PubMed Health⌕ Search

Biomedical subjects

Richard Kennedy

Publications and source records attributed to Richard Kennedy.

17 recordsLinked to original sources
PubMed2006

T helper lymphocytes rescue CTL from activation-induced cell death.

T cell activation is characterized by a vast expansion of Ag-specific T cells followed by an equally extensive reduction in T cell numbers. This decline is due, in part, to activation-induced apoptosis of the responding T cells during repeated encounter with Ag. In the current study, we used solid-phase MHC class I/peptide monomers to cause activation-induced cell death (AICD) of previously activated CD8 T cells in an Ag-specific manner. AICD occurred rapidly and was mediated primarily by Fas-FasL interactions. Most interestingly, we observed that Th cells could provide survival signals to CTL significantly reducing the level of AICD. Both Th1 and Th2 subsets were capable of protecting CTL from AICD, and a major role for soluble factors in this protection was ruled out, as cell-to-cell contact was an essential component of this Th-mediated protection. Upon encounter with Ag-expressing tumor cells, CTL underwent significant apoptosis. However, in the presence of Th cells, the CTL not only were protected against death, but also had significantly greater lytic ability. In vivo tumor protection studies using peptide immunization showed that the activation of Ag-specific Th cells was crucial for optimal protection, but did not affect the magnitude of the CTL response in the lymphoid tissues. In this study, we examine the type of help that CD4 T cells may provide and propose a model of Th cell-CTL interaction that reduces CTL death. Our results show a novel role for Th cells in the maintenance of CTL responses.

Animals↗
PubMed2006

Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway.

Cisplatin resistance occurs, at least in part, through the function of the Fanconi anemia (FA)/BRCA pathway, a DNA-damage response pathway required for repair of cisplatin cross-links. In the current study, we designed a cell-based screening strategy to identify small-molecule inhibitors of the FA/BRCA pathway with the hypothesis that such molecules could restore sensitivity to platinum agents. We identified four inhibitors, including three protein kinase inhibitors (wortmannin, H-9, and alsterpaullone) and one natural compound (curcumin) that inhibit the FA/BRCA pathway. We show that curcumin, a compound that is generally regarded as safe, inhibits the monoubiquitination of the FANCD2 protein as predicted by the screen and consequently sensitizes ovarian and breast tumor cell lines to cisplatin through apoptotic cell death. We believe that this study shows an efficient, high-throughput method for identifying new compounds that may sensitize cancer cells to DNA-damaging chemotherapy.

Androstadienes↗
PubMed2005

Direct cross-priming by th lymphocytes generates memory cytotoxic T cell responses.

Under optimal Ag stimulation, CTL become functional effector and memory T cells. Professional APCs (pAPC) are considered essential for the activation of CTL, due to their unique capacity to provide costimulation and present exogenous Ags through MHC class I molecules. In this study, we report a novel means by which Th lymphocytes acquire and present MHC class I determinants to naive CTL. Although previous studies have looked at T cell Ag presentation to activated T cells, this study presents the first example of Ag presentation by Th cells to naive CTL. We report that activated Th cells can function as effective pAPC for CTL. Our results show that: 1) In addition to acquisition of cell surface molecules, including MHC class I/peptide complexes, from pAPC, Th cells can acquire and present MHC class I-binding peptides through TCR-MHC class II interactions with pAPC; 2) the acquired Ag can be functionally presented to CTL; and 3) Ag presentation by Th cells induces naive CTL to proliferate and preferentially differentiate into cells that phenotypically and functionally resemble central memory T cells. These findings suggest a novel role of Th cells as pAPC for the development of memory immune responses.

Animals↗
PubMed2005

Investigation and current management of recurrent IVF treatment failure in the UK.

