Biomedical subjects

A J Barrett

Publications and source records attributed to A J Barrett.

At least 73 records · Page 4Linked to original sources

PubMed1999

MEROPS: the peptidase database.

The MEROPS database (http://www.bi.bbsrc.ac.uk/Merops/Merops.+ ++htm) provides a catalogue and structure-based classification of peptidases (i.e. all proteolytic enzymes). This is a large group of proteins (approximately 2% of all gene products) that is of particular importance in medicine and biotechnology. An index of the peptidases by name or synonym gives access to a set of files termed PepCards each of which provides information on a single peptidase. Each card file contains information on classification and nomenclature, and hypertext links to the relevant entries in online databases for human genetics, protein and nucleic acid sequence data and tertiary structure. Another index provides access to the PepCards by organism name so that the user can retrieve all known peptidases from a particular species. The peptidases are classified into families on the basis of statistically significant similarities between the protein sequences in the part termed the 'peptidase unit' that is most directly responsible for activity. Families that are thought to have common evolutionary origins and are known or expected to have similar tertiary folds are grouped into clans. The MEROPS database provides sets of files called FamCards and ClanCards describing the individual families and clans. Each FamCard document provides links to other databases for sequence motifs and secondary and tertiary structures, and shows the distribution of the family across the major kingdoms of living creatures. Release 3.03 of MEROPS contains 758 peptidases, 153 families and 22 clans. We suggest that the MEROPS database provides a model for a way in which a system of classification for a functional group of proteins can be developed and used as an organizational framework around which to assemble a variety of related information.

Archaea↗

PubMed1999

A technique for dual determination of cytotoxic and helper lymphocyte precursor frequency by a miniaturized dye release method.

Helper (HTLPf) and cytotoxic (CTLPf) lymphocyte precursor frequency assays are increasingly used in bone marrow stem cell and organ transplant compatibility testing. Current techniques require large cell numbers and radioisotopes. To improve the technique, we developed a miniaturized fluorescent read-out combined HTLPf/CTLPf limiting dilution assay. The assay requires only 5 x 10(6) stimulators, 2 x 10(6) responders and 0.24 x 10(6) target cells in Terasaki plates (40 microl/well). For the HTLPf, culture supernatants from each well were assayed for IL-2 production. The IL-2-dependent proliferation of the mouse 9.12 cell line was detected by a semi-automated fluorescent dye technique. After addition of rhIL-2 (recombinant human IL-2) on days 3 and 7, CTLPs were detected on day 10 by measuring the lysis of dye-labeled targets. Results were comparable to standard radioisotope-based techniques. The assay had a coefficient of variation of approximately 30%. The assay detected helper CD4 cells, pure cytotoxic CD8, helper CD8 cells and helper/cytotoxic CD8 cells. Discrimination was demonstrated between HLA-matched related and non-related pairs. The ease of testing and small cell numbers required should facilitate further evaluation of HTLPf and CTLPf for compatibility testing in unrelated donor transplantation and monitoring immune responses following adoptive transfer of lymphocytes.

Animals↗

PubMed1999

Circulating basic fibroblast growth factor declines during Cy/TBI bone marrow transplantation.

Basic fibroblast growth factor (bFGF) inhibits radiation-induced apoptosis, and radioprotects haematopoietic, cartilage growth plate, pulmonary and gastrointestinal tissues. Conversely, chronic overexpression of bFGF may promote fibrosis. We measured the endogenous circulating bFGF in blood of patients undergoing conditioning TBI. Twenty-six patients with haematopoietic malignancies were conditioned with cyclophosphamide/TBI for allogeneic BMT. Daily blood samples were collected each morning prior to, during, and for several days after TBI. bFGF levels in plasma of normal volunteers are 0.8-26 pg/ml. bFGF was below detectability in 22%, 30% and 45% of patients pre-TBI, during TBI or post-TBI respectively. Mean circulating plasma levels of bFGF decreased from a median of 52 pg/ml pre-TBI to 26 pg/ml during TBI, and to 5 pg/ml post-TBI. Among the 26 patients, 13 had more than one non-detectable plasma bFGF level, an additional five had at least one non-detectable level, and only eight patients had detectable levels in all daily samples. Naturally high levels of bFGF were observed in some patients undergoing fractionated TBI. In contrast, as many as 79% of patients had low bFGF levels in one or more samples. The impact of endogenous bFGF on the tolerance of normal tissues to irradiation is unknown, and warrants further study.

