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Biomedical subjects

H G Prentice

Publications and source records attributed to H G Prentice.

At least 181 records · Page 10Linked to original sources
PubMed1989

Effects of recombinant interleukin-2 administration on cytotoxic function following high-dose chemo-radiotherapy for hematological malignancy.

Activated killer cells, unrestricted by major histocompatibility (MHC) antigens circulate in the peripheral blood of patients who have undergone autologous and allogeneic bone marrow transplant (BMT) and may contribute to the reduced risk of leukemic relapse observed after these procedures. Interleukin-2 (IL-2) in vitro augments this cytotoxicity and used therapeutically might thereby promote the eradication of minimal residual disease. In order to assess whether these effects on cytotoxicity can be reproduced in vivo, we studied changes in number, phenotype, and MHC unrestricted cytotoxicity of peripheral blood mononuclear cells obtained from patients with hematologic malignancy receiving IL-2 infusions. Patients with acute myeloid leukemia and multiple myeloma were treated after cytotoxic chemotherapy or autologous BMT. IL-2 infusions produced an initial lymphopenia, followed by a progressive recovery in mononuclear cell numbers and a rebound lymphocytosis after the termination of treatment. This affected all lymphocyte subsets; in particular CD25 (IL-2 receptor) positive cell numbers rose sevenfold. Cells with the ability to kill a natural killer (NK)-resistant, lymphokine activated killer cell (LAK)-sensitive target appeared in the circulation during 16 of 19 infusions and mean LAK activity rose from 5.9% to 15.5% during infusion (E:T ratio, 50:1; P less than .001). During IL-2 infusion, cells present in the peripheral blood inhibited the growth of myeloid leukemia blasts in agar after overnight co-culture. Depletion experiments showed that LAK activity was mediated by cells of both CD3- CD16+ (NK derived) and CD3+ CD16- (T derived) subsets. LAK precursor activity in peripheral blood also significantly increased during IL-2 infusion. Increases in major histocompatibility complex (MHC) unrestricted cytotoxicity can be produced by IL-2 infusions in vivo and may result in improved relapse-free survival following chemotherapy or BMT.

Antigens, CD↗
PubMed1989

Titration of IgG antibodies against varicella zoster virus before bone marrow transplantation is not predictive of future zoster.

Serum antibodies to varicella zoster virus (VZV) were measured in 77 patients about to undergo allogeneic bone marrow transplantation, and in 65 of their donors. Ten patients developed zoster within the first 6 months following transplant. There was no significant difference in the mean pretransplant antibody titre between those patients who did or did not subsequently develop zoster. Likewise, the level of antibody to VZV amongst donors had no effect on the subsequent development of zoster. We conclude that the pretransplant level of antibody to VZV is not predictive of subsequent zoster infection, and would not be helpful in identifying patients for trials of antiviral prophylaxis. These results contrast with those previously found for another herpesvirus, herpes simplex (HSV), where antibody level pretransplant is predictive of future HSV recurrence.

Adolescent↗
PubMed1989

A comparison of double beta-lactam combinations with netilmicin/ureidopenicillin regimens in the empirical therapy of febrile neutropenic patients.

In a randomized trial ceftazidime plus piperacillin or azlocillin, and netilmicin plus piperacillin or azlocillin were used as initial empirical therapy in 202 febrile neutropenic episodes. Netilmicin plus azlocillin was the most effective combination with a clinical response rate of 81% in clinically and microbiologically documented infections compared with 63% for ceftazidime plus piperacillin. All of the episodes of Gram-negative bacteraemia treated with azlocillin responded compared with 43% of those treated with piperacillin. Gram-positive organisms accounted for 52% of all bacteriologically documented infections and 40% of the febrile episodes were treated with vancomycin for presumptive or documented Gram-positive infection. Patients treated with netilmicin had significantly more nephrotoxicity than those given the double beta-lactam combinations (14.8% vs 3.5%; P less than 0.05). However, this difference was not shown in those patients who did not receive concurrent vancomycin or amphotericin. The double beta-lactam combinations were associated with more hypokalaemia (58.2% vs. 37.7%; P less than 0.05) and more colonization with yeasts (24% vs. 10.4%; P less than 0.05) but there was no evidence that their use was associated with prolongation of neutropenia. These results indicate that ceftazidime plus a ureidopenicillin would be adequate empirical therapy in situations where the concomitant use of nephrotoxic agents precludes the use of aminoglycoside containing combinations.

