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Biomedical subjects

J S Cairns

Publications and source records attributed to J S Cairns.

At least 19 recordsLinked to original sources
PubMed2000

Current evidence and future directions for targeting HIV entry: therapeutic and prophylactic strategies.

Great strides have been made in developing potent antiretroviral regimens that block human immunodeficiency virus (HIV) transcription and assembly. Despite these therapeutic advances, problems of drug resistance, latent viral reservoirs, and drug-induced toxic effects that compromise effective viral control point to the need for new classes of anti-HIV drugs with different modes of action. One promising approach involves blocking HIV entry into human cells, a complex process that involves multiple protein interactions. The process of HIV entry begins with binding of the viral envelope glycoprotein to both the CD4 receptor and one of several chemokine receptors and ends with fusion of viral and cell membranes. Conceptually, there are 3 steps in the HIV entry process that could serve as therapeutic targets: binding of the viral envelope glycoprotein with the CD4 receptor, binding of the envelope-CD4 complex to chemokine receptors, and fusion of the viral and cell membranes. Preclinical and clinical assessment of these entry inhibitors is ongoing and will determine if they possess properties required for drug licensure. Moreover, the worldwide epidemic is largely occurring in developing countries that cannot afford these drugs: a prophylactic vaccine is necessary and urgent. New knowledge of the HIV-envelope glycoprotein has also provided insight into possibilities for the design of novel HIV vaccines. JAMA. 2000;284:215-222

AIDS Vaccines↗
PubMed1994

Granulocyte-macrophage colony-stimulating factor augmentation of T-cell receptor-dependent and T-cell receptor-independent thymocyte proliferation.

The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) are not confined to cells of the myeloid lineage. GM-CSF has been shown to have effects on mature T cells and both mature and immature T-cell lines. We therefore examined the GM-CSF responsiveness of murine thymocytes to investigate whether GM-CSF also affected normal immature T lymphocytes. The studies presented here indicate that GM-CSF augments accessory cell (AC)-dependent T-cell receptor (TCR)-mediated proliferation of unseparated thymocyte populations. To identify the GM-CSF responsive cell type, thymic AC and T cells were examined for GM-CSF responsiveness. We found that GM-CSF augmentation of TCR-induced thymocyte proliferation appears to be mediated via augmentation of AC function, and not via direct effects on mature single-positive (SP) thymocytes. Enriched double-negative (DN) thymocytes were also tested for GM-CSF responsiveness. GM-CSF induced the proliferation of adult and fetal DN thymocytes in an AC-independent and TCR-independent single-cell assay. Thus, in contrast to the SP thymocytes, a DN thymocyte population was directly responsive to GM-CSF. GM-CSF therefore may play a direct role in the expansion of DN thymocytes and an indirect role in the expansion of SP thymocytes.

Animals↗
PubMed1993

Effect of granulocyte-macrophage colony-stimulating factor on lymphokine-activated killer cell induction.

The treatment of cancer with lymphokine-activated killer (LAK) cells in conjunction with high-dose interleukin-2 (IL-2) has been limited by the toxicity of IL-2 and the narrow range of tumors that respond to therapy. Cytokines that are capable of augmenting lower doses of IL-2 are, therefore, a major focus of research. We report here that granulocyte-macrophage colony-stimulating factor (GM-CSF) can augment low-dose IL-2 LAK induction from murine splenocytes. Anti-tumor necrosis factor alpha (anti-TNF alpha) or anti-interferon gamma (anti-IFN gamma) monoclonal antibodies did not inhibit (IL-2 + GM-CSF)-induced LAK generation, indicating that GM-CSF augmentation does not require TNF alpha or IFN gamma activity. Depletion of natural killer cells before culture did not inhibit low-dose IL-2-induced LAK generation or the ability of GM-CSF to augment LAK generation. In contrast, depletion of both CD4+ and CD8+ T cells before culture inhibited the generation of LAK activity. However, depletion of only CD4+ T cells, or only CD8+ T cells, did not inhibit the generation of IL-2 or (IL-2 + GM-CSF) LAK activity. These results suggest that LAK precursors are present in both the CD4+ and CD8+ T-cell populations and suggest that the addition of GM-CSF to low-dose IL-2 may result in the generation of T-derived LAK cells.