Adult↗

PubMed1999

Donor-recipient polymorphism of the proteinase 3 gene: a potential target for T-cell alloresponses to myeloid leukemia.

The curative effect of allogeneic bone marrow transplantation (BMT) is in part due to an alloresponse of donor lymphocytes against recipient leukemia termed the graft versus leukemia (GvL) effect. To identify target antigens for the GvL response on leukemia cells, we looked for polymorphism of proteinase 3, a primary granule protein overexpressed in myeloid leukemias. The study was carried out in 10 patients with hematologic diseases and their HLA-identical marrow donors. By polymerase chain reaction (PCR)-single strand conformation polymorphism assay, followed by direct sequencing of the PCR products, we found seven DNA polymorphisms. One of them encodes for either an isoleucine or a valine at position 119 of the amino acid sequence. Peptides that span the polymorphic site, at amino acids 115-124, were shown to bind in vitro to the HLA-A2 molecule. We screened 23 HLA-A2 patients with myeloid leukemia and their HLA-identical donors for this polymorphism. No relapse was found in the group of 4 evaluable patients who possessed at least one allele absent in their donor, whereas 7 of the 15 remaining evaluable patients relapsed. These data support the possibility that T-cell responses to allelic differences of proteinase 3 could be used as a basis for designing leukemia-specific adoptive T-cell therapy in acute and chronic myeloid leukemias.

Alleles↗

PubMed1998

Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases.

We show by site-directed mutagenesis that the catalytic residues of mammalian legumain, a recently discovered lysosomal asparaginycysteine endopeptidase, form a catalytic dyad in the motif His-Gly-spacer-Ala-Cys. We note that the same motif is present in the caspases, aspartate-specific endopeptidases central to the process of apoptosis in animal cells, and also in the families of clostripain and gingipain which are arginyl/lysyl endopeptidases of pathogenic bacteria. We propose that the four families have similar protein folds, are evolutionarily related in clan CD, and have common characteristics including substrate specificities dominated by the interactions of the S1 subsite.

Adhesins, Bacterial↗

PubMed1998

An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation.

Foreign protein antigens must be broken down within endosomes or lysosomes to generate suitable peptides that will form complexes with class II major histocompatibility complex molecules for presentation to T cells. However, it is not known which proteases are required for antigen processing. To investigate this, we exposed a domain of the microbial tetanus toxin antigen (TTCF) to disrupted lysosomes that had been purified from a human B-cell line. Here we show that the dominant processing activity is not one of the known lysosomal cathepsins, which are generally believed to be the principal enzymes involved in antigen processing, but is instead an asparagine-specific cysteine endopeptidase. This enzyme seems similar or identical to a mammalian homologue of the legumain/haemoglobinase asparaginyl endopeptidases found originally in plants and parasites. We designed competitive peptide inhibitors of B-cell asparaginyl endopeptidase (AEP) that specifically block its proteolytic activity and inhibit processing of TTCF in vitro. In vivo, these inhibitors slow TTCF presentation to T cells, whereas preprocessing of TTCF with AEP accelerates its presentation, indicating that this enzyme performs a key step in TTCF processing. We also show that N-glycosylation of asparagine residues blocks AEP action in vitro. This indicates that N-glycosylation could eliminate sites of processing by AEP in mammalian proteins, allowing preferential processing of microbial antigens.

Amino Acid Sequence↗

PubMed1998

Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection.