Adult↗
PubMed1989

Prophylaxis and treatment of cytomegalovirus infections in the bone marrow transplant recipient.

Almost all viral infections after bone marrow transplant (BMT) are attributable to reactivation of latent DNA viruses, especially those of the Herpesvirus family. The first to reactivate is herpes simplex virus, followed by cytomegalovirus (CMV) with a reported peak incidence between 60 and 90 days in most studies and varicella zoster virus about three to 18 months after BMT. Epstein-Barr virus rarely causes detectable illness after BMT and reactivation is only seen in the most profoundly immunosuppressed. The most lethal infection and indeed the most prominent cause of failure overall after allogenic BMT is interstitial pneumonitis which is frequently due to CMV infection. This article considers prophylactic measures against viral infection and preliminary studies of regimens for the treatment of established CMV infections.

Bone Marrow↗
PubMed1989

Enhancement of monoclonal antibody dependent cell mediated cytotoxicity by IL2 and GM-CSF.

Rodent monoclonal antibodies (MAb) directed against cells of the immune system may be used in vivo for applications including conditioning prior to marrow transplantation and treatment of lymphoid malignancies. Although some MAb may lyse targets by complement fixation, MAb dependent cell mediated cytotoxicity (MAb-DCC) appears to be an important additional effector mechanism. We have investigated the cellular basis of the phenomenon and the response of the effector cells to recombinant cytokines in an attempt to maximize the efficacy of MAb-DCC and thereby increase the therapeutic potency of MAbs. Blood mononuclear cells (PBM) coated with CAMPATH 1G (pan lymphocyte reactive rat IgG2b) MAb were used as targets (T) and autologous lymphocytes or granulocytes were used as effector (E) cells. We studied function in normal donors as well as patients 1 week before and 3-6 weeks after bone marrow transplantation (BMT). In the absence of CAMPATH 1G, specific 51Cr release from autologous PBM was less than 1% in all groups, even after pre-incubation of the effector cells with granulocyte-macrophage, colony stimulating factor (GM-CSF) or interleukin-2 (IL2). In the presence of 5 micrograms/ml of MAb, and at an E:T ratio of 50:1, lymphocytes from normal donors induced a low level (6.5%) of 51Cr release from auto PBM rising to 9% after pre-incubation of effector cells with IL2 (P = 0.02). Granulocytes had greater activity inducing 10% 51CR release (range 2-23%) which rose to 21.6% with GM-CSF (range 12-48%) (P less than 0.001). Pre-BMT, killing by lymphocytes and granulocytes was not significantly different from normal, and responded to IL2 and GM-CSF. In contrast, granulocyte killing after BMT was significantly impaired (51Cr release 3%) and showed no rise with GM-CSF. Killing by lymphocytes, however, remained normal, as did their IL2 response. Loss of granulocyte mediated MAb-DCC coincided with significant post-BMT impairment of oxidative metabolism; expression of Fc receptors II and III, however, was normal. Optimum therapeutic effect of MAb-DCC is likely to be achieved when MAb are given together with appropriate cytokines, the choice of which will depend upon the clinical circumstances.

Antibodies, Monoclonal↗
PubMed1989

Spontaneous and interleukin 2 induced secretion of tumour necrosis factor and gamma interferon following autologous marrow transplantation or chemotherapy.

Culture of lymphocytes from allograft recipients or from normal donors with Interleukin 2 (IL2) induces high levels of gamma-interferon (gamma IFN) and tumour necrosis factor (TNF) secretion. We now show that production of these two cytokines can also be increased after autologous bone marrow transplantation (BMT) and induced following chemotherapy for haematological malignancy. These effects occur even though the regenerating IL2 responsive lymphocytes in this context have previously been extensively exposed to cytotoxic agents. IL2 induced secretion of gamma-IFN and TNF is higher in autograft recipients than in patients treated by chemotherapy alone. This effect may be related to differences in the phenotypic profile between recovering lymphocytes in the two groups and to an increased degree of prior in vivo lymphocyte activation in the autologous bone marrow transplant recipients. In both groups of patients, IL2 acts on CD3+ T cells and on CD16+ NK cells so that depletion of either subset incompletely abrogates IL2 dependent gamma-IFN secretion. As both TNF and gamma-IFN possess anti-leukaemic and anti-infective activity, enhancement of their secretion by IL2 infusion after autologous bone marrow transplant and induction after chemotherapy may be of therapeutic benefit.

