An evaluation of approaches to asthma self-management education for adults: the AIR/Kaiser-Permanente Study.

The purpose of the AIR/Kaiser-Permanente asthma project is to evaluate various approaches to the education of adults with asthma, identifying those types of patients for whom particular approaches are most cost effective. Critical self-management practices for adults with asthma were identified using the critical incident technique. An individualized and a group administered educational program are being developed to teach the identified critical skills, using the instructional models previously employed in AIR WISE and AIR POWER programs for children with asthma. Three hundred patients with moderate to severe asthma from Northern California Kaiser-Permanente Medical Group clinics will participate in a trial of these programs. Patients will be randomly assigned to one of four conditions: One of two educational programs, an information/attention control, or a data-only control condition. Data will be collected on all patients for 15 months; health care utilization data covering a two-year period will be available from medical records. Program effectiveness will be evaluated in terms of pre-post changes in the patients' knowledge, attitudes, self-management practices, medical condition, daily functioning, and utilization of services. Cost effectiveness will be evaluated, paying specific attention to the cost effectiveness of different educational approaches for different types of patients.

The role of patient education in the management of childhood asthma.

Because patient behavior plays a major role in the prevention or precipitation of acute asthma attacks, patient education is an important adjunct to its medical management. A number of self-management education programs for patients with asthma recently have been developed and made available for widespread use. Many are aimed at children over the age of 6 years and their parents. They are designed for use with several types of patients in a variety of settings. Evidence of program effectiveness is of uneven quality, but what is available suggests that a number of the programs can be of significant value in reducing asthma morbidity. Self-management education programs for parents of preschool-age children and for adults with asthma are much less numerous and well developed than those for school-age children. Particular attention is given to the process by which the AIR POWER and AIR WISE programs for children were developed, since this systematic development process is generalizable to patient education programs for other age groups and health problems.

Self-management education of children with asthma: AIR WISE.

This study was conducted to test the efficacy of AIR WISE, an individually administered asthma self-management program. Subjects were paired and randomly assigned to either an experimental group (N = 7) or a control group (N = 7). The frequency of experimental group emergency visits, analyzed over a 12-month posttreatment period, was substantially less than those of the control group, supporting the hypothesis that AIR WISE is effective in high-utilizer children through improved self-management.

Differentiation and activation phenotypes of lung T lymphocytes differ from those of circulating T lymphocytes.

We used dual laser two-color flow cytometry to compare the expression of surface markers associated with activation and with differentiation in lung and peripheral blood T lymphocytes from normal subjects. T cell subsets, defined based on their reactivity with monoclonal antibodies (MAb) OKT3, OKT4, and OKT8, were analyzed for expression of activation antigens as detected by MAbs to the interleukin-2 receptor, the transferrin receptor, and HLA-DR determinants. Whereas circulating T lymphocytes expressed the three activation antigens at low levels, and the total of T4+ and T8+ cells always approximated the number of T3+ cells, lung T lymphocytes of the T3+, T4+, and T8+ populations expressed the activation antigens at variable levels in combinations not seen in circulating lymphocytes, and the sum of T4+ and T8+ cells always exceeded the T3+ total. A proportion of T4+T8+ cells was detected in lung lymphocytes.

The T3/T cell receptor complex: antigenic distinction between the two 20-kd T3 (T3-delta and T3-epsilon) subunits.

Clonally distributed (clonotypic) antigen receptors on human T lymphocytes (alpha and beta chains) are associated with three invariable T3 polypeptide chains (T3 gamma, delta and epsilon), together forming the T3/T cell receptor complex. Monoclonal antibodies prepared against the two 20-kd T3 polypeptide chains demonstrated that T3-delta and T3-epsilon are distinct polypeptide chains. Only one monoclonal antibody (anti-T3-delta chain) reacted with the T cell surface as judged by indirect immunofluorescence, and by its mitogenicity for quiescent peripheral blood lymphocytes. Immunohistological staining and immunoprecipitation experiments showed that both the T3-delta and T3-epsilon chains are T cell-specific. As seen with the anti-alpha/beta chain reagent WT-31, anti-T3-delta chain monoclonal antibodies stained medullary thymocytes more intensely than cortical thymocytes, whereas the difference between the staining of cortical and medullary thymocytes was generally not apparent with anti-T3-epsilon chain antibodies. Because of this specificity and their ability to react with both the denatured and the native forms of each polypeptide chain, these new monoclonal reagents will be useful tools in studies of the biosynthesis and cell surface expression of the T3/T cell receptor complex during normal and malignant thymic differentiation.