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T-cell depletion increases the risk of graft rejection. This study examined the use of CD52 monoclonal antibodies to eliminate T cells from both donor marrow and recipient to prevent both GVHD and rejection. Seventy patients receiving HLA-identical sibling transplants for acute myelogenous leukemia (AML) in first remission were studied. An IgM (CAMPATH-1M) was used for in vitro depletion of the graft and an IgG (CAMPATH-1G) for in vivo depletion of the recipient before graft infusion. No posttransplant immunosuppression was given. Results were compared with two control groups: (1) 50 patients who received bone marrow depleted with CAMPATH-1M, but no CAMPATH-1G in vivo; and (2) 459 patients reported to the International Bone Marrow Transplant Registry (IBMTR) who received nondepleted grafts and conventional GVHD prophylaxis with cyclosporin A (CyA) and methotrexate (MTX). The incidence of acute GVHD was 4% in the treatment group compared with 35% in the CyA/MTX group (P <.001). Chronic GVHD was also exceptionally low in the treatment group (3% v 36%; P <.001). The problem of graft rejection, which had been frequent in the historic CAMPATH-1M group (31%), was largely overcome in the treatment group (6%). Thus, transplant-related mortality of the treatment group (15% at 5 years) was lower than for the CyA/MTX group (26%; P =.04). There was little difference in the risk of leukemia relapse between the treatment group (30% at 5 years) and the CyA/MTX group (29%). Survival of the treatment group at 6 months was better than the CyA/MTX group (92% v 78%), although at 5 years the difference was not significant (62% v 58%) and neither was the difference in leukemia-free survival (60% v 52%). We conclude that T-cell depletion is a useful strategy to prevent GVHD, provided that measures are taken to ensure engraftment. Using CAMPATH-1G to deplete residual host lymphocytes is a simple and practical method to do this. At least in AML, the beneficial reduction in GVHD can be achieved without an increased risk of relapse.

Alemtuzumab↗

PubMed1998

Cloning and expression of mouse legumain, a lysosomal endopeptidase.

Legumain, a recently discovered mammalian cysteine endopeptidase, was found in all mouse tissues examined, but was particularly abundant in kidney and placenta. The distribution in subcellular fractions of mouse and rat kidney showed a lysosomal localization, and activity was detectable only after the organelles were disrupted. Nevertheless, ratios of legumain activity to that of cathepsin B differed considerably between mouse tissues. cDNA encoding mouse legumain was cloned and sequenced, the deduced amino acid sequence proving to be 83% identical to that of the human protein [Chen, Dando, Rawlings, Brown, Young, Stevens, Hewitt, Watts and Barrett (1997) J. Biol. Chem. 272, 8090-8098]. Recombinant mouse legumain was expressed in human embryonic kidney 293 cells by use of a vector containing a cytomegalovirus promoter. The recombinant enzyme was partially purified and found to be an asparagine-specific endopeptidase closely similar to naturally occurring pig kidney legumain.

Amino Acid Sequence↗

PubMed1998

Thimet oligopeptidase: site-directed mutagenesis disproves previous assumptions about the nature of the catalytic site.

Zinc metallopeptidases that contain the His-Glu-Xaa-Xaa-His (HEXXH) motif generally have a third ligand of the metal ion that may be either a Glu residue (in clan MA) or a His residue (in clan MB) (Rawlings and Barrett (1995) Methods Enzymol. 248, 183-228). Thimet oligopeptidase has not yet been assigned to either clan, and both Glu and His residues have been proposed as the third ligand. We mutated candidate ligand residues in the recombinant enzyme and identified Glu, His and Asp residues that are important for catalytic activity and/or stability of the protein. However, neither of the Glu and His residues close to the HEXXH motif that have previously been suggested to be ligands is required for the binding of zinc. We conclude that thimet oligopeptidase is not a member of clan MA or clan MB and it is likely that the enzyme possesses a catalytic site and protein fold different from those identified in any metallopeptidase to date. The definitive identification of the third zinc ligand may well require the determination of the crystallographic structure of thimet oligopeptidase or one of its homologues.

Amino Acid Sequence↗

PubMed1998

Graft-versus-leukemia effects in T lineage and B lineage acute lymphoblastic leukemia.

T and B lineage ALL cells express different levels of HLA-class II antigens, which may serve as targets for graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). The object of this study was to determine whether GVL effects after HLA-identical sibling bone marrow transplantation differed in T and B lineage ALL. We studied 1132 patients with ALL of T lineage (n = 416) or of B lineage (cALLa+) (n = 716) transplanted in first (n = 605) or second (n = 527) remission with bone marrow from an HLA-identical sibling donor, between 1982 and 1992, and reported to the IBMTR by 165 teams. Cox proportional hazards regression models were used to determine the relative risk (RR) of relapse in patients with acute (grades II-IV) or chronic GVHD vs patients without GVHD. Acute and chronic GVHD were considered as time-dependent covariates. Patients transplanted in first and second remission were analyzed separately. GVHD decreased relapse risks to a similar extent in T and B lineage ALL. For first remission transplants, relative risks of relapse for patients with vs those without GVHD was 0.34 for T lineage ALL and 0.44 for B lineage ALL. Corresponding relative risks in second remission transplants were 0.54 and 0.61. This study confirms earlier findings of an antileukemia effect of GVHD in ALL. This effect was similar in T lineage and B lineage ALL, despite probable differences in HLA-class II antigen expression.

