Biomedical subjects

M K Brenner

Publications and source records attributed to M K Brenner.

At least 145 records · Page 8Linked to original sources

PubMed1990

Immunity against Pseudomonas aeruginosa adoptively transferred to bone marrow transplant recipients.

Infection is a common problem for bone marrow transplant (BMT) recipients during the period of neutropenia that immediately follows the procedure. Gram-negative infections present a particular hazard in these immunocompromised hosts. To augment host defenses against one such pathogen, Pseudomonas aeruginosa, we immunized bone marrow transplant donors and/or recipients with a polyvalent O-polysaccharide-toxin A conjugate vaccine. When either donor or recipient alone was vaccinated before transplant, no increase in specific antibody titers to any of the vaccine components was observed in the recipient. However, when both donor and recipient were vaccinated before transplant, increases in antibody titers to all polysaccharide components occurred to levels shown to be protective in animal models of gram-negative sepsis. Specific antibodies were primarily of the IgG1 and IgG2 subclass even though IgG2 subclass deficiency is common after BMT. The requirement for both donor and recipient immunization reflects the need for primed donor B lymphocytes in the marrow inoculum to be transferred into an antigen-containing environment so that maximum B-cell proliferation and antibody secretion can occur. Adoptive transfer of antibody responses to Pseudomonas aeruginosa and other common bacterial pathogens has the potential to reduce infection-related morbidity and mortality after allogeneic bone marrow transplantation.

Adolescent↗

PubMed1990

Effects of interferon alpha on autocrine growth factor loops in B lymphoproliferative disorders.

The B lymphoproliferative disorders B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) produce a number of autocrine growth factors, including tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-1, all of which may induce positive feedback growth loops. If such malignancies depend on these autocrine growth loops for survival, their interruption may be therapeutically valuable. Interferon alpha (IFN-alpha) abrogates TNF- or IL-6-induced proliferation of HCL and B-CLL cells in vitro and has therapeutic activity in these diseases. We have investigated the possibility that IFN-alpha may act by interrupting autocrine growth factor loops. If purified B-CLL or HCL cells are cultured in the presence of TNF, there is induction of mRNA for TNF, IL-1 alpha, IL-1 beta, and IL-6. However, culture in the presence of IFN-alpha in addition to TNF reduced the level of mRNA for all these cytokines, compared with cells cultured in TNF alone. While cytokine mRNA levels were diminished, levels of mRNA for the ribonuclease activator 2-5A synthetase were increased. Analysis of the kinetics of cytokine mRNA production showed that levels fall shortly after the rise of 2-5A synthetase mRNA. IFN-alpha may produce these effects by shortening the half-life of cytokine mRNA, since TNF mRNA half-life in B-CLL and HCL cells is substantially reduced when the cells are cultured with IFN-alpha. These data suggest that IFN-alpha may mediate its therapeutic effects in these malignancies by blocking autocrine growth factor loops.

Adult↗

PubMed1990

Transfection and gene expression in normal and malignant primary B lymphocytes.

Although many different protocols for transfection of lymphoid cell lines exist, successful DNA transfer into primary B lymphocytes has, to date, not been demonstrated. We now describe a simple method for gene transfer into highly purified normal and malignant B lymphocytes by electroporation. Using a powerful expression vector containing two copies of the cytomegalovirus (CMV) immediate early enhancer linked to the human T cell lymphotropic virus I (HTLV I) promoter, we could demonstrate transfected gene expression in both high density small 'resting' B cells and in low density 'activated' B cells. Successful transfection was detected by expression of chloramphenicol acetyl transferase and by immunofluorescence. The neoplastic cells of B cell chronic lymphocytic leukemia could also be transfected with an efficiency of 5-10%, but only after preactivation. This method of transfection will permit analysis of the contribution of individual genes and their products to normal and malignant B cell growth and differentiation.