Animals↗
PubMed1993

Regulation of apoptosis in thymocytes.

Programmed cell death, or apoptosis, is tightly regulated during the development of T lymphocytes. Several studies have indicated that in normal mice, thymocyte are sensitive to apoptosis primarily during a brief period relatively late in the CD4+8+ maturation stage, when both positive and negative selection are thought to occur. One factor regulating sensitivity to apoptosis may be the expression and signalling capacity of the TcR/CD3 complex on developing thymocytes. In the present study, we report that sensitivity to apoptosis in immature thymocytes may also be regulated by a mechanism that can prevent induction of apoptosis in many thymocytes. This protective mechanism is induced by TcR/CD3 engagement and cross-linking, as well as by agents that mimic TcR/CD3-dependent phosphoinositol bisphosphate hydrolysis and activate Ca++ fluxes and Protein Kinase C. Cyclosporin A (CsA) inhibits the protective mechanism, permitting the induction of apoptosis by TcR/CD3 or TcR/CD3-mimicking stimuli in otherwise resistant thymocytes. In contrast, mature naive T cells do not undergo apoptosis following stimulation by these agents, even in the presence of CsA, suggesting that in mature naive T-cells the apoptotic machinery itself is normally no longer inducible. We discuss the possible implications of these results for regulation of T-cell development. In this study we also demonstrate that CsA can inhibit the ability of accessory cells to trigger thymocyte apoptosis in accessory cell-dependent assays, which may explain previous reports that CsA can inhibit the induction of thymic clonal deletion in vivo.

Animals↗
PubMed1992

Identification of a novel gene expressed in activated natural killer cells and T cells.

We have isolated a cDNA clone from a human activated NK cell-derived cDNA library that identifies a transcript (NK4) that is selectively expressed in lymphocytes. The expression of this transcript is increased after activation of T cells by mitogens or activation of NK cells by IL-2 (lymphokine-activated killer cells). The transcript levels demonstrated by Northern blot analysis increase by 12 h after activation, remain high for at least 48 h, and require protein synthesis for expression. Southern blot analysis of B lymphoblastoid lines derived from 18 unrelated individuals reveal variable banding patterns suggestive of polymorphism within the NK4 gene. No homology was found between the sequence of the coding region of this transcript and any sequences in the GenBank data base. Sequence homology to the U1 small nuclear RNA was found within the 3' untranslated region immediately upstream of the site of polyadenylation, suggesting a possible role for U1 in the polyadenylation process. Sequence analysis indicates the transcript would encode a protein having a mass of 27 kDa. The presence of a signal sequence and lack of a transmembrane region suggests that the protein is secreted. In addition, the protein contains an RGD sequence that may be involved in cellular adhesion. This transcript appears to encode a novel product common to the activation pathways of both NK cells and T cells.

Amino Acid Sequence↗
PubMed1992

The effects of immunosuppressive drugs on the regulation of activation-induced apoptotic cell death in thymocytes.