The delta- and epsilon-chains of the human T3/T-cell receptor complex are distinct polypeptides.

The T3/T-cell receptor complex on the surface of human thymus-derived lymphocytes consists of four glycoproteins: the alpha-chain of relative molecular mass (Mr) 40,000-50,000 (40-50K), the beta-chain (37-45K); the gamma-chain (25K) and the delta-chain (20K). The T3 alpha- and beta-chains have been identified as clonotypic T-cell receptors, but functionally the T3/T-cell receptor chains seem to form a single complex: monoclonal antibodies directed at the 20K T3 components are mitogenic for normal human T lymphocytes and, at higher concentrations, anti-clonotypic and anti-20K reagents block T-cell function. Recently, Zanders et al. showed that incubation of human T-helper clones with high concentrations of antigen abolishes antigen-specific proliferation and induces disappearance of T3 from the cell surface. Thus, the T3/T-cell receptor complex consists of two variable subunits, the T3 alpha- and beta-chains, which interact with antigen and the monomorphic 20K/25K T3 chains. Recently, the existence of a fifth polypeptide chain, the unglycosylated T3 epsilon-chain, has been postulated. Here we confirm that a 20K epsilon-chain does exist. The T3 epsilon-chain differs from the T3 delta-chain in primary structure as judged by N-terminal amino acid sequencing, peptide mapping and immunoblotting with anti-T3-delta and anti-T3-epsilon antibodies. Treatment with endoglycosidase F revealed two nonglycosylated T3 delta polypeptide backbone chains (16K and 14K) with identical amino termini. Together with previous pulse-chase experiments this observation suggests that the 14K T3 polypeptide is derived from the 16K T3 precursor by proteolytic processing near the C-terminus of the molecule.

Surface phenotype of clonogenic cells in acute myeloid leukemia defined by monoclonal antibodies.

Colony-forming cells in ten cases of acute myeloid leukemia (AML) were studied with six cytotoxic monoclonal antibodies that react with antigens expressed at discrete stages of differentiation of normal and leukemic hematopoietic cells. The reactivity of the whole leukemic population was measured by indirect immunofluorescence, and the reactivity of the colony-forming cells was established by complement-mediated cytotoxicity and by fluorescence activated cell sorting. Comparison of the immunofluorescent reactivity with cytotoxicity and cell sorting showed that colony-forming cells were found within a fraction of the leukemic subpopulations that expresses these antigens. This finding implies that immunofluorescence reactivity of the total leukemic population does not necessarily predict the phenotype of the clonogenic cells. When the surface phenotype of the clonogenic leukemic cells was compared to that previously established for normal marrow hemopoietic clonogenic cells, several patterns were seen: (1) in four of ten cases, the clonogenic cells expressed a phenotype like that of relatively mature normal granulocyte-macrophage colony-forming cells (late CFU-GM) or, (2) in two cases, a phenotype similar to the less mature colony-forming cells (early CFU-GM or CFU-GEMM), and (3) in four cases, a composite phenotype of early and late CFU-GM. Thus, the level of impairment of differentiation in AML may vary from case to case. In those cases phenotypically similar to the late CFU-GM, it may be possible to separate leukemic clonogenic cells from less mature normal clonogenic cells using monoclonal antibodies selectively cytotoxic for the late CFU-GM.

Subpopulation heterogeneity in human acute myeloid leukemia determined by monoclonal antibodies.

