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Cancer-related cognitive impairment (CRCI) is a broad term encompassing subtle cognitive problems to more severe impairment. CRCI severity is influenced by host, disease, and treatment factors and affects patients prior to, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a Clinical Trial Planning Meeting (CTPM) to review the state of the science on CRCI and to develop both Phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system (CNS) disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of CRCI, members of the SxQOL SC, patient advocates, representatives from all seven NCI Community Oncology Research Program (NCORP) Research Bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacologic and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three CTPM working groups (longitudinal studies and pharmacologic and behavioral intervention trials) convened for one year to discuss and report on top priorities and to design studies. The CTPM experts concluded sufficient data exist to advance Phase II/Phase III trials utilizing selected pharmacologic and behavioral interventions for the treatment of CRCI in the non-CNS setting with recommendations included herein., (© The Author(s) 2024. Published by Oxford University Press.)

Little is known about how the biological stress response systems--the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and the immune system--function during psychosis. Results of studies on the effect of stress on the immune and autonomic system in patients with schizophrenia are inconsistent. The present study investigates whether the stress response is impaired in medication-naive patients with a first episode of psychosis. Ten male patients with a first episode of psychosis and 15 controls were exposed to the stress of public speaking. Parameters of the ANS (heart rate and catecholamines), the HPA axis (plasma adrenocorticotropic hormone [ACTH] and cortisol), and the immune system (number and activity of natural killer [NK] cells) were measured. Peak responses were calculated to examine the relationship between stress-induced activation of the different systems. Subjective stress and anxiety before and during the task were assessed. Patients and controls displayed similar autonomic responses to acute stress. However, there was an impaired HPA axis response, slow onset and return of ACTH, and flattened cortisol response and a reduced increase in number NK cells and NK cell activity in patients with a first episode of psychosis. Furthermore, in patients, the relationship between the different stress response systems was weaker or absent compared with controls. These findings indicate that impairments in stress processing are associated with the endophenotype of psychosis and are not a result of illness progression or antipsychotic medication.

Background: The study of human endometrial-embryonic interactions is complicated by the disruptive impact of endometrial sample collection on the process of implantation itself. Endometrial secretion analysis is a novel technique, non-disruptive to implantation. The primary aim of this prospective cohort study was to explore whether a cytokine profile predictive of implantation and clinical pregnancy can be identified in endometrial secretions aspirated immediately prior to embryo transfer following IVF., Methods: Endometrial secretions, aspirated immediately prior to embryo transfer from 210 women undergoing IVF, were analyzed using a multiplex immunoassay for 17 soluble regulators of implantation, namely interleukin (IL)-1beta, IL-5, IL-6, IL-10, IL-12, IL-15, IL-17, IL-18, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, macrophage migration inhibitory factor, eotaxin, IFN-gamma-inducible 10 kDa protein (IP-10), monocyte chemo-attractant protein-1 (MCP-1), Dickkopf homolog 1, heparin-binding epidermal growth factor and vascular endothelial growth factor (VEGF). In order to detect implantation, daily urine samples were collected after embryo transfer, and human Chorionic Gonadotropin (hCG) concentrations were analyzed by an immunoassay., Results: Multivariable logistic regression analysis revealed significant associations (negative and positive association, respectively) between MCP-1 (P = 0.005) and IP-10 (P = 0.037) levels and implantation, and between IL-1beta (P = 0.047) and TNF-alpha (P = 0.023) levels and clinical pregnancy. The predictive value for pregnancy of IL-1beta and TNF-alpha was observed to be equivalent and additive to that of embryo quality., Conclusions: Endometrial secretion cytokine profiling offers a novel, non-disruptive approach to study the role of the endometrium in human embryo implantation and identifies a profile which appears to be conducive to clinical pregnancy., Clinical Trial Registration: www.clinicaltrials.gov (nCT00264992).

