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Biomedical subjects

K Karjalainen

Publications and source records attributed to K Karjalainen.

At least 19 recordsLinked to original sources
PubMed1992

Specific low-affinity recognition of major histocompatibility complex plus peptide by soluble T-cell receptor.

The T-cell receptor is necessary and sufficient for recognition of peptides presented by major histocompatibility complex molecules. Other adhesion molecules, like CD4 or CD8, play an auxiliary role in antigen recognition by T cells. Here we analyse T-cell receptor (TCR) binding using a soluble rather than a cell-bound receptor molecule. A TCR-immunoglobulin chimaera is constructed with the variable and the first constant regions of both the TCR alpha- and beta-chains linked to the immunoglobulin light-chain constant regions. This soluble TCR is expressed, assembled and secreted as an alpha beta heterodimer by a myeloma cell line transfected with the recombinant genes. Furthermore, the soluble TCR is biologically active: it specifically inhibits antigen-dependent activation of the relevant T-cell clones and thus discriminates between proper and irrelevant peptides presented by major histocompatibility complex molecules.

Animals↗
PubMed1992

Janusin: new molecular design for bispecific reagents.

It is well established that soluble CD4 (sCD4) inhibits HIV infection in vitro, regardless of the virus strain or genetic variant. Most effective molecules, thus far, based on sCD4 are those in which CD4 is combined with immunoglobulin constant regions (CD4-IgG or CD4-IgM). Such molecules maintained HIV-gp120 specificity mediated by CD4 and also antibody effector functions such as complement activation, Fc receptor binding, long serum half-life or transport across the placental barrier. We have now developed sCD4 molecules which are even more potent anti-HIV reagents. These molecules are based on the principle of bispecific antibodies and they have properties capable of retargeting cytotoxic T lymphocytes onto HIV-infected cells and inducing efficient killing. CD4 combined with anti-human CD3 (FvCD3) single-chain combining site has been produced (CD4-FvCD3-JANUSIN). This molecule shows the expected biological activities, namely, binding to the 2 ligands, human CD3 and gp120, also efficiently retargeting CTLs of any specificity onto HIV-infected cells. In addition, several advantages over classical bispecific antibodies can be achieved: only one polypeptide, not a mixture containing the desired product, is produced, thus simplifying the purification process. In addition, Janusin designs do not contain the Ig Fc portion, which could mediate illegitimate retargeting of T-cells. In addition to CD4-FvCD3-JANUSIN, receptor-Fv, Fv-Fv or ligand-Fv Janusins can be produced.

Antibodies↗
PubMed1991

A transcriptional enhancer of the mouse T cell receptor delta gene locus.

T cells express receptors for antigen on their surface (TcR) which consists either of alpha/beta or of gamma/delta polypeptide chains. Since the TcR delta chain gene is located within the TcR alpha chain gene locus, strict regulation of expression of the region must operate to ensure that the two loci are not concomitantly expressed in T cells bearing either alpha/beta or gamma/delta TcR. In this report it is demonstrated that elements within the mouse TcR delta gene locus, located between the J delta 2 and C delta exons, enhance transcription from a heterologous promoter five- to tenfold in a T cell hybridoma expressing a TcR gamma/delta, whereas enhancement was only twofold in an alpha/beta-bearing T cell hybridoma. No enhancement of expression was observed in a B cell hybridoma. The sequences responsible for this enhancing activity are largely confined to a 766-bp Hae III DNA restriction fragment. A region within this DNA segment shows significant homology (73% identify) to a recently identified enhancer of the human TcR delta gene locus.

Animals↗
PubMed1991

Mouse LFA-3 studied with chimeric soluble CD2 shows preferential expression on lymphoid cells.

Here we have used a soluble, polyvalent form of mouse CD2, i.e. CD2-hC mu, to detect its ligand LFA-3. Mouse LFA-3 is preferentially expressed on lymphoid cells unlike human LFA-3 which shows a wide tissue distribution. Mouse LFA-3 is one of the early surface molecules expressed on developing thymocytes appearing on the surface of fetal thymocytes on day 13 of gestation. Like human LFA-3, the mouse homolog could be shown to be a phosphatidyl inositol-linked membrane protein. Since mouse LFA-3 is preferentially expressed on lymphoid cells and since CD2 is expressed by both T and B lymphocytes, we would favor the view that the CD2/LFA-3 adhesion system in the mouse may play a role in interactions between lymphocytes (T-T and/or T-B) rather than in cell interactions between lymphocytes and non-lymphoid cells in the thymic, bone marrow or spleen microenvironments.