The leukemic population in 63 patients with acute myeloid leukemia (AML) was studied with 15 monoclonal antibodies that detect lineage-related and stage-related antigens on normal hemopoietic cells. Indirect immunofluorescence and fluorescence-activated cell sorting showed that subpopulations of leukemic cells reacted with some or all antibodies, but the percentage of cells reacting with a single antibody varied widely among patients. The composite antigenic phenotype of the various cases, as determined by immunofluorescence assay, did not correlate with the French-American-British morphological classification. Furthermore, some cells in each case failed to express any antigen normally expressed on myelomonocytic precursors from the level of the early CFU-GM to the mature granulocyte or monocyte. In double-fluorescence experiments, the individual cells expressed none, one, or both antigens. These results demonstrate that there is considerable subpopulation heterogeneity in AML. This heterogeneity may considerably limit or complicate the use of monoclonal antibodies for diagnosis, prognosis, and treatment of acute nonlymphocytic leukemia (ANLL).

Characterization of gastrointestinal tumor-associated carcinoembryonic antigen-related antigens defined by monoclonal antibodies.

Four major carcinoembryonic antigen-related glycopeptides (Mr 180,000, 160,000, 50,000, and 40,000) were detected in SW948 colon carcinoma cells and in colon adenocarcinoma tissue using a monoclonal antibody (C(4)20-32) generated by immunizing mice with SW1222 human colon carcinoma cells. Only the Mr 50,000 polypeptide was immunoprecipitated from normal colon mucosa by this antibody. Binding studies using other monoclonal antibodies and lectins indicated the different epitopes and carbohydrate attachment sites on each of the four polypeptides. Only monoclonal antibody C(4)20-32 recognized a common determinant on all four polypeptides which was revealed by its reactivity with each affinity-purified component.

Differentiation antigens of human hemopoietic cells: patterns of reactivity of two monoclonal antibodies.

Two mouse anti-human monoclonal antibodies (S3.13 and S5.7) raised against cells of acute myelogenous leukemia were found to react with antigens expressed on the surface of subsets of monocytes and lymphocytes. S3.13 precipitates a peptide of Mr 29,000, and S5.7 precipitates a peptide of Mr 20,000 present on the surface of all the cell types tested. These two surface antigens were distributed on discrete subpopulations of normal hemopoietic cells. The antibodies reacted with all (S5.7) or a subpopulation (S3.13) of peripheral blood T-lymphocytes, and with a subset of monocytes. Both antibodies reacted with bone marrow blast cell progenitors of the myelomonocytes and erythroid lineage. S5.7 also reacted with non-T-lymphocytes and with cells of the eosinophilic lineage. Both antigens disappeared from the cell surface during normal myeloid and erythroid differentiation. Thus, these monoclonal antibodies define the molecular characteristics and the cellular distribution of two differentiation antigens present on cells of the hemopoietic lineage.

Human granulocyte surface molecules identified by murine monoclonal antibodies.

We have investigated the nature of the antigens recognized by four classes of mouse anti-human monoclonal antibodies that characteristically reacted with neutrophilic granulocytes and their precursor cells, but not with monocytes or other normal hemopoietic cells. The antigenic targets of the majority (9/12) of the independently isolated monoclonal antibodies were present on two surface glycoproteins (Mr 145,000 and 105,000) and glycolipids. This antigen(s) was also detected on granulocyte precursor cells, including the bone marrow granulocyte/monocyte progenitor cells (CFU-GM). The same antigen(s) detected by these monoclonal antibodies was also present in non-hemopoietic cell lines (colon carcinoma and neuroblastoma). Three other antigens, defined by monoclonal antibodies AHN-8, L12.2, and L13.1 and present on granulocytes and their mid-late precursor cells, could not be identified as proteins but were detected in a protein-free glycolipid extract of these cells. The diversity of the antigens was confirmed by cross-competition experiments and by the identification of their different patterns of reactivity with cell lines and bone marrow cells.

