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A M Weissman

Publications and source records attributed to A M Weissman.

71 records · Page 4Linked to original sources
PubMed1988

Tyrosine phosphorylation of the human T cell antigen receptor zeta-chain: activation via CD3 but not CD2.

TCR stimulation by Ag or anti-receptor antibodies in murine T cells results in the activation of two independent protein kinases, protein kinase C (PKC) and a protein tyrosine kinase. Similarly, stimulation of murine Thy-1 or Ly-6 with mAb also results in activation of both of these kinase pathways. Tyrosine phosphorylation in all cases occurs on the TCR zeta-chain. It is known that Ag and anti-receptor antibodies activate PKC in human T cells. In this study we demonstrate that mitogen or anti-CD3 antibodies activate tyrosine phosphorylation of the human TCR-zeta-chain. PMA, which activates PKC, does not result in zeta-chain tyrosine phosphorylation. Stimulation of human T cells by antibodies that bind the CD2 molecule is an alternate mode of inducing T cell proliferation. These antibodies surprisingly do not induce tyrosine phosphorylation of the zeta-chain. Thus, different methods of cellular activation can result in distinguishable patterns of receptor-mediated biochemical signaling events.

Antibodies, Monoclonal↗
PubMed1988

Molecular cloning of the zeta chain of the T cell antigen receptor.

The T cell antigen receptor is a multi-subunit receptor complex present on the surface of all mature and many developing T cells. It consists of clonotypic heterodimers noncovalently linked to five invariant chains that are encoded by four genes and referred to as the CD3 complex. The CD3 gamma, delta, and epsilon chains have been molecularly characterized. In this report the molecular cloning of a complementary DNA encoding the zeta chain of the murine T cell antigen receptor is described. The predicted protein sequence of the zeta chain suggests a structure distinct from those of any of the previously described receptor subunits.

Amino Acid Sequence↗
PubMed1988

Failure to synthesize the T cell CD3-zeta chain: structure and function of a partial T cell receptor complex.

The T cell antigen receptor is composed of two variable chains (alpha and beta, termed Ti), which confer ligand specificity, and five constant chains (gamma, delta, epsilon, zeta, and p21, collectively termed CD3) whose functions are poorly understood. To explore the roles of the individual CD3 components, an antigen-specific murine T cell hybridoma was chemically mutagenized and antigen-induced growth inhibition was used to select CD3/Ti expression variants. One variant produced all CD3/Ti components except CD3-zeta and was able to express small amounts of surface CD3/Ti. This variant failed to respond normally to either antigen or a mitogenic anti-Thy-1 antibody. Surprisingly, in the absence of CD3-zeta, direct cross-linking of the partial receptor induced both phosphatidylinositol hydrolysis and interleukin 2 production. These data indicate that CD3-zeta determines the normal intracellular fate of the T cell antigen receptor and is likely to play an important role in physiologically relevant transmembrane signaling.

Animals↗
PubMed1988

Molecular cloning and chromosomal localization of the human T-cell receptor zeta chain: distinction from the molecular CD3 complex.

The T-cell antigen receptor (TCR) is a multisubunit receptor complex specific to T cells subserving both antigen recognition and signal transduction functions. The zeta chain of the TCR is a component of all surface receptor complexes. This chain was first identified in murine T cells by virtue of the fact that it coimmunoprecipitates with the TCR complex using antibodies directed against either the clone-specific subunits or invariant CD3 subunits of the receptor. Recently, we have isolated a cDNA encoding the murine zeta. Using this as a probe, we have now isolated cDNAs encoding the human zeta. Sequence analysis of cDNAs encoding human and murine zeta reveals that it is a highly conserved protein. In addition to amino acid homology, there is remarkable interspecies conservation in the nucleotide sequence of the 5' and 3' untranslated regions of the zeta mRNA. The previously characterized invariant delta, epsilon, and gamma chains of the TCR, referred to as the CD3 complex, share significant sequence and structural homology with each other and are all located within 300 kilobases of each other on human chromosome 11 (11q23). zeta has no sequence similarity to the CD3 chains and the localization of the human zeta gene to the centromeric region of chromosome 1 underscores the fact that it is a distinct genetic component of the TCR.

Amino Acid Sequence↗
PubMed1987

Building a multichain receptor: synthesis, degradation, and assembly of the T-cell antigen receptor.

The murine T-cell antigen receptor consists of at least seven chains and six different proteins. The two clonotypic chains alpha and beta are glycoproteins of 40-45 kDa present as a disulfide-linked heterodimer. Four clonally invariant chains include delta (a 26-kDa glycoprotein), gamma (a 21-kDa glycoprotein), epsilon (a 25-kDa protein), and zeta (a 16-kDa protein). zeta is found in the complex as a disulfide-linked homodimer. The clonotypic chains and the invariant chains form a noncovalent complex on the cell surface. We have developed antibodies against each of the chains and used them to examine the assembly of the mature complex in the murine antigen-specific T-cell hybridoma 2B4. Pulse-chase studies of metabolically labeled cells demonstrate that many of the chains are synthesized in great excess over the amount assembled into the mature complex. These excess chains, either as free components or as partially assembled complexes, are rapidly degraded. This degradation most likely takes place in the lysosomes. The complete complex is quite stable with a long half-life. A specific hierarchy of partially assembled complexes can be discerned.