Adolescent↗

PubMed1998

T cell-depleted granulocyte colony-stimulating factor (G-CSF) modified allogenic bone marrow transplantation for hematological malignancy improves graft CD34+ cell content but is associated with delayed pancytopenia.

To increase the stem cell content of T cell-depleted bone marrow transplants (BMT), we treated 12 patients with hematological malignancies with BMT from HLA-identical sibling donors given G-CSF 10 microg/kg/day for 5 days before marrow harvest. After CD34+ cell selection, patients received a median of 1.7 (range, 0.82-3.1) x 10(6) CD34+ cells/kg and 2.3 (range, 0.25-4.0) x 10(5) CD3+ cells/kg. All patients had initial engraftment but four developed pancytopenia between days 55-130 post-BMT. In two patients, this required a second infusion of G-CSF-mobilized donor peripheral blood progenitor cells. We observed no delayed pancytopenia in a matched historical group of 24 patients receiving T cell-depleted BMT without prior G-CSF stimulation. Compared to this control group, G-CSF-stimulated marrow recipients showed a significant decline in neutrophil and monocyte counts after 8 weeks. However, outcome after BMT was otherwise comparable, with a similar incidence of acute graft-versus-host disease and transplant-related mortality. Disease-free survival was 63 vs 67% for controls matched for CD34+ cell dose (P = NS). These results indicate that G-CSF stimulation can increase the CD34+ cell content of T cell-depleted marrow but carries a risk of late graft failure.

Adolescent↗

PubMed1998

T cell-depleted bone marrow transplantation and delayed T cell add-back to control acute GVHD and conserve a graft-versus-leukemia effect.

Thirty-eight patients with hematological malignancies, received T cell-depleted marrow transplants (BMT) and cyclosporine to prevent acute graft-versus-host disease (aGVHD), followed by delayed add-back of donor lymphocytes to prevent leukemia relapse. In 26 patients scheduled for donor T cell add-back of 2 x 10(6) cells/kg on day 30 and 5 x 10(7) cells/kg on day 45 (schedule 1), the overall probability of grade > or = II aGVHD developing was 31.5%, with a 15.5% probability of aGVHD occurring after T cell add-back. In 12 patients receiving 10(7) donor T cells/kg on day 30 (schedule 2), the probability of grade > or = II aGVHD was 100%. The incidence of grade III-IV aGVHD was higher in schedule 2 than in schedule 1 (P=0.02). Of 24 evaluable patients, 10 (46%) developed chronic GVHD which was limited in eight and extensive in two. Current disease-free survival for 18 patients at standard risk for relapse (chronic myeloid leukemia (CML) in chronic or accelerated phase, acute myeloid leukemia in remission) vs 20 patients with more advanced leukemia or multiple myeloma were respectively 72% vs 12% (P < 0.01) with a 29% vs 69% probability of relapse (P=0.08). In 12 CML patients surviving more than 3 months, PCR analysis of the BCR/ABL transcript showed that minimal residual disease after T cell add-back was transient except in two patients who developed hematological relapse. Results indicate that the risk of acute GVHD is low following substantial T cell doses, transfused 45 days after transplant, using cyclosporine prophylaxis. Furthermore a graft-versus-leukemia effect was conserved.

Adult↗

PubMed1998

Influence of protective isolation on outcome of allogeneic bone marrow transplantation for leukemia.