Antigenically distinct subpopulations of myeloid progenitor cells (CFU-GM) in human peripheral blood and marrow.

Two types of progenitor cells of the human granulocytic and monocytic lineages (CFU-GM) can be distinguished by using mouse monoclonal antibodies against human hemopoietic cells. Type 1 CFU-GM contribute all of the peripheral blood CFU-GM as well as a small fraction of bone marrow CFU-GM and express surface antigens recognized by "anti-lymphomonocytic" monoclonal antibodies S3-13 and S17-25 but not the antigens recognized by R1B19 and WGHS-29-1 (two monoclonal antibodies that react with all the cells of the granulocytic lineage). Type 2 CFU-GM are present only in the marrow and react with S3-13, R1B19, and WGHS-29-1. Partial reactivity with S17-25 was observed only in the complement-dependent cytotoxicity test. In vitro culture of type 1 CFU-GM in liquid medium in the presence of granulocyte-macrophage colony-stimulatory factor (GM-CSF) generates colony-forming cells that have the surface phenotype of type 2 CFU-GM. This finding supports the idea of two different stages of maturation of myelomonocytic progenitor cells represented by type 1 and type 2 CFU-GM.

Target antigen of monoclonal reagent S5.7: comparison with T3 antigen.

S5.7 recognizes a 20 kD cell surface protein which is present on T lymphocytes. S5.7 binds to a nonglycosylated protein, which can be labeled by cell-surface radioiodination and by a hydrophobic reagent [125I]-iodo-5-naphthyl-1-azide (INA). As the T-lymphocyte-specific T3 complex was found to contain a nonglycosylated 20 kD species, and since this 20 kD T3 form can be labeled preferentially by INA, a comparison between T3 and S5.7 was made. Isoelectric focusing experiments showed, however, that the two proteins are different. Moreover, the S5.7 monoclonal antibody does not block CML, is not mitogenic, reacts with immature cells of several hemopoietic lineages, and differs in that respect from anti-T3 monoclonal antibodies.

Induction of differentiation of human myeloid leukemias: surface changes probed with monoclonal antibodies.

The surface changes occurring in three acute myeloid leukemia cell lines (HL60, ML3, and KG1) induced to differentiate by a variety of agents (dimethylsulfoxide, retinoic acid, 12-O-tetradecanoylphorbol-13-acetate, and factors present in lymphocyte conditioned medium) were probed using monoclonal antibodies that are differentiation stage- and lineage-specific. In all cases, the differentiated phenotype was defective and varied with the inducing agent and the cell line used. HL60 proved to be the most sensitive to the effect of the inducers. Retinoic acid was better than DMSO, and TPA was better than the medium factors in the ability to induce granulocytic and monocytic differentiation, respectively, in HL60 cells. These findings indicate that the differentiation block in acute myeloid leukemias is heterogeneous and that each cell line has different phenotypic characteristics that are responsible for the extent of differentiation obtained with a given inducer. These results also suggest that the extent of the differentiation response in vitro may be improved by the use of more suitable inducers for each specific leukemic line.

Induction of differentiation of human myeloid leukemias by phorbol diesters: phenotypic changes and mode of action.

Treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) of acute myeloblastic leukemia cells halts proliferation and induces expression of monocyte/macrophage markers. Surface characteristics of leukemic HL60 cells, as defined using a panel of monoclonal antibodies, were found to be similar to those of normal human promyelocytes. TPA treatment, however, induced a phenotype that, unlike normal monocytes, contained several myeloid-specific markers and lacked several monocyte-specific markers. TPA treatment of HL60 cells causes the rapid disappearance of the transferrin receptor from the cell surface. Because transferrin is essential for HL60 cell proliferation in culture, the disappearance of this receptor is followed by an irreversible accumulation of the cells in the G1 phase of the cell cycle. The TPA-induced arrest of cell proliferation suggests the potential of this agent in experimentally treating myeloblastic leukemias.