This study investigated the effects of immunosuppressive drugs on the regulation of thymocyte sensitivity to clonal deletion via programmed cell death, or apoptosis. We have previously shown that TcR/CD3 cross-linking and intracellular stimuli that mimic TcR/CD3 cross-linking induce apoptosis in many immature thymocytes in the presence, but not in the absence, of cyclosporine (CsA). We have interpreted those results to suggest that TcR/CD3-associated signals induce a CsA-sensitive mechanism that protects the cells from activation-induced apoptosis. In the present study, we compared the effects of CsA, FK506, and rapamycin (RAP) on the regulation of thymocyte apoptosis. Optimal concentrations of CsA and FK506 augmented apoptosis to similar levels. However, FK506 was approximately 100-fold more potent than CsA in thymocytes, which parallels the relative potencies of these drugs in inhibiting mitogen-induced proliferation of mature T cells. In contrast to CsA and FK506, RAP did not exhibit substantial apoptosis-augmenting activity. However, RAP interfered with the activity of FK506. This pattern mirrors that of RAP in TcR/CD3-mediated signaling pathways in mature T cells. Together these results provide evidence (1) that CsA, FK506, and RAP can act on immature thymocytes, (2) that the mechanisms by which the drugs affect mature and immature T cell responses are similar, and (3) that immunosuppressive drug therapy may affect not only mature peripheral T cells but also developing immature thymic T cells.

Animals↗
PubMed1990

Isolation of a cDNA clone encoding a novel form of granzyme B from human NK cells and mapping to chromosome 14.

We have isolated cDNA clones from a human NK cell cDNA library that encode the serine protease granzyme B. Although the sequence of the entire coding region for the mature protein and the 3' untranslated region of the clone are identical to other cDNA isolates of this gene obtained from human T cell cDNA libraries, the 5' end of two clones is 103 bp longer than the previously described sequences and would encode a protein with a 54-amino-acid-long signal sequence. Experiments characterizing granzyme B mRNA suggest that transcripts that initiate at or before the 5' end of these clones comprise a detectable but infrequent class of granzyme B transcripts in NK and T cells. We have mapped this gene to human chromosome 14 in the region 14q11----14q32, distal to the T cell receptor alpha locus and proximal to the immunoglobulin heavy chain locus. The chromosomal location of this gene, together with the previously described high sequence homology between this gene and the mouse CTLA 1/ccp1 gene, make it likely that this is the human equivalent of the mouse CTLA1/ccp1.

Animals↗
PubMed1990

A rapid method for determining the relationship between cDNA clones.

We describe a technique for rapidly screening the inserts of plasmids for homology to each other by using DNA fragments isolated in agarose gels to probe Southern blots of DNA prepared by the "miniprep" alkaline lysis method. The procedure includes a technique for labeling DNA fragments in agarose gel slices without further purification. The protocol results in a significant savings in time and expense and a considerable increase in fragment yield over methods involving fragment purification from polyacrylamide or agarose gels.

Base Sequence↗
PubMed1987

DQ beta sequences in HLA-DR4 haplotypes.

A cDNA clone encoding the entire mature DQ beta chain was isolated and sequenced from the DR4-Dw14 homozygous cell line, LS40. The sequence was compared with published DQ beta sequences from cells expressing DR4-DQw3, and found to be identical. The lack of DQ beta sequence polymorphism within this serotype (to date, DQ beta sequences have been derived from five cell lines comprising three Dw subtypes) adds to the data that suggest a recent evolutionary divergence of Dw subtypes within DR4-DQw3.

Base Sequence↗
PubMed1987

Evolutionary and genetic implications of sequence variation in two nonallelic HLA-DR beta-chain cDNA sequences.

Most HLA haplotypes carry two expressed DR beta-chain genes; in the DR4 haplotype, the polymorphic locus has been called DR beta 1 and the apparently nonpolymorphic locus has been called DR beta 2. We have isolated nearly full-length DR beta-chain cDNA clones representing each of these two loci from a cell line homozygous for DR4 and Dw4. The clones have been sequenced and the sequences compared with published DR beta cDNA sequences derived from other haplotypes. A comparison of our sequences with other published cDNA sequences did not allow assignment of these other sequences to either the beta 1 or beta 2 locus. Comparison of our DR4 beta 1 sequence with DR beta 1 sequences isolated from other DR4-positive cells suggests that the alleles of DR4 beta 1 may have recently diverged from a common ancestor. The apparent lack of polymorphism of DR beta 2 may in part be a reflection of this recent divergence.

Alleles↗