Animals↗
PubMed1991

Bispecific single chain molecules (Janusins) target cytotoxic lymphocytes on HIV infected cells.

The human immunodeficiency virus type 1 (HIV-1) uses cell surface CD4 as a receptor to infect susceptible cells. Therefore, different forms of soluble CD4 (sCD4) molecules have been developed recently for potential therapeutic purposes. Here we describe a novel design of sCD4 molecules which exploit cytotoxic T cells as their effector function. The principle of bispecific antibodies was exploited and further developed to create new bispecific reagents which could retarget cytotoxic T cells of any specificity and thus, induce killing of HIV-1 infected cells. The most advanced molecules, Janusins, contain in one polypeptide chain the first two N-terminal CD4 domains and single chain combining site against the human CD3 complex (FvCD3).

Amino Acid Sequence↗
PubMed1991

Surface expression of the beta T cell receptor (TCR) chain in the absence of other TCR or CD3 proteins on immature T cells.

T cell receptor (TCR) beta genes are rearranged prior to TCR alpha genes. A productively rearranged TCR beta gene suppresses further V beta gene rearrangement. Here we show that in beta TCR transgenic mice the TCR beta-chain can be expressed on the surface of immature CD4-8- thymocytes, but not on mature T cells, in the absence of any other known TCR chain and proteins of the CD3 complex. Analysis by NEPHGE and SDS-PAGE showed that at least some beta TCR exists on the surface as a large disulfide-linked complex with unknown acidic molecules. The introduction of the beta TCR gene into scid mice resulted in the expression of the beta TCR on the cell surface of thymocytes and induced the expression of CD4 and CD8 co-receptors as well as transcription of the alpha TCR locus.

Animals↗
PubMed1991

Comparison of incentive spirometry and intermittent positive pressure breathing after coronary artery bypass graft.

Fifty-two patients were randomized to receive either incentive spirometry (IS) or intermittent positive pressure breathing (IPPB) in addition to conventional chest physical therapy following coronary artery bypass grafting. Slow vital capacity and peak expiratory flow readings decreased rapidly and to an equal extent in both groups after surgery, and partly recovered by the sixth postoperative day (POP). Arterial PO2 values were similar for the groups on the first three POPs. On the POPs 2, 3, and 6, the number of chest films showing atelectases as well as the number of individual patients having atelectases revealed no statistically significant differences between the two groups. Based on the three variables studied, we consider both devices equal in efficiency after coronary surgery.

Blood Gas Analysis↗
PubMed1991

Piperacillin compared with cefuroxime plus metronidazole in diffuse peritonitis.

Eighty-five patients were randomly allocated to receive either piperacillin (n = 38) or cefuroxime plus metronidazole (n = 45) after surgical treatment of diffuse peritonitis; 78 were evaluable. A mean of 1.5 (piperacillin group) and 1.7 (cefuroxime/metronidazole group) pathogens/patient were identified. Twenty-seven patients (71%) were successfully treated in the piperacillin group compared with 29 (64%) in the cefuroxime/metronidazole group. These data suggest that piperacillin was neither better nor worse than cefuroxime/metronidazole in diffuse, secondary peritonitis.

Acute Disease↗
PubMed1990

Long-term maintenance of therapeutic response to lovastatin in patients with familial and non-familial hypercholesterolemia: a 3-year follow-up.

The 3-year efficacy of lovastatin alone or in combination with colestipol was evaluated in 54 patients with type 2 hyperlipoproteinemia (22 non-familial and 32 familial hypercholesterolemic patients). A sufficient and sustained reduction in LDL cholesterol was achieved in non-familial hypercholesterolemia with lovastatin alone (average dose 74 mg/day, range 40-80 mg/d), whereas combination therapy with lovastatin 80 mg/d and colestipol (average dose 11.9 g/d, range 5-20 g/d) was required in familial hypercholesterolemia. The percentage changes from baseline at 3 years in serum LDL cholesterol, HDL cholesterol and total triglycerides were in the lovastatin-only group -53%, +10% and -15%, respectively, and in the two-drug group -58%, +22% and -18%, respectively. A subgroup analysis in patients with non-familial hypercholesterolemia indicated that the lipid-modifying effects of lovastatin were similar in type 2A and 2B phenotypes, except for a greater triglyceride lowering effect in type 2B. The lovastatin-alone regimen was well tolerated, whereas addition of colestipol caused subjective side effects in many patients. Serious side effects or discontinuations due to therapies did not occur. Both therapies caused slight but significant increases (within normal limits) in average serum transaminase levels. After 36 months a significant rise of 1.7 kg in mean body weight was observed in the lovastatin-only group. The ophthalmological follow-up did not reveal any cataractogenic effect attributable to treatment during the 3.8-year follow-up period.