Antigens, Differentiation↗

PubMed1990

Gamma-interferon and tumor necrosis factor production after bone marrow transplantation is augmented by exposure to marrow fibroblasts infected with cytomegalovirus.

After bone marrow transplantation (BMT), mortality from viral infections such as cytomegalovirus (CMV) remains high. Gamma-Interferon (gamma IFN) and tumor necrosis factor (TNF) are produced constitutively after BMT and have anti-viral properties. To study the effects of these cytokines on CMV interaction with host cells, we have used patient marrow fibroblasts since marrow stroma is a target for CMV infection correlating with myelosuppression in vivo. Both gamma IFN and TNF are constitutively produced by recipient CD3+ and CD16+ lymphocytes, but not by their marrow fibroblasts. Secretion by peripheral blood mononuclear cells is increased if they are cultured with host fibroblasts infected with CMV in vitro and the levels of gamma IFN and TNF produced are within the range that protects fresh fibroblasts from CMV infection. Constitutive secretion of cytokines by lymphocytes declines by 8 weeks after BMT, a time when the risk of CMV disease increases sharply. The in vitro phenomenon that we have described needs to be evaluated in correlative studies on individual BMT recipients to determine whether such a cytokine-mediated defense mechanism against CMV may operate in vivo.

Antigens, CD↗

PubMed1990

Requirements for the adoptive transfer of antibody responses to a priming antigen in man.

Antibody responses to recall vaccines can be adoptively transferred after marrow transplantation in man. Transfer of responses to priming Ag has not been successful, although this would broaden the range of organisms to which recipients could be protected. To investigate the importance of T cells and Ag in such transfer we primed marrow donors with keyhole limpet hemocyanin (KLH) 1 or 3 wk before marrow harvesting. B cells secreting IgM and IgG anti-KLH antibody were present in donor marrow at both 1 and 3 wk after immunization. After T cell depletion, donor marrow was infused into chemo-irradiated recipients, half of whom were immunized pretransplant with KLH. We found no evidence for the transfer of the IgM component of the response. Clonal expansion of the transferred IgG antibody-secreting cells with a corresponding rise in recipient serum IgG antibody levels was seen only when donors were primed 3 wk before marrow harvest and when the recipients were also immunized. IEF and immunoblotting demonstrated that successful transfer coincided with maturation of the IgG primary response from a polyclonal to an oligoclonal pattern and confirmed that donor oligoclonal bands appeared in the recipient serum. We conclude that the immunization protocols required for the transfer of antibody responses to priming Ag reflect the initial dependence of unprimed B cells on T cell help and on prolonged Ag stimulation. Ag-stimulated primary B cells in T cell-depleted marrow respond only to the noncognate growth and differentiation signals available in the chemo-irradiated recipient after an initial period of clonal selection and expansion in the donor which is both T cell and Ag dependent. Even after this initial selection, continued expansion of antibody-secreting clones in recipients retains an absolute dependence on Ag stimulation. Immunization techniques to protect transplant recipients against organisms such as Pseudomonas and CMV may need to be modified accordingly.

Antibody Formation↗

PubMed1990

Origin of marrow stromal cells and haemopoietic chimaerism following bone marrow transplantation determined by in situ hybridisation.

The origin and cell lineage of stromal cells in the bone marrow is uncertain. Whether a common stem cell exists for both haemopoietic and stromal cells or whether these cell lines arise from distinct stem cells is unknown. Using in situ hybridisation for detection of the Y chromosome, we have examined histological sections of bone marrow from seven patients who received marrow transplants from HLA-matched donors of the opposite sex. Stromal cells (adipocytes, fibroblasts, endothelial cells, osteoblasts and osteocytes) were identified in these recipients as being of host origin. This result is consistent with the concept of a distinct origin and separate cell lineage for cells of the haemopoietic and stromal systems. It also shows that engraftment of marrow stromal cell precursors does not occur and that host stromal cells survive conditioning regimens for marrow transplantation. With the exception of one case, with a markedly hypocellular marrow, mixed chimaerism was seen in haemopoietic cells, indicating that this is not a rare event after marrow transplantation.