OBJECTIVE: To determine current practice in the management of recurrent in vitro fertilisation (IVF) treatment failure in licensed UK infertility centres. DESIGN: National postal questionnaire study and literature review. SETTING: University Hospital, Centre for Reproductive Medicine, Coventry, UK. SAMPLE: Human Fertilisation and Embryology Authority licensed centres providing IVF/intracytoplasmic sperm injection (ICSI) in the UK (n = 79). METHODS: A survey was designed that sought to determine how recurrent treatment failure was defined and which, if any, investigations were initiated. Furthermore, we asked which therapeutic options were subsequently recommended. MAIN OUTCOME MEASURES: Definition of recurrent treatment failure. Investigations undertaken. Clinical or embryology changes recommended following recurrent treatment failure. RESULTS: The response rate was 82%. The most common definition was three unsuccessful IVF cycles (range 2-6). Nineteen percent included frozen embryo replacements (FERs) in this figure. Anticardiolipin antibodies and lupus anticoagulant were the most frequent investigations suggested, followed by hysteroscopy and karyotype. A majority of centres would use a different treatment strategy in a subsequent cycle with blastocyst culture and assisted hatching being most popular. CONCLUSIONS: The results of this survey suggest that there is considerable variation in the approach to investigation and management of recurrent IVF treatment failure in the UK, although in some areas (e.g. the definition) there was broad concordance. Not all of these approaches are evidence based.

Adult↗
PubMed2004

The Loss Inventory: preliminary reliability and validity data for a new measure of emotional and cognitive responses to disability.

PURPOSE: To examine the utility, reliability and validity of a new scale, The Loss Inventory (LI) for measuring symptoms unique to grief following disablement. METHODS: Prospective survey study in which two self-report measures, the LI and Zung Self-Rating Depression Scale, were administered to 103 hospitalized rehabilitation patients. Correlational analyses, t tests, t score conversions of raw data, and analysis of variance used to determine reliability (internal consistency) of the LI and compare means of scores across several variables. RESULTS: Cronbach's Alpha=0.90 for the LI. The Zung and the LI correlated 0.59 but study subjects were significantly (p<0.001) more likely to score higher on the LI than on the Zung. Certain LI items were significantly more frequently endorsed by depressed patients. Significant gender and ethnic differences were found. CONCLUSIONS: Rehabilitation patients sampled in this study were no more likely to be depressed than most people. Grief symptoms reported following functional losses are similar to those reported by persons who have experienced the death of someone close. The Loss Inventory reliably measures these grief symptoms. Gender and ethnicity affect the manner in which grief symptoms are reported. The LI may improve mental health clinicians' diagnostic accuracy in rehabilitation and medical settings.

Brain Injuries↗
PubMed2003

Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade.

Although peptide immunization often leads to the induction of strong T-cell responses, it is seldom effective against established tumors. One possibility is that these T-cell responses are not strong enough or do not last sufficiently long to have an effect in tumor eradication. Here, we examined the role of synthetic oligodeoxynucleotide (ODN) adjuvants containing unmethylated cytosine-guanine motifs (CpG-ODN) and CTLA-4 blockade in enhancing the antitumor effectiveness of peptide vaccines intended to elicit CTL responses. The results show that combination immunotherapy consisting of vaccination with a synthetic peptide corresponding to an immunodominant CTL epitope derived from tyrosinase-related protein-2 administered with CpG-ODN adjuvant and followed by systemic injection of anti-CTLA-4 antibodies increased the survival of mice against the poorly immunogenic B16 melanoma. Interestingly, whereas this combination therapy was effective when administered to tumor-bearing mice (therapeutic protocol), it had no significant effect when applied in the prophylactic mode (i.e., before the tumor challenge). Moreover, the antitumor effect of the combination immunotherapy required the participation of CD4+ and CD8+ T lymphocytes and was accompanied by the induction of antitumor CD4+ T-cell responses. The overall results suggest that peptide vaccination of tumor-bearing mice, applied in combination with a strong adjuvant and CTLA-4 blockade, is capable of eliciting durable antitumor T cell responses that provide survival benefit. These findings bear clinical significance for the design of peptide-based therapeutic vaccines for human cancer patients.