Various isolation strategies are used to prevent infections during bone marrow transplantation; data on their efficacy are lacking. We studied whether use of high efficiency particulate air filtration (HEPA) and/or laminar airflow (LAF) units affect transplant-related mortality (TRM) or survival in the first year after allogeneic transplantation. 5065 patients with leukemia receiving bone marrow transplants from an HLA identical sibling (n = 3982) or alternative related or unrelated donors (n = 1083) between 1988 and 1992 were reported to the International Bone Marrow Transplant Registry by 222 teams. Two types of isolation were considered: (1) conventional protective isolation with single patient room and any combination of hand-washing, gloves, mask and gown; and (2) HEPA and/or LAF. Cox proportional hazards regression models were used to determine the relative risks (RRs) of transplant-related mortality (TRM) and of deaths from any cause in patients treated in HEPA/LAF units compared to patients treated in conventional isolation. HLA-identical sibling and alternative donor transplants were analyzed separately. Risks of TRM and overall mortality in the first 100 days post-transplant were significantly lower among patients treated in HEPA/LAF units than in those treated conventionally. RRs of TRM were 0.76 (P = 0.009) for recipients of HLA-identical sibling transplants and 0.65 (P = 0.003) for recipients of alternative donor transplants. Correspondingly RRs of overall mortality were 0.80 (P = 0.02) and 0.65 (P = 0.0006). Decreased risks of TRM and of death in the first 100 days post-transplant resulted in significantly higher 1-year survival rates in patients treated in HEPA/LAF rather than in conventional isolation units. Use of HEPA and/or LAF to prevent infections decreases TRM and increases survival after allogeneic bone marrow transplants for leukemia.

Adolescent↗

PubMed1998

High incidence of adeno- and polyomavirus-induced hemorrhagic cystitis in bone marrow allotransplantation for hematological malignancy following T cell depletion and cyclosporine.

Nine of 56 (20% actuarial) patients receiving a T cell-depleted, HLA-identical sibling BMT for hematological malignancy developed hemorrhagic cystitis (HC) 15-368 days post BMT. Hematuria was severe and prolonged (median duration 18 days). In eight patients (89%), a viral etiology was confirmed (four adenovirus, four polyomavirus). HC was associated with significant morbidity, with all patients requiring continuous bladder irrigation and transfusion support for blood loss and thrombocytopenia. HC occurring before day 100 was significantly associated with a reduction in long-term survival: 1/7 (14.3%) patients developing HC before day 100 became long-term survivors vs 21/49 (42.8%) without HC by day 100 (P = 0.034). In univariate analysis, HC was associated with a diagnosis of multiple myeloma (P = 0.02). There was a trend towards a higher incidence of HC in patients reactivating cytomegalovirus (CMV) compared with those remaining CMV negative (18.4 vs 5.5% respectively, P = 0.17). HC was not associated with graft-versus-host disease, or with the transplant dose of CD34+ progenitors or CD3+ cells, patient age or sex. Life-threatening, viral-induced HC and the unusually high incidence of adenovirus-induced HC may have been caused by immune deficiency associated with T cell depletion in this series.

Adenoviridae Infections↗

PubMed1998

Specific depletion of alloreactive T cells in HLA-identical siblings: a method for separating graft-versus-host and graft-versus-leukaemia reactions.

Accumulating evidence indicates that alloreactive donor T cells confer both graft-versus-host (GVH) and graft-versus-leukaemia (GVL) reactivity following allogeneic bone marrow transplantation. We have developed a method to deplete alloreactive donor T cells with an immunotoxin targeting the alpha chain of the IL-2 receptor. In patients with chronic myeloid leukaemia and their HLA-identical sibling donors, we measured donor helper T-lymphocyte precursor frequencies (HTLPf) against recipient peripheral blood mononuclear cells (PBMNC; donor versus host), recipient leukaemia cells (donor versus leukaemia) and third-party PBMNC, before and after the depletion. In seven pairs there was a 4.3-fold reduction of donor-versus-host HTLPf (P=0.017), without a significant change in the donor frequencies against third party (P=0.96). In eight further donor-recipient pairs, immunotoxin-depleted donor versus patient PBMNC HTLPf 4.5-fold (mean 1/155,000 before and 1/839,000 after depletion, P=0.007). There was a smaller non-significant 1.8-fold reduction in donor-versus-leukaemia HTLPf from 1/192,000 to 1/334,000 (P=0.19). These results suggest that selective T-cell depletion can significantly deplete donor anti-host reactivity while conserving anti-leukaemia reactivity in HLA-matched donor-recipient pairs.

Bone Marrow Transplantation↗

PubMed1998

Polymorphism in CD33 and CD34 genes: a source of minor histocompatibility antigens on haemopoietic progenitor cells?