Adolescent↗
PubMed1989

Prevention of urate nephropathy in the tumour lysis syndrome.

Patients with acute lymphoblastic leukaemia and a high tumour burden are at risk of developing acute renal failure when given chemotherapy. Rapid cell lysis releases a high urate load which may result in an obstructive urate nephropathy. This complication should be prevented by establishing an alkaline diuresis before initiating steroid or other chemotherapy.

Adolescent↗
PubMed1989

Do double-beta-lactam combinations prolong neutropenia in patients undergoing chemotherapy or bone marrow transplantation for hematological disease?

The total period of neutropenia was assessed in 174 episodes after chemotherapy or bone marrow transplantation in which patients received antibiotics for fever in a randomized prospective trial. Log rank analysis demonstrated no significant difference in the total duration of neutropenia between patients receiving netilmicin plus either piperacillin or azlocillin and those given ceftazidime plus either piperacillin or azlocillin. Of 86 patients in the single-beta-lactam group, 27 had a persistent neutrophil count of 0.1 x 10(9) per liter during treatment compared with 27 of 88 patients in the double-beta-lactam group, and 29 of 68 patients treated with the single-beta-lactam combination had a total period of neutropenia greater than 30 days versus 36 of 75 in the double-beta-lactam group. The use of two beta-lactam antibiotics rather than one does not appear to prolong neutropenia in patients undergoing treatment of hematological malignancy. However, in order to determine the effect of a single-beta-lactam combination, a similar carefully controlled prospective randomized study in which such treatment is compared with a non-beta-lactam-containing regimen is required.

Adult↗
PubMed1989

Carriage of Candida species and C albicans biotypes in patients undergoing chemotherapy or bone marrow transplantation for haematological disease.

Six hundred and seventy four yeast isolates obtained from routine microbiological screening of 153 patients with haematological disease were identified and Candida albicans isolates biotyped over nine months to determine longitudinal and cross sectional patterns of yeast colonisation. A yeast microflora persisted in many patients despite the routine prophylactic use of oral antifungal agents. Analysis of the yeast species isolated on a cross sectional basis showed that C albicans accounted for 65% of yeasts isolated from the oral cavity but only 45% of the faecal yeast flora. Longitudinal changes in yeast flora occurred significantly more often in faecal samples than in oral samples and significantly less often in sites colonised with C albicans than in sites colonised with other species. No associations were found between the yeasts isolated and the nature of antifungal prophylaxis used, or the extent of a patient's stay in hospital.

Antifungal Agents↗
PubMed1989

Pulmonary cell populations in recipients of bone marrow transplants with interstitial pneumonitis.

The immunological basis of the inflammatory response in the lungs of patients with pneumonitis after bone marrow transplantation has been investigated by means of bronchoalveolar lavage. Ten episodes of pneumonitis associated with cytomegalovirus and nine episodes due to various other infectious and non-infectious causes were investigated in 16 patients (three patients had two episodes of pneumonitis). Total lavage cell counts and differential cell counts were determined and compared with results from normal control subjects. In most patients with pneumonitis the total cell yield was greater than normal (mean 6.8 (SD 6.0) x 10(5) cells/ml; normal 1-2 x 10(5) cells/ml). The percentage distribution of these cells was 71.9 (17) macrophage like cells, 24.1 (15.8) lymphocytes, 5.0 (5.0) polymorphonuclear cells, and 0.7 (1.0) eosinophils. None of the patients had peripheral lymphocytosis despite the increased number of lymphocytes in the lavage fluid. Further analysis of the lymphocyte population using monoclonal antibodies with immunocytochemical techniques showed that B cells were generally present in normal proportions, whereas the proportion of cells expressing T lymphocyte markers (CD2+, CD5+, CD8) were reduced in nine out of 19 cases. In 10 of the 19 episodes there were substantial numbers of cells expressing none of the B or T cell antigens studied ("null" cells). These abnormalities bore no relation to survival. The total cell yield, the proportion and number of lymphocytes, and the proportion and number of T cells in the bronchoalveolar lavage fluid were all lower in the group with cytomegalovirus infections than in those with pneumonitis from other causes. These results suggest that the pneumonitis in recipients of bone marrow transplants is associated with a local immune response despite the fact that the individuals are otherwise immunosuppressed.

Adolescent↗
PubMed1989

Clonal evolution in Ph-negative, bcr-positive chronic myeloid leukaemia before and after bone marrow transplantation.

