PubMed Health⌕ Search

Biomedical subjects

J L Greene

Publications and source records attributed to J L Greene.

14 recordsLinked to original sources
PubMed2003

Enhanced sensitivity to the antinociceptive effects of kappa opioids in naltrexone-treated rats: dose- and time-dependent effects.

The purpose of the present study was to examine sensitivity to the antinociceptive effects of kappa opioids during chronic treatment with the nonselective opioid antagonist naltrexone. In a warm-water tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from water maintained at 50 and 55 degrees C were recorded. Prior to chronic treatment, spiradoline, U50,488 and (-)-pentazocine produced dose-dependent increases in tail-withdrawal latencies at both 50 and 55 degrees C. Chronic treatment with 3.0 mg/kg naltrexone twice daily (b.i.d.) failed to alter sensitivity to the antinociceptive effects of spiradoline when tested 24 h following naltrexone administration. When the maintenance dose of naltrexone was increased to 30 mg/kg b.i.d., sensitivity to the effects of spiradoline was reduced when tested 24 h after naltrexone administration, but enhanced when tested 48 h after naltrexone administration. Enhanced sensitivity was also observed to the antinociceptive effects of U50,488 and (-)-pentazocine when tested 48 h after chronic treatment with 30 mg/kg naltrexone. After termination of chronic treatment, sensitivity to the antinociceptive effects of spiradoline, U50,488 and (-)-pentazocine returned to that originally observed prior to naltrexone treatment. These data indicate that chronic naltrexone treatment enhances sensitivity to the antinociceptive effects of kappa opioids, and that this effect is both dose and time dependent.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1996

Covalent dimerization of CD28/CTLA-4 and oligomerization of CD80/CD86 regulate T cell costimulatory interactions.

T lymphocyte receptors CD28 and CTLA-4 bind costimulatory molecules CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells and regulate T cell activation. While distinct functional roles have been ascribed to each of these molecules, little is known about how they interact. To better characterize these interactions, we have used surface plasmon resonance to perform equilibrium and kinetic binding analyses of extracellular fragments of CD28/CTLA-4/CD80/CD86. We show that CTLA-4 and CD28 binding are both characterized by rapid kinetic on-rates and rapid dissociation rates. Native disulfide-linked homodimers of CD28 and CTLA-4 bound with two kinetically distinct binding sites, one of high avidity and slow dissociation and one of low avidity and more rapid dissociation. Monomeric CTLA-4 bound only with low affinity and rapid dissociation. Therefore, covalent dimerization of CTLA-4 is required for its high avidity binding. Oligomerization of CD80/CD86 is also required for high avidity CTLA-4 binding since CTLA-4 bound with low avidity to monomeric CD86. This contrasts with the ability of CD80/CD86 on antigen-presenting cells to bind CTLA4Ig with high avidity and predicts their organization as oligomers or clusters that permit multivalent binding. Thus, covalent receptor dimerization and ligand oligomerization are two key features of the CD28/CTLA-4/CD80/CD86 receptor system that control ligand binding and may regulate signal transduction by controlling the duration of receptor occupancy.

Abatacept↗
PubMed1994

Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors.

B7-0 or B7-2 (CD86) is a T cell costimulatory molecule that binds the same receptors (CD28 and CTLA-4) as B7-1 (CD80), but shares with it only approximately 25% sequence identity and is expressed earlier during an immune response. Here we show that human CD86 maintains similar (within approximately 2- to 3-fold) overall receptor binding and T cell costimulatory properties as CD80. However, CD80 and CD86 did not bind equivalently to CTLA-4: CD80 bound Y100A, a form of CTLA4lg with a mutation in the CDR3-like region, > 200-fold better than did CD86; inhibition of CD80-mediated cellular responses required approximately 100-fold lower CTLA4lg concentrations; and CD80-CTLA4lg complexes dissociated 5- to 8-fold more slowly, Thus, CD80 and CD86 utilize different binding determinants and have different kinetics of binding to CD28 and CTLA-4.

Abatacept↗
PubMed1992

Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.