Following bone marrow stem cell transplantation allo-responses against haemopoietic progenitor cells (HPC), causing graft rejection and graft-versus-leukaemia effects, can be induced by donor T cells recognizing peptides derived from polymorphic endogenous proteins present in HPC. Since CD33 and CD34 are both expressed on HPC, we looked for genetic polymorphisms that might be the source of minor histocompatibility antigens (mHA) on such cells. Bone marrow from 14 donors and their HLA-identical recipients undergoing BMT for haematological malignancies were studied. Using non-radioactive single-strand conformation polymorphism analysis (cold SSCP) of complementary DNA encoding CD33 and CD34, three DNA polymorphisms, two in CD33 and one in CD34 were found and sequenced. Two were in non-coding regions, but in CD33, ATA or ATG at codon 183 resulted in an Ile or Met in the protein sequence. Nonapeptides derived from both alleles were predicted to bind to HLA A68.1. Thus two alleles of CD33 protein exist that could be mHA. With an alternate allele frequency of < 10%, allo-responses against CD33 would be uncommon after marrow transplantation. However, donors homozygous for this allele could be used to generate cytotoxic T cells against the frequent CD33 allele, for adoptive therapy of leukaemia.

Antigens, CD34↗

PubMed1998

Haematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte-mediated inhibition of CFU-GM and alterations in T-cell receptor Vbeta profiles.

We have demonstrated that 44% of myelodysplastic syndrome (MDS) patients with cytopenia have a haematological response to antithymocyte globulin (ATG). Three ATG responders and two non-responders with refractory anaemia were further studied for lymphocyte-mediated inhibition of bone marrow using a standard CFU-GM assay. In responders, peripheral blood lymphocytes (PBL) added at a 5:1 ratio suppressed CFU-GM by 54+/-9% (P=0.04) and was reversed by ATG treatment. Pre-treatment marrow depleted of CD3 lymphocytes, increased CFU-GM by 32% (P=0.02) in an ATG responder, but not in a non-responder. CD3 lymphocytes from 6-month post-treatment marrow did not inhibit pre-treatment CFU-GM, indicating ATG had affected the T cells. Pre-treatment marrow depleted of CD8 lymphocytes, increased CFU-GM by 60% (P=0.01) and 49% (P=0.03) in two ATG responders, but not in a non-responder. Inhibition required cell-cell interaction through MHCI. TCRVbeta families, analysed by SSCP, changed from clonal to polyclonal in one ATG responder after 6 months, but clones persisted in a non-responder. These results indicate patients with refractory anaemia who respond to ATG have CD8 T-cell clones that mediate MHCI-restricted suppression of CFU-GM which are replaced by polyclonal T cells that do not suppress CFU-GM after ATG treatment.

Adult↗

PubMed1997

Regulation of a graft-versus-leukemia effect by major histocompatibility complex class II molecules on leukemia cells: HLA-DR1 expression renders K562 cell tumors resistant to adoptively transferred lymphocytes in severe combined immunodeficiency mice/nonobese diabetic mice.

To understand the role of key molecules in determining the strength and nature of allogeneic T-cell response to leukemia, we transfected HLA-DR1 into the major histocompatibility complex (MHC)-deficient, natural killer (NK)-cell sensitive K562 leukemia cell line. Untransfected K562 cells stimulated NK proliferation in vitro and formed subcutaneous tumors in severe combined immunodeficiency/non-obese diabetic (SCID/NOD) mice. Tumor growth was inhibited by adoptive intravenous transfer of fresh unprimed peripheral blood mononuclear cells (PBMC). In contrast, HLA-DR1 transfected cells stimulated CD4(+) T cells, but not NK-cell proliferation in vitro and formed tumors resistant to fresh PBMC in SCID/NOD mice. Tumors not expressing MHC were infiltrated with CD16(+)CD56(+) lymphocytes whereas nonregressing HLA-DR1 expressing tumors showed only a scanty infiltration with both T-cell and NK-cell subsets. The results indicate that MHC class II expression by leukemia cells can determine the effector cell type that it engages. In vivo MHC class II expression rendered K562 cell tumors resistant to NK-cell mediated antitumor reactivity.

Adoptive Transfer↗