A 26-year-old man, who presented with bilateral fundal haemorrhages, was found to have chronic myeloid leukaemia (CML). The Ph chromosome was not present but a clone with t(1;9) (p32;q34) was detected. On referral for bone marrow transplant (BMT) he was found to be in accelerated phase with clonal evolution in three cell lines inv(3)(q21q26); inv(3)(q),i(17q); inv(3q)+8. Molecular investigation revealed a breakpoint on chromosome 22 within the breakpoint cluster region (bcr) similar to that found in Ph+ cases. After BMT, from an HLA-identical sister, successful engraftment (46,XX) was accompanied by evidence of a residual host cell population with further evolution (del(7)(q22)) and persistence of the bcr+ clone. Acute myeloid leukaemia, detected 5 months later, was associated with predominance of the clone 46XY,t(1;9),inv(3q),del(7)(q22) which failed to respond to treatment and the patient died 6.5 months after BMT. This case indicates that BMT, after the acquisition of additional chromosomal change in accelerated phase, may fail owing to persistence of the leukaemic clone. In addition the BMT conditioning regimen may produce further abnormalities which confer drug resistance on the persisting clone, which can emerge as an intractable myeloid blast crisis.

Adult↗
PubMed1989

Endogenously generated activated killer cells circulate after autologous and allogeneic marrow transplantation but not after chemotherapy.

After marrow transplantation, major histocompatibility complex (MHC)-unrestricted natural killer (NK) lymphocytes are among the first cells to appear in the circulation. After T-cell-depleted bone marrow transplantation (TD-BMT), these cells have an activated pattern of target cell killing; they also secrete lymphokines including gamma-interferon (gamma-IFN), interleukin-2 (IL-2), and tumor necrosis factor (TNF) and may have a significant role as a primary defense against viral reactivation and in the elimination of residual host malignancy. We studied 43 patients with hematologic malignancy, treated by allogeneic TD-BMT, autologous nondepleted BMT, or chemotherapy alone to investigate (a) the mechanisms underlying the generation of these activated killer cells, (b) the range of conditions under which they are produced, and (c) their surface phenotype. We showed that gamma-IFN-secreting activated killer cells with the capacity to kill MHC-nonidentical NK-resistant targets are generated 4 to 6 weeks after either allogeneic TD-BMT or autologous BMT but do not appear after treatment with chemotherapy. Production therefore is not owing to T-cell depletion per se or to host donor alloreactivity, nor is it caused by stimulation by alloantigens contained in blood product support since no significant difference exists between allograft and chemotherapy patients in the number of units of blood platelet support given in the posttreatment period. Because most patients had no evidence of stimulation from virus reactivation/infection, the phenomenon of activation therefore appears to represent posttransplant immune disregulation following repopulation of the host immune system with lymphoid subsets derived exclusively from blood and marrow. Activated killing is predominantly mediated by the CD16+ CD3- subset, but substantial activity remains in the CD16- CD3+ cell fraction. Monoclonal antibodies (MoAbs) that block interaction with class-I MHC molecules at the level of target cell (W6/32 anti-HLA class I) or effector cell (CD8) do not inhibit killing by CD16- CD3+ cells. Activated killer cells may contribute to the lower risk of relapse after marrow transplantation as compared with intensive chemotherapy.

Adolescent↗
PubMed1989

In vivo induction of gamma interferon and tumor necrosis factor by interleukin-2 infusion following intensive chemotherapy or autologous marrow transplantation.