Animals↗
PubMed1986

Characterization of an anti-peptide antibody that recognizes the murine analogue of the human T cell antigen receptor-T3 delta-chain.

The T cell antigen receptor consists of two disulfide-linked 40,000 to 45,000 dalton glycoproteins (alpha and beta) that contain variable and constant regions analogous to those found in immunoglobulin molecules. The antigen receptor on murine T cells is noncovalently associated with four additional nonpolymorphic structures. We describe an antibody that binds one of these molecules, a 26,000 dalton glycoprotein homologous to the human T3 delta-chain. This antibody immunoprecipitates the entire antigen receptor complex from a T cell hybridoma and from normal murine thymocytes. It represents the first reagent that can immunoprecipitate the antigen receptor complex on all murine T cells.

Animals↗
PubMed1986

Antigen activation of murine T cells induces tyrosine phosphorylation of a polypeptide associated with the T cell antigen receptor.

The antigen receptor complex on murine MHC class II-restricted T cells consists of disulfide-linked alpha and beta chains noncovalently associated with four additional polypeptides, two that are endoglycosaminidase F-sensitive, gp26 and gp21, and two that are endoglycosaminidase F-resistant, p25 and p16. We demonstrate here that treatment of murine T cell hybridomas with phorbol 12-myristate 13-acetate results in phosphorylation of p25 and gp21 on serine residues. However, activation of cells by antigen results in the phosphorylation of the gp21 chain and a heretofore unidentified 21 kd protein. This newly defined polypeptide, p21, is specifically immunoprecipitated with the antigen receptor complex, is endoglycosaminidase F-resistant, and is itself part of a disulfide-linked molecule. Unlike antigen-induced phosphorylation of gp21, which occurs on serine residues, phosphorylation of p21 occurs uniquely on tyrosine residues.

Animals↗
PubMed1986

Only high-affinity receptors for interleukin 2 mediate internalization of ligand.

Interleukin 2 (IL-2) receptors are expressed on activated T cells and in select T-cell leukemias. Recently, it has been demonstrated that at least two classes of receptor for IL-2 exist with markedly different affinities for ligand. All known biological actions of IL-2 have been correlated with occupancy of high-affinity sites; the function of the low-affinity sites remains unknown. Receptor-mediated endocytosis is the primary means of internalization of cell-surface receptors and their ligands. The internalization of IL-2 bound to high- and low-affinity receptor sites was studied in a human T-cell lymphotrophic virus type 1 (HTLV-1)-infected human T-cell leukemia cell line and in a cloned murine cytotoxic T-cell line (CTLL). Internalization of IL-2 occurred only when bound to high-affinity sites. In addition, an anti-receptor antibody (anti-Tac), which binds equally well to high- and low-affinity sites, demonstrated no detectable internalization. The implications of these findings as they relate to IL-2 receptor structure and function are discussed.

Antibodies, Monoclonal↗
PubMed1986

Exposure of K562 cells to anti-receptor monoclonal antibody OKT9 results in rapid redistribution and enhanced degradation of the transferrin receptor.

When the human erythroleukemia cell line K562 is treated with OKT9, a monoclonal antibody against the transferrin receptor, effects on receptor dynamics and degradation ensue. The apparent half-life of the receptor is decreased by greater than 50% as a result of OKT9 treatment. The transferrin receptor is also rapidly redistributed in response to OKT9 such that a lower percentage of the cellular receptors are displayed on the cell surface. OKT9 treatment also leads to a decrease in the total number of receptors participating in the transferrin cycle for cellular iron uptake. The reduction in iron uptake that results from the loss of receptors from the cycle leads to enhanced biosynthesis of the receptor. Receptors with bound OKT9 continue to participate in multiple cycles of iron uptake. However, OKT9 treatment appears to result in a relatively small increase per cycle in the departure of receptors from participation in iron uptake to a pathway leading to receptor degradation. Radiolabeled OKT9 is itself degraded by K562 cells and this degradation is inhibitable by leupeptin or chloroquine. In the presence of leupeptin, OKT9 treatment results in the enhanced intracellular accumulation of transferrin. Because the time involved in the transferrin cycle is shorter (12.5 min) than the normal half-life of the receptor (8 h), a small change in recycling efficiency caused by OKT9 treatment could account for the marked decrease in receptor half-life. In this paper the implications of these findings are discussed as they relate to systems in which receptor number is regulated by ligand.

Antibodies, Monoclonal↗
PubMed1976

Computer support of pharmaceutical services for ambulatory patients.