T cell costimulation by molecules on the antigen presenting cell (APC) is required for optimal T cell proliferation. The B7 molecule on APC binds the T lymphocyte receptor CD28, triggering increased interleukin 2 (IL-2) production and subsequent T cell proliferation. CTLA-4 is a predicted T cell membrane receptor homologous to CD28, which also binds the B7 counter receptor, but whose distribution and function are unknown. Here we have developed monoclonal antibodies (mAbs) specific for CTLA-4 and have investigated these questions. mAbs were produced that bound CTLA-4 but not CD28, and that blocked binding of CTLA-4 to B7. CTLA-4 expression as measured by these mAbs was virtually undetectable on resting T cells, but was increased several hundred-fold during T cell activation. On activated lymphocytes, CTLA-4 was expressed equally on CD4+ and CD8+ T cell subsets and was coexpressed with CD25, CD28, and CD45RO. CTLA-4 expression was lower than that of CD28, reaching a maximum of approximately 1/30-50 the level of CD28. Despite its lower expression, CTLA-4 was responsible for much of the B7 binding by large activated T cells. Anti-CTLA-4 mAb 11D4 and anti-CD28 mAb 9.3 acted cooperatively to inhibit T cell adhesion to B7, and to block T cell proliferation in primary mixed lymphocyte culture. When coimmobilized with anti T cell receptor (TCR) mAb, anti-CTLA-4 mAbs were less effective than anti-CD28 mAb 9.3 at costimulating proliferation of resting or activated T cells. However, coimmobilized combinations of anti-CD28 and anti-CTLA-4 were synergistic in their ability to augment anti-TCR-induced proliferation of preactivated CD4+ T cells. These results indicate that CTLA-4 is coexpressed with CD28 on activated T lymphocytes and cooperatively regulates T cell adhesion and activation by B7.

Abatacept↗
PubMed1992

Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule.

In vitro, when the B7 molecule on the surface of antigen-presenting cells binds to the T cell surface molecules CD28 and CTLA-4, a costimulatory signal for T cell activation is generated. CTLA4Ig is a soluble form of the extracellular domain of CTLA-4 and binds B7 with high avidity. CTLA4Ig treatment in vivo suppressed T cell-dependent antibody responses to sheep erythrocytes or keyhole limpet hemocyanin. Large doses of CTLA4Ig suppressed responses to a second immunization. Thus, costimulation by B7 is important for humoral immune responses in vivo, and interference with costimulation may be useful for treatment of antibody-mediated autoimmune disease.

Abatacept↗
PubMed1990

Synthesis and radiobiological applications of [35S]L-homocysteine thiolactone.

[35S]L-Homocysteine thiolactone ([35S]L-HCTL) was synthesized and its biodistribution evaluated as a potential brain radioprotective agent and as a tissue hypoxia marker. Drug uptake in mouse brain exceeded that in s.c. tumor 3 h post injection only. Multiple indicator dilution experiments in the rabbit heart indicate that membrane permeability of [35S]L-HCTL does not limit its usefulness as a hypoxia marker. In addition, a positive correlation was observed between regional coronary blood flow and myocardial content of [35S]adenosylhomocysteine formed from [35S]homocysteine and adenosine.

Animals↗
PubMed1987

Studies on the cellular localization and distribution of glucocorticoid receptor and estrogen receptor immunoreactivity in the central nervous system of the rat and their relationship to the monoaminergic and peptidergic neurons of the brain.

By means of monoclonal antibodies against the rat liver glucocorticoid receptor (GR) and the human estrogen receptor (ER), in combination with an immunocytochemical analysis, it has been possible to map out GR and ER immunoreactive (IR) neurons in the rat central nervous system and GR IR glial cells in the white matter. The GR IR is located in the cytoplasm and especially in the nucleus while the ER IR is only demonstrated in the nuclei of the neurons. Upon adrenalectomy the GR IR appears to be present exclusively in the cytoplasm, while after castration the ER IR is still exclusively present in the nuclei. Upon corticosterone treatment of the adrenalectomized rat the GR IR is again predominantly found in the nuclei of the neurons. These results indicate that the occupied GR and the unoccupied and occupied ER are located in the nuclei and the unoccupied GR in the cytoplasm. Evidence has been presented that large numbers of monoamine and peptide nerve cell bodies contain GR IR. Furthermore, neuronal GR IR is found in neuronal populations all over the central nervous system, especially in the cerebral cortex, the thalamus and the hypothalamus, indicating a major role of GR in regulating the metabolic and synaptic functions of the brain. The ER IR is instead limited to certain neuronal populations, mainly those of the preoptic area, the bed nucleus of the striae terminalis and the arcuate nucleus, suggesting a specific role in control of LHRH secretion and reproductive behaviour.

Adrenalectomy↗