Interleukin-2 (IL-2) therapy may improve immune reconstitution and reduce the risk of leukemic relapse in the setting of minimal residual disease by augmenting cytotoxic effector mechanisms directed at residual malignant cells. In addition, IL-2 in vitro promotes the release of cytokines including gamma-interferon (gamma-IFN) and tumor necrosis factor (TNF), which also possess antileukemic activity and can enhance granulocyte function. To determine if IL-2 infusion induces release of gamma-IFN and TNF in vivo in sufficient quantity to mediate these effects, we have measured serum levels of these cytokines and secretion by lymphocytes obtained from patients receiving this cytokine in a phase 1 trial. Serum gamma-IFN was undetectable pre-IL-2 and increased to 1.5 to 17 U/mL during IL-2 infusion (P less than .05). Culture of patient lymphocytes for 48 hours produced 1.2 U gamma-IFN/2 x 10(6) cells/mL pre-IL-2 rising to 50 U/2 x 10(6) cells/mL when the lymphocytes were obtained during therapy (P less than .05). Lymphocyte subset analysis showed that both CD3+ and CD16+ cells secreted gamma-IFN in response to IL-2. TNF secretion by lymphocytes also rose during IL-2 infusion from a mean of 5 U/mL to 14.4 U/mL (P less than .01) although no rise was seen in serum levels. The material secreted by IL-2-stimulated lymphocytes is bioactive as addition of supernatants from lymphocytes obtained during IL-2 therapy to cultures of myeloid blasts significantly inhibited clonogenic growth. IL-2-induced secretion of these cytokines mediated this inhibition as it could be partially blocked by either anti-gamma-IFN or anti-TNF antibodies. Preincubation of granulocytes with the same supernatants produced enhanced oxidative metabolism, measured by chemiluminescence in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP). This effect also could be partially abrogated by anti-gamma-IFN and anti-TNF antibodies. Therefore, secondary cytokine secretion may boost granulocyte function and contribute to the antileukemic effects of IL-2 infusion in patients following bone marrow transplantation or chemotherapy.

Adolescent↗
PubMed1989

Fatal hepatitis B reactivation after autologous bone marrow transplantation.

We report a fatal case of hepatitis B reactivation following autologous bone marrow transplantation for acute lymphocytic leukaemia. The presence of antibodies to HBs and HBc at presentation indicated previous infection with hepatitis B; these antibodies disappeared during the course of treatment for leukaemia. HBsAg was first detected in serum 5 weeks post-transplant; liver function tests began to deteriorate 8 weeks later, when HBeAg was first detected. The hepatitis followed a fulminant course, and the patient died 10 days later, in the 15th week following transplant.

Adolescent↗
PubMed1989

Current role and status of bone marrow transplantation.

The applications of bone marrow transplantation have been limited by the serious morbidity and mortality associated with the procedure. In this article we discuss improvements in our understanding of the immunobiology of marrow transplantation. We also describe how the availability of recombinant growth factors for the haemopoietic and immune systems and the introduction of immunomodulatory monoclonal antibodies are beginning to make a major impact on the practice and outcome of the procedure.

Adolescent↗
PubMed1989

Autologous bone marrow transplantation with monoclonal antibody purged marrow for high risk acute lymphoblastic leukemia.

Fifty-four patients with acute lymphoblastic leukemia (ALL: 1 relapse, 21 high risk first complete remission (CR 1), 29 second CR (CR 2), and 3 third CR (CR 3) were treated by autologous bone marrow transplantation at three centers. Before storage, the marrows were purged ex vivo with appropriate MAbs RFAL3 (CD10), SB4 (CD19), and RFT2 (CD7), with rabbit serum as the source of complement. All patients received total body irradiation either 750 cGy (middose 15 cGy/min) as a single fraction or 6 x 200 cGy over 3 days (midline dose 16 cGy/min) with lung shielding from 1,100 cGy. The patients who received 750 cGy also received cyclophosphamide or the same drug combined with ara-C or prednisone, teniposide, vincristine, ara-C, and dauno-rubicin. Patients receiving 200 cGy x 6 also received either cyclophosphamide, melphalan, or ara-C and cyclophosphamide. Three patients died of post transplantation complications (interstitial pneumonia, hepatitis B liver necrosis, or encephalitis). This gives a procedure related mortality of 5%. Nonfatal complications were 10 cases of septicemia, 4 interstitial pneumonia, 2 interstitial nephritis, 1 veno-occlusive disease (VOD), and 1 case of hemolytic uremic syndrome. The patient autografted in relapse died of relapse within 2 months. In CR 1 6 or 21 patients have had a relapse, and the actuarial leukemia free survival from CR is 65% (median follow-up 16 months). In CR 2-3 18 of 32 patients have relapsed, and the actuarial leukemia free survival is 31% (median follow-up 18.5 months) from CR. Twelve patients have achieved an inversion, (i.e., present CR longer than previous CR), with a further seven with the potential to achieve inversion. We conclude that ABMT in high risk ALL has a low procedure related mortality (5%), and there are few other complications. The in vitro purging with MAbs had no adverse effect on bone marrow reconstitution, but this study was not designed to demonstrate its antileukemic efficacy. The actuarial leukemia free survival time in the present study for patients with high risk CR 1 and the inversions in CF 2-3 are promising and indicate a potential beneficial effect of ABMT.

Antibodies, Monoclonal↗