Adolescent↗

PubMed1990

Unrelated donor marrow transplantation between 1977 and 1987 at four centers in the United Kingdom.

Retrospectively we analyzed the histocompatibility data and clinical results of bone marrow transplantation in 51 patients who received marrow from unrelated donors (UD) from 1977 to 1987 at one of four UK BMT centers. We compared the results with those obtained in 51 transplants carried out at the same centers using HLA-identical (ID) sibling donors. Of the UD/recipient pairs 32 (63%) were serologically identical for HLA A, B, and DR antigens, and 37% showed varying degrees of mismatch. UD-BMT primary diagnoses were: severe aplastic anemia or Fanconi's anemia (n = 17), acute leukemia (n = 11), chronic myeloid leukemia (n = 21), and other conditions (n = 2). T cell depletion of the graft was associated with a significant improvement in survival in both UD and ID-BMT. Graft failure was more common in recipients of UD than of ID transplants (13 [25%] vs. 5 [10%] P = 0.05) but there was no significant difference in the frequency of acute or chronic graft-versus-host disease. Actuarial survival was superior for recipients of ID transplants (UD vs. ID: 49% vs. 78%, respectively, at 3 months; 32% vs. 63% at one year). Reduced survival for recipients of UD-BMT was confirmed in case control regression analysis (relative risk 3.0, P = 0.01). Nevertheless in patients whose only alternative is a partially mismatched family donor we think that UD-BMT is justified.

Bone Marrow Transplantation↗

PubMed1990

Malignant plasma cells are sensitive to LAK cell lysis: pre-clinical and clinical studies of interleukin 2 in the treatment of multiple myeloma.

To assess the role of the cytokine interleukin 2 (IL2) in the treatment of patients with multiple myeloma, we examined the sensitivity of plasma cell lines and malignant plasma cells from multiple myeloma (MM) patients to cell and cytokine-mediated killing induced by IL2. Unstimulated peripheral blood mononuclear cells (PBM) from normal donors produced little killing (mean lysis 1.0 +/- 1.0%, effector:target (ET) ratio 50:1), but cytotoxicity was modestly increased when PBM were incubated with IL2 prior to assay (8.0 +/- 2.9%). Unstimulated PBM from patients with MM also failed to kill autologous malignant plasma cells (mean 0.6 +/- 0.6%), but after exposure to IL2 they induced substantial lysis of autologous malignant cells (mean 55.3 +/- 22.1%). In addition, tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma), two cytokines released from mononuclear cells in response to IL2, also reduced the survival and thymidine uptake of malignant plasma cells in culture. To determine whether these potentially beneficial immunomodulatory effects could be reproduced by in vivo administration of IL2, we have administered seven courses of IL2 to four patients with MM after autologous bone marrow transplant (ABMT). No serious adverse effects were noted. Increases in natural killer (NK) and lymphokine-activated killer (LAK) activity of PBM occurred during IL2 infusion, although cells capable of killing autologous MM cells did not circulate. However, IL2 infusions also induced substantial increases in the production of the cytokines TNF and IFN-gamma from peripheral blood lymphocytes. These results suggest that the in vivo administration of IL2 in MM deserves further evaluation, particularly for its potential to control minimal residual disease.

Adult↗

PubMed1989

Tumor necrosis factor mediates autocrine growth inhibition in a chronic leukemia.