A prototype computerized pharmaceutical services support system (CPSSS) is described. CPSSS maintains records on approximately 40,000 patients; 1,300 outpatient prescriptions are dispensed per day. Using Univac hardware and software developed inhouse, CPSSS provides an online drug therapy profile. The prescription label, including auxiliary information, storage and stability guidelines as well as the traditional information, is automatically generated. Prior to medication dispensing, all information is verified by a pharmacist after the computer searches the patient medication profile for 5,400 potential drug-drug, 1,500 drug-disease state, over 100 drug-allergy and 200 drug-laboratory test interactions as well as identifying duplicate pharmacological therapy. Retrospectively, the patient population is described as to sex, age and number of diagnoses. The number of prescriptions per physician also is reported. Twenty drugs represent one-half of the total prescriptions, with 32% of patients taking diuretics and 30% taking tranquilizers. All new prescriptions were prospectively reviewed. Approximately 2% had potential interactions or pharmacological duplication of therapy problems. Approximately 30% of all new prescriptions duplicated exactly an active prescription on file. When a pharmacist initiated physician contact as a result of CPSSS and profile review, physicians changed therapy approximately 73% of the time when informed of duplicate therapy, 27% of the time when informed of potential drug-disease state interactions and 32% of the time when informed of potential drug-drug interactions.

Ambulatory Care↗
PubMedDate not supplied

A new subunit of the human T-cell antigen receptor complex.

The T-cell antigen receptor binds antigen in association with a cell surface molecule encoded by the major histocompatibility complex (MHC). MHC restricted recognition of antigen by this receptor leads to the complex pattern of programmed gene expression that characterizes T-cell activation. The eventual understanding of human T-cell function will require the complete elucidation of the structure of the human T-cell antigen receptor. On human T cells, clonally determined, disulphide-linked alpha and beta chains of the receptor are non-covalently and stoichiometrically associated with three additional polypeptides known as the T3 complex. These receptor subunits are glycoproteins of relative molecular mass (Mr) 25,000 (25K) and 20K (gamma and delta) and a non-glycosylated 20K protein (epsilon). Our studies of murine T cells show that the mouse T-cell antigen receptor consists of at least seven distinct polypeptide chains. In addition to clonotypic alpha and beta chains, the murine complex consists of glycoproteins of 26K and 21K and endoglycosaminidase F (endo F)-insensitive polypeptides of 25K, 21K and 16K. The latter, which we have termed zeta (zeta), exists as a homodimer within the complex. The 26K component (gp26) has been shown to be the murine analogue of the human delta chain. Other cross species homologies remain to be established, however none of the described human receptor components appear similar to the murine zeta polypeptide. We report here the use of an antiserum raised against the murine zeta subunit to identify a previously unrecognized component of the human T-cell antigen receptor. This human protein is T-cell specific and biochemically similar to the murine zeta polypeptide.

Animals↗
PubMedDate not supplied

Advances in computer-based pharmacy systems.

This paper summarizes recent advances in computer-based pharmacy information systems for both hospitalized and ambulatory patients. It discusses the clinical pharmacy applications of: pharmacokinetic modeling (which allows for the optimization of patient-specific dosage regimens); drug interaction and adverse drug therapy monitoring (to decrease therapeutic problems); intravenous additive and hyperalimentation programs (to aid in formulating complex solutions); drug usage review (to develop and utilize guidelines for appropriate prescribing); drug information services; and drug distribution systems. Administrative and management control systems are briefly described. Automated label preparation and identification of patient noncompliance with physician-directed therapy are also described. The advantages of a computerized integrated hospital information system are also discussed.

Ambulatory Care↗
PubMedDate not supplied

Preventive health care and screening of Latin American immigrants in the United States.

BACKGROUND: The Central and South American immigrant population in the United States is large and growing. A review of the preventive health care needs of this population has not previously been done but would be helpful to clinicians caring for immigrants in this country. METHODS: Using MEDLINE, the literature related to immigrants and their health status was searched, using the key words "immigrant," "refugee," "South/Central/Latin America," "health status," "screening," "nutrition," "parasites," "stomach/gastric cancer," "children," and "psychological." The American Statistics Index and Index to International Statistics were also resources. The available literature was reviewed and led to the recommendations in this article. RESULTS: Screening strategies for Latin American immigrants are discussed for intestinal parasites, tuberculosis, hepatitis B, schistosomiasis, leprosy, American trypanosomiasis (Chagas disease), malaria, human immunodeficiency virus (HIV) infection, cervical and gastric cancer, sickle cell trait, malnutrition, iron-deficiency anemia, incomplete immunizations, dental problems, psychological problems, impairment in the elderly, alcohol use, smoking, physical inactivity, and hypertension. There are not enough data to evaluate fully the screening strategies for most of these conditions, but recommendations are offered based on current knowledge. CONCLUSIONS: Screening is recommended for intestinal parasites and schistosomiasis, tuberculosis, hepatitis B in prenatal patients, leprosy in immigrants from high-risk areas, yearly Papanicolaou smears, malnutrition, iron-deficiency anemia, incomplete immunizations, dental problems, history of violence, and depression. Screening for sickle cell trait in prenatal patients from South America and universal hepatitis B screening are less clearly indicated but could be appropriate. Screening for American trypanosomiasis (Chagas disease), malaria, and gastric cancer is not recommended. Screening for HIV infection, functional impairment in the elderly, alcohol use, cigarette smoking, physical inactivity, and hypertension should be the same as for the general population.

Central America↗