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Biomedical subjects

M K Brenner

Publications and source records attributed to M K Brenner.

At least 163 records · Page 9Linked to original sources
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↗
PubMed1988

In vitro analysis of the interactions of recombinant IL-2 with regenerating lymphoid and myeloid cells after allogeneic marrow transplantation.

Although administration of rIL-2 post-T depleted allogeneic bone marrow transplantation (TD-BMT) offers the prospect of augmenting immune reconstitution and thereby reducing the risks of infection and relapse, it has been unclear what direct or indirect effects this agent would have on the regenerating myeloid system. We find that addition of 200 IU or rIL-2 to patient lymphocytes obtained within 6 wk of TD-BMT results in a substantial (2 to 3 log) increase in INF-gamma secretion and the production of TNF. Cytokines present in supernatants obtained from IL-2-stimulated patient lymphocytes have two contrasting effects on myeloid cells from normal donors and from marrow recipients. They prime granulocytes for enhanced oxidative metabolism as measured by ability to generate chemiluminescence in response to FMLP, whereas IL-2 added directly to neutrophils has no effect. However, these IL-2-induced cytokines also act to inhibit myeloid progenitor growth and reduce granulocyte macrophage (GM) colony formation by a mean of 53%. Preincubation of supernatants with anti-IFN-gamma antibody partially abrogates both enhancement of granulocyte chemiluminescence and suppression of marrow CFU-GM. Addition of IL-2 directly to recipient marrow also produces inhibition, leading to a 25% reduction of GM-colony growth. This effect is not due to direct interaction between myeloid progenitor cells and IL-2, because it is completely abrogated by removal of CD8 and Leu-7+ lymphocytes from the marrow. Although the suppressive effects on marrow growth in vitro are of particular concern after BMT, the potential of IL-2 to promote granulocyte function, immune reconstitution, and anti-leukemic activity after TD-BMT justify further consideration of IL-2 therapy in this setting.

Adolescent↗
PubMed1988

Tumour necrosis factor as an autocrine tumour growth factor for chronic B-cell malignancies.

Recombinant tumour necrosis factor (TNF) promotes survival and induces proliferation in the tumour cells from two malignancies of B lymphocytes--hairy-cell leukaemia and B-chronic lymphocytic leukaemia. Culture with TNF also induces TNF mRNA and protein, so the cytokine may act as an autocrine tumour growth factor. These growth promoting effects are antagonised by alpha but not by gamma interferon.

B-Lymphocytes↗
PubMed1988

Differential recovery of phenotypically and functionally distinct circulating antigen-presenting cells after allogeneic marrow transplantation.

Low-density cells (LDC) prepared from peripheral blood by fractionation over hypertonic metrizamide contain 95% of cells with veiled morphology, almost all of which are HLA-DR-positive and have characteristics of antigen-presenting cells. In normal individuals the monoclonal antibodies RFD1 and RFD2 divide these cells into three phenotypically distinct populations, D1+D2-, D1-D2+ and D1-D2-. The RFD1-positive population is nonphagocytic. We have investigated the recovery of LDC in peripheral blood after (T cell-depleted) marrow transplantation, to assess whether defects in antigen-presenting cell (APC) subpopulations could contribute to the prolonged immune-paresis of marrow graft recipients. We find that APC of donor origin and with apparently normal morphology, phenotype, and function appear within 6 weeks of BMT. By three months the donor-derived nonphagocytic RFD1-positive subset has disappeared, although phagocytic RFD2-positive cells remain. The disappearance of the RFD1-positive subset is associated with a loss of antigen presentation by patients' LDC of the soluble protein antigen tetanus toxoid, though the capacity to present alloantigen and stimulate in a mixed lymphocyte reaction is retained. Donor-derived RFD1-positive cells and soluble antigen-presenting capacity do not reappear for one year or more. This biphasic recovery of RFD1-positive cells contrasted with the continued production of RFD2-positive APC, implies that the phenotypic and functional distinction between APC subpopulations in peripheral blood also reflects a separate ontogeny. Since these marrow graft recipients retain the phagocytic (RFD2-positive) APC but lose the nonphagocytic (RFD1-positive) APC subset, there is now an opportunity to explore the role of each subset in antigen processing and presentation.