Adult↗
PubMed1989

Production and secretion of recombinant soluble CD3 polypeptides by myeloma-derived transfectant clones.

Soluble forms of three human CD3 proteins have been produced by recombinant DNA techniques. The extracellular domain of CD3-gamma, -delta or -epsilon has been linked to the constant region of mouse immunoglobulin kappa light chain to form gamma-kappa, delta-kappa and epsilon-kappa chimaeric proteins. These are secreted by mouse myeloma-derived transfectant cell lines and are immunoprecipitable by CD3- or kappa-specific polyclonal antisera. Yields of 100-500 micrograms secreted recombinant proteins per litre of culture medium were obtained, which could be purified by anti-kappa affinity chromatography. The production of soluble CD3 illustrates the applicability of this technology to a loosely associated protein complex.

Antigens, Differentiation↗
PubMed1989

Highly efficient neutralization of HIV with recombinant CD4-immunoglobulin molecules.

The human immunodeficiency virus type 1 (HIV-1) exploits the cell surface CD4 molecule to initiate the infection which can lead, eventually, to acquired immunodeficiency syndrome (AIDS). The HIV-1 envelope protein, gp120, interacts specifically with CD4 and soluble CD4 molecules have been shown to inhibit HIV infectivity in vitro. Effective inhibition in vivo may, however, require more potent reagents. We describe here the generation of molecules which combine the specificity of CD4 and the effector functions of different immunoglobulin subclasses. Replacing the VH and CH1 domains of either mouse gamma 2a or mu heavy chains with the first two N-terminal domains of CD4 results in molecules that are secreted in the absence of any immunoglobulin light chains. We find that the pentameric CD4-IgM chimaera is at least 1,000-fold more active than its dimeric CD4-IgG counterpart in syncytium inhibition assays and that effector functions, such as the binding of Fc receptors and the first component of the complement cascade (Clq), are retained. Similar chimaeric molecules, combining CD4 with human IgG were recently described by Capon et al., but these included the CH1 domain and did not bind Clq. Deletion of the CH1 domain may allow the association and secretion of heavy chains in the absence of light chains, and we suggest that the basic design of our constructs may be generally and usefully applied.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Solubilizing the T-cell receptor--problems in solution.

Recombinant DNA technology has been central in answering some of the most important questions in immunology and has recently helped to define the complex of membrane associated proteins on T-cell surfaces responsible for antigen recognition. Here André Traunecker and colleagues describe attempts to facilitate the analysis of this complex using genetic engineering to produce solubilized T-cell receptor and associated molecules.

Animals↗
PubMed1988

Soluble CD4 molecules neutralize human immunodeficiency virus type 1.

Human immunodeficiency virus (HIV) infection can bring about total collapse of the immune system by infecting helper T lymphocytes which express CD4, the molecule which mediates interaction between the cell surface and viral envelope glycoprotein gp120 (refs 3-10). HIV apparently escapes the effects of neutralizing antibodies in vivo by generating new variants which must still interact with CD4 to maintain a cycle of infection. One route to block HIV infection, therefore, could use solubilized CD4 protein to inhibit attachment of the virus to its target cell. We have used recombinant DNA techniques to generate soluble forms of CD4, and show here that these are potent inhibitors of HIV infection in vitro.

Animals↗
PubMed1988

Suprasellar meningioma 47 years after bilateral retinoblastoma.

Development of an additional primary tumour, a suprasellar meningioma, is reported 47 years after successful treatment of bilateral retinoblastoma. The left eye of the patient was enucleated at the age of 1.5 years and the left orbit radiated with a total dose of 1200 rads. The right eye was treated by orthovoltage radiation only at the age of 4 years, the total dose being 5100 rads. The right eye became blind and phthisical, and it was enucleated at the age of 42 years. No active retinoblastoma was found. At the age of 48 years a large suprasellar meningioma was diagnosed and partially removed.

Eye Neoplasms↗