Autocrine production of growth factors may contribute to the rapid and fatal proliferation of acute hematologic malignancies. We have investigated whether the more controlled growth of less aggressive malignancies such as chronic myeloid leukemia (CML) may be associated with autocrine production of growth inhibitory factors. TNF inhibits the growth of both normal and leukemic hemopoietic progenitor cells. We find that exogenous TNF reduces the viability and DNA synthesis of purified myeloid cells from patients with CML and inhibits myeloid colony formation by patient progenitor cells. However, unlike progenitor cells from normal donors, patient myeloid progenitor cells also constitutively express mRNA for TNF and secrete functional TNF protein in culture. This endogenous TNF impedes the growth of CML cells because anti-TNF mAb shown to neutralize bioactive human TNF increases CML cell DNA synthesis whereas non-neutralizing anti-TNF mAb has no effect. Production of TNF by CML cells is not associated with production of lymphotoxin (TNF-beta), IL-1 or IL-6. TNF-mediated autocrine growth inhibition may contribute to the maintenance of the stable, chronic phase of this disease and similar mechanisms may operate in other malignancies to limit tumor proliferation. Competition between autocrine growth promoting and inhibiting factors may underlie the observed differences in biologic behavior between acute and chronic malignancies.

Antibodies, Monoclonal↗

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

Rapid expression of protooncogenes c-fos and c-myc in B-chronic lymphocytic leukemia cells during differentiation induced by phorbol ester and calcium ionophore.

The peripheral blood mononuclear cells from patients with B-chronic lymphocytic leukemia (B-CLL) were incubated for 0.5 h to 72 h in the presence of the phorbol ester TPA, the calcium ionophore A23187, or a combination of these reagents. Using Northern blot analysis, total cellular RNA was prepared from cells harvested at different time points and hybridized with DNA clones specific for the protooncogenes c-fos and c-myc. While untreated control cells lacked detectable amounts of messenger RNA (mRNA), increase in the level of c-fos mRNA was noted as early as 0.5 h after exposure to the inducers. Peaks of c-fos and c-myc transcript accumulation were seen at 1 h and 4 h after induction, respectively. The most effective inducer was double stimulation with TPA plus A23187. The kinetics of c-fos and c-myc mRNA accumulation in B-CLL appear to be similar to those reported for normal lymphocytes that have been either activated by physiologic external stimuli or by direct activators of protein kinase C and calcium flux (such as TPA and A23187). No direct link between oncogene expression and proliferation or differentiation parameters could be established. These results document that expression of c-fos and c-myc genes, which are among the earliest events following stimulation of the protein kinase signal transduction pathway, can be successfully induced in B-CLL cells. The data provide further evidence for the hypothesis that signal transmission downstream of protein kinase C is intact in B-CLL.

Blotting, Northern↗

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 phase I clinical trial of recombinant interleukin 2 following high dose chemo-radiotherapy for haematological malignancy: applicability to the elimination of minimal residual disease.

Biological response modifiers such as interleukin 2 (IL2) may be most effective in the setting of minimal residual disease. In a phase I-II clinical trial, IL2 was administered to 10 patients in remission of acute myeloid leukaemia and three with multiple myeloma 1-4 weeks after treatment with ablative chemotherapy or chemotherapy and autologous bone marrow transplantation. The aim was to assess the capacity of these patients to tolerate IL2 after intensive therapy and to determine whether regenerating lymphocytes were capable of responding to IL2 with the generation of anti-leukaemic effector cells. Toxicity was severe in two patients treated with escalating doses of IL2 and 19 subsequent infusions administered to 11 patients on a fixed dose schedule for periods of 3-5 days were well tolerated. Major toxicity was confined to hypotension (two courses) which responded rapidly to treatment cessation. No patients required intensive care unit support. IL2 infusions produced no significant adverse effects on marrow regeneration; while there were transient falls in platelet counts there were no episodes of clinical bleeding and neutrophil counts increased from a mean of 1.1 pre-infusion to 2.5 x 10(9)l-1 during the infusion (P = 0.004). A significant biochemical abnormality was hypokalaemia which responded rapidly to correction. Cells with activity against leukaemic progenitor cells appeared in peripheral blood within 48 h of beginning treatment. We conclude that IL2 may be used in minimal residual haematological malignancy, and by producing anti-neoplastic effector cells has the potential, as yet unproven, to prolong disease-free survival of patients entering remission.

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

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

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

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↗