Adolescent↗
PubMed1988

Cytokine-induced enhancement of the susceptibility of hairy cell leukaemia lymphocytes to natural killer cell lysis.

In seven patients with HCL we have investigated how the cytokines TNF, alpha and gamma IFN and IL2 modify the interactions between HCL lymphocytes and MHC unrestricted cytotoxic effector cells [natural killer (NK) and lymphokine activated killer (LAK), cells]. We find that IL2 and alpha IFN increase patient NK activity against K562, though killing remains subnormal. IL2 and alpha IFN also induce normal levels of LAK activity, measured against an NK resistant B lymphoblastoid cell line. In contrast, gamma IFN has no effect on patient effector function. However, promotion of cytotoxic effector activity is unlikely to produce therapeutic benefit since HCL cells themselves are entirely resistant to NK/LAK killing. Susceptibility of HCL cells can be induced by culturing the cells in the presence of both gamma IFN and TNF, but not by culture with either cytokine alone. This synergy is not mediated by a gamma IFN induced increase in TNF receptors on HCL lymphocytes, and therefore occurs at a post-receptor level.

Biological Factors↗
PubMed1988

Expression of tartrate-resistant acid phosphatase in B-CLL treated with phorbol ester or phorbol ester plus calcium ionophore.

Cells from 3 patients with B-chronic lymphocytic leukaemia (B-CLL) and 1 with B-prolymphocytic leukaemia (B-PLL) were treated in vitro with the phorbol ester 12-0-tetradecanoylphorbol (TPA), the calcium ionophore A23187, or a combination of TPA and A23187. TPA induced the cells to adhere to the culture flask or to clump in dense clusters; single cells became enlarged, often with cytoplasmic elongations. Cells treated with TPA plus A23187 acquired a plasmacytoid morphology and formed regular aggregates in culture. Only TPA alone induced the expression of tartrate-resistant acid phosphatase (TRAP) as documented by isoelectric focusing on horizontal thin-layer gels. The TRAP isoenzyme was first detected after 24 h of TPA treatment; its intensity increased during further TPA exposure, being maximally expressed at 72/96 h. The results suggest that, while TPA triggers B-CLL cells to convert to hairy cell leukaemia (HCL)-type cells, the double stimulus which more closely imitates physiological activation initiates a 'normal' differentiation programme which leads to plasma cells.

Acid Phosphatase↗
PubMed1988

Allogeneic bone marrow transplantation. Recent developments and the potential expansion of the donor pool.

Graft versus host disease is a preventable complication of allogenic bone marrow transplantation. A complex biological manoeuvre has enabled us to achieve this. Unfortunately T-cell depletion of the donor marrow shifts the delicate immunological balance in favour of the recipient immune system. The consequence has been an increased risk of graft rejection and leukaemia relapse. It is necessary to shift this balance back in favour of the donor (derived) immune system. This can be achieved by increasing the immunosuppressive power of the 'conditioning' chemoradiotherapy. Toxicity considerations limit our scope although single fraction fast dose rate radiotherapy appears to diminish the risks inherent with T-cell depletion. Logically an approach with greater promise will be to use specific immunological means of eliminating the recipient T lymphocytes in vivo. Early experience with a monoclonal anti-lymphoid antibody in vivo in an HLA matched unrelated donor programme suggests that this approach has great promise whilst lacking toxicity. We hypothesise that a shift in immunological superiority to the donor derived immune system will not only allow T-cell depletion whilst minimising the risk of graft rejection, but also enhance the anti-leukaemic properties of the graft. Of further interest will be the potential for application of lymphokines (e.g. IL2) without increasing the risk of lethal graft versus host disease.

Bone Marrow Transplantation↗
PubMed1988

Differential expression of MHC class II antigens in chronic B-cell disorders.

