous acyclovir (i.v./PCB) significantly reduced the risk of CMV infection when compared to the control group. The frequency of adverse events reported was comparable among the three groups. The mortality rate was significantly reduced by the sequential use of i.v. acyclovir followed by oral acyclovir, resulting in a 19% survival advantage at 1 year from transplant.

Acyclovir↗