Abatacept↗
PubMed2003

Economic evaluation of highly purified menotropin compared with recombinant follicle-stimulating hormone in assisted reproduction.

OBJECTIVE: To determine the cost of achieving pregnancy with different gonadotropin preparations. DESIGN: Cost-minimization analysis of a prospective randomized clinical trial. SETTING: Twenty-two centers in six countries. PATIENT(S): Women 18 to 36 years of age with infertility for more than 1 year who were undergoing IVF or ICSI. INTERVENTION(S): Highly purified hMG or recombinant FSH. RESULT(S): Mean cost of achieving an ongoing pregnancy. The mean cost per patient treatment cycle was estimated to be pound 2423 with highly purified hMG (95% CI, pound 2356 to pound 2495) and pound 2745 with recombinant FSH (95% CI, pound 2658 to pound 2830). The ongoing pregnancy rate was 22% with highly purified hMG and 19% with recombinant FSH. The cost per ongoing pregnancy was pound 10781 with highly purified hMG (95% CI, pound 9056 to pound 12919) and pound 14284 with recombinant FSH (95% CI, pound 11883 to pound 17891). CONCLUSION(S): Highly purified hMG and recombinant FSH are equally effective, but highly purified hMG is less expensive per cycle. Using highly purified hMG instead of recombinant FSH would translate into a 13% increase in the number of cycles that could be offered.

Adult↗
PubMed2003

Electroconvulsive therapy in movement disorders: an update.

Electroconvulsive therapy (ECT) is a well-recognized treatment for psychiatric illness, primarily depressive disorders. Its use in patients with neurological illnesses is steadily increasing. Older reviews indicate that ECT may also benefit Parkinson's disease and similar movement disorders independent of its effects on comorbid psychiatric disorders. In this updated review, recent literature regarding ECT and movement disorders is summarized from 1990 to 2000. Considerable evidence indicates that ECT improves motor symptoms of Parkinson's disease in patients with and without mood disorders. A few case reports, ranging from one to six patients per disorder, suggest that ECT may ameliorate the motor symptoms of other movement disorders. ECT affects a variety of neurotransmitters that play a role in these diseases. Limitations of current reports are reviewed, and recommendations for further investigation are made.

Akathisia, Drug-Induced↗
PubMed2002

The stimulation of tumor necrosis factor and inhibition of glucose transport and lipoprotein lipase in adipose cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is found throughout the environment in industrialized countries, and most people have had some exposure. TCDD has very high lipid solubility and is concentrated in adipose tissue. Because an epidemiologic association between TCDD exposure and diabetes has been described, we examined the effects of TCDD in adipocytes. The addition of TCDD to 3T3-F442a cells, both at the initiation of differentiation and after cells were fully differentiated, resulted in a 2-fold increase in the secretion of tumor necrosis factor (TNF). When added during differentiation, there was also a 25% decrease in lipid accumulation. In addition to the stimulation of TNF, TCDD affected glucose transport and lipoprotein lipase (LPL) activity. When added to cultures of cells that were undergoing differentiation, TCDD inhibited total 2-deoxyglucose transport in a dose-dependent fashion, with 50% inhibition of glucose transport when added to cultures for 48 hours at 5 nmol/L TCDD. In addition, when cells were exposed to 50 nmol/L TCDD for 48 hours, there was a 40% reduction in LPL activity. Thus, the addition of TCDD to adipocyte cultures resulted in an increase in TNF secretion and a decrease in glucose transport and LPL activity. Because TCDD is concentrated in adipose tissue, these studies provide a possible physiologic mechanism for epidemiologic studies that link dioxin to diabetes.

3T3 Cells↗
PubMed2002

Direct costimulation of tumor-reactive CTL by helper T cells potentiate their proliferation, survival, and effector function.