Cells from the peripheral blood of 22 patients with chronic B-cell disorders were examined for the expression of surface MHC class II antigens. We made use of well-characterized monoclonal antibodies (McAbs) specific for HLA-DP, -DQ and -DR molecules (B7/21, Tü22, RFDR1 and RFDR2) and of another McAb, RFD1, associated with the class II system. By using indirect immunofluorescence and flow cytometry we found both non-coordination and heterogeneity in expression of MHC class II antigens but generally with a hierarchy of positivity: DR greater than DQ greater than DP. This suggests a sequence of gradual acquisition of HLA-D antigens and indicates distinct differences in maturation arrest of the individual cases. However, after treatment with phorbol ester TPA and calcium ionophore A23187, all cases expressed the previously absent molecules indicating that the structural genes for these products remained intact. TPA and A23187 increased both the number of positive cells in most cases and the fluorescence staining intensities of all class II markers including RFD1. Thus, leukaemic cells may express different combinations of class II antigens reflecting: (i) a predetermined order of gradual acquisition of class II molecules; (ii) differences in the stages of maturation arrest; and (iii) in the cases of disordered expression a desynchronized regulation of these markers.

Adult↗
PubMed1988

Analysis of signal transduction in B chronic lymphocytic leukemia cells.

We report here experiments on the analysis of cellular signal transduction in a series of patients with chronic B cell disorders (B cell chronic lymphocytic leukemia [B-CLL] and prolymphocytic leukemia). We compared the response of the leukemic cells with primary external signals (interleukin 2 [IL-2] or B cell differentiation factors [BCDF or IL-6]) with their response to secondary inducers (the phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA] or the calcium ionophore A23187) that circumvent the first part of the signal transduction pathway by directly activating the key enzyme protein kinase C. One BCDF was synthesized by mitogen-activated peripheral blood B lymphocytes; a second BCDF was constitutively produced by the human bladder carcinoma cell line T24. Changes in morphology, Tac (IL-2 receptor) expression, RNA synthesis measured by 3H-uridine uptake, and immunoglobulin production tested by enzyme-linked immunosorbent assay were used as parameters of successful signal transduction. TPA alone and TPA plus A23187 (synergistically) effectively initiated differentiation in all the leukemia cases. Neither IL-2 nor BCDF (singly or in combinations) caused equivalent responses. On the other hand, IL-2 and BCDF produced a substantial differentiation effect on normal B lymphocytes. Our data suggest that (a) B-CLL cells are able to respond to direct stimulation of the second messenger pathway (through protein kinase C) but not to the physiological stimuli IL-2 or BCDF; (b) the defect in signal transduction appears to be located upstream of protein kinase C (a possible candidate is a G protein); (c) malignant B cells may spontaneously or after treatment with inducers express the IL-2 receptor (Tac antigen) in the absence of a functional differentiating response to IL-2; and (d) signs of proliferation/differentiation in B-CLL samples after incubation with IL-2 or BCDF might be due to contamination of the cell populations with residual normal B cells.

Antibodies, Neoplasm↗
PubMed1988

Effects of tumour necrosis factor and alpha interferon on chronic B cell malignancies.

Tumour necrosis factor (TNF) induces the lysis of many malignant cells in vitro and regression of some tumours in vivo. However, TNF is also a growth factor for normal fibroblasts, T cells and B cells and we have recently shown that TNF can also act as a growth factor for chronic B cell neoplasms, including hairy cell leukaemia and B-CLL. In these cells it promotes proto-oncogene expression, RNA and DNA synthesis and increases overall cell survival. Stimulation appears to be autocrine in nature since exposure of the neoplastic cells to recombinant TNF protein induces the corresponding messenger RNA and synthesis of the protein itself. TNF induced proto-oncogene expression and DNA synthesis occur over a substantially longer time period than when the cells are stimulated with agents such as TPA and Calcium ionophore (2), but we have no evidence that the delay represents the time taken to generate TNF dependent secondary cytokines such as IL-1 and IL6. Alpha interferon opposes TNF mediated activation and our recent data indicate that this effect is independent of alpha interferon down regulation of TNF receptors. It appears to be related instead to a decreased accumulation of TNF mRNA which occurs contemporaneously with an alpha interferon induced rise in 2-5 A synthetase. If TNF dependent growth is important for the survival of B-CLL cells, then agents which mimic alpha interferon or which block TNF induced autocrine growth would be predicted to be of therapeutic benefit.

B-Lymphocytes↗