The survival and proliferation of CTL during the effector phase of the immune response is critical for the elimination of infectious agents and tumor cells. We report here that in an in vitro model system, the expansion and cytolytic function of tumor-reactive human CTL can be enhanced by CD4(+) helper T lymphocytes through costimulatory signals that are mediated by cell surface molecules. The results presented here suggest that costimulatory receptors on CTL such as CD27, CD134 (4-1BB), and MHC class II are capable of directly interacting with the corresponding ligands on T-helper lymphocytes resulting in enhanced proliferation and survival of the CTL during the effector phase of antitumor immune responses. These findings underline the importance of antigen-specific helper T lymphocytes for the regulation and maintenance of CTL immunity, and have implications for the design of therapeutic vaccines for cancer.

Antigens, CD↗
PubMed2002

Interleukin 15 promotes antigen-independent in vitro expansion and long-term survival of antitumor cytotoxic T lymphocytes.

The survival and expansion of effector cytotoxic T lymphocytes (CTLs) during an immunological response are critical for the successful elimination of life-threatening attacks by microorganisms, parasites, or malignant cells. Among the numerous factors that regulate the immune response, interleukin (IL)-2, and its close relative, IL-15 are known to function as growth and survival factors for antigen-experienced T cells. However, major differences appear to exist between these lymphokines in their capacity to act on various T-cell types such as CD4+ versus CD8+ or effector versus memory T lymphocytes. Although several studies have been done in the mouse system, less information is available regarding the function of these lymphokines in the human system. Here, we report that IL-15 or high concentrations of IL-2 induced antigen-independent expansion of effector CD8+ CTLs. Neither IL-2 nor IL-15 induced the proliferation of CD4+ T cells. In the absence of antigen, at least one of these lymphokines was required for the long-term survival of the cells in tissue culture. Most significantly, the effector cytolytic activity of CTLs expanded and maintained in IL-15 for up to 60 days remained stable, indicating that these cells do not differentiate into a memory functional phenotype. The expression of IL-15Ralpha, which was detected on CD8+ CTLs but not on CD4+ helper T cells, suggests that this receptor subunit somehow participates in the transduction of the mitogenic signals of IL-15. The present findings have practical implications for the propagation of antigen-specific T-cell lines in vitro and could be useful for expansion of therapeutic T cells for adoptive transfer.

CD4-Positive T-Lymphocytes↗
PubMedDate not supplied

T-Cell epitope discovery for variola and vaccinia viruses.

Variola major, the causative agent of smallpox, afflicted mankind throughout history until the worldwide World Health Organisation WHO vaccination campaign successfully eradicated the disease. Unfortunately, recent concerns about bioterrorism have renewed scientific interest in this virus. One essential component of our biodefense and preparedness efforts is an understanding of poxvirus immunity. To this end a number of laboratories have sought to discover T- and B-Cell epitopes from select agents such as variola virus. This review focuses on the efforts to identify CD8(+) T-Cell epitopes from poxviruses as a means to develop new vaccines and therapeutics. A wide variety of techniques have been employed by several research groups to provide complementary information regarding cellular immune responses to poxviruses. In the last several years well over 100 T-Cell epitopes have been identified and the work rapidly continues. The information gleaned from these studies will not only give us a greater understanding of immunity to variola virus and other viruses, but also provide a foundation for next generation vaccines and additional tools with which to study host-pathogen interactions.

Amino Acid Sequence↗
PubMedDate not supplied

Differences in characteristics and outcome of delirium as based on referral patterns.

The authors studied factors associated with referral of delirium patients to psychiatry consultation and its outcome implications. Characteristics and treatment outcomes of delirium patients referred to psychiatry were compared with those not referred. Referred patients were younger, had a more hyperactive subtype, greater substance abuse, less comorbid dementia, were more likely to be recognized as having delirium, and be prescribed medications. Improvement in referred patients was indicated by lower readmission rate postdischarge. No differences were noted in length of stay, discharge status, or mortality within 1 year of the index episode. Psychiatric interventions were moderately helpful. Patients' characteristics and delirium subtypes may influence referral and should inform future liaison efforts.

Age Factors↗