Successful implantation is an absolute requirement for the reproduction of species, including humans. The process by which a foreign blastocyst is accepted by the maternal endometrium is complex and requires interplay of many systems. Implantation occurs during the putative implantation window, in which the maternal endometrium is ready to accept the blastocyst, which on the other hand, also plays a specific role. It produces cytokines and chemokines and expresses adhesion molecules and certain classes of MHC molecules. We review the most important players in implantation. Concerning the cytokines, the establishment of controlled aggression is key; an excess of pro- or anti-inflammation is detrimental to pregnancy outcome. Chemokines control the orientation of the embryo. The adhesion molecules are necessary to establish the required physical interaction between mother and blastocyst. Finally, immune cells and in particular, uterine NK and regulatory T cells are pivotal in inducing tolerance to the blastocyst. The aim of this review is to discuss mechanisms at play and their relative importance to the establishment of pregnancy.

In the immune system, signaling by G protein-coupled receptors (GPCRs) is crucial for the activity of multiple mediators, including chemokines, leukotrienes, and neurotransmitters. GPCR kinases (GRKs) and arrestins control GPCR signaling by mediating desensitization and thus, regulating further signal propagation through G proteins. Recent evidence suggests that the GRK-arrestin desensitization machinery fulfills a vital role in regulating inflammatory processes. First, GRK/arrestin levels in immune cells are dynamically regulated in response to inflammation. Second, in animals with targeted deletion of GRKs or arrestins, the progression of various acute and chronic inflammatory disorders, including autoimmunity and allergy, is profoundly affected. Third, chemokine receptor signaling in vitro is known to be tightly regulated by the GRK/arrestin machinery, and even small changes in GRK/arrestin expression can have a marked effect on cellular responses to chemokines. This review integrates data about the role of GRKs and arrestins in inflammation, with results on the molecular mechanism of action of GRKs/arrestins, and describes the pivotal role of GRKs/arrestins in inflammatory processes, with a special emphasis on regulation of chemokine responsiveness.

Chemokine receptors belong to the family of G-protein-coupled receptors (GPCR). Phosphorylation of GPCR by GPCR kinases (GRKs) is considered to play an important role in desensitization of these receptors. We have recently shown in patients with rheumatoid arthritis that the level of GRK2 in lymphocytes is reduced by approximately 50%. However, the physiological relevance of reduced GRK2 levels in lymphocytes is not known. Here, we investigated whether reduced GRK2 expression changes the chemotactic response of T cells to the chemokines CCL3, CCL4, and CCL5. Activated T cells from GRK2+/- mice, which have a 50% reduction in GRK2 protein levels, showed a significant 40% increase in chemotaxis toward the CCR5 ligand CCL4. In addition, chemotaxis toward the CCR1 and CCR5 ligands CCL3 and CCL5 was also increased. Binding of CCL4 to activated T cells from GRK2+/- and wild-type (WT) mice was similar, but agonist-induced CCR5 phosphorylation was attenuated in GRK2+/- cells. Moreover, the calcium response and phosphorylation of protein kinase B and extracellular-regulated kinase in response to CCL4 were significantly increased in GRK2+/- T cells, showing that signaling is increased when the level of GRK2 is reduced. GRK2+/- and WT cells do become refractory to restimulation with CCL4. In conclusion, a 50% decrease in T cell GRK2 expression results in increased responsiveness to CCL3, CCL4, and CCL5, suggesting that the 50% reduction in lymphocyte GRK2 level as observed during inflammation can have functional consequences for the response of these cells to chemokines.

The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) signaling pathway is thought to play an important role in the induction of neutrophil mobilization from the bone marrow in response to granulocyte-colony stimulating factor (G-CSF) treatment. CXCR4 belongs to the family of G protein-coupled receptors. Multiple members of this receptor family are desensitized by agonist-induced G protein-coupled receptor kinase (GRK)-mediated phosphorylation. Here, we demonstrate that in vitro SDF-1-induced chemotaxis of bone marrow-derived neutrophils from GRK6-deficient mice is significantly enhanced and that desensitization of the calcium response to SDF-1 is impaired in GRK6-/- neutrophils. CXCR4 activation by SDF-1 provides a key retention signal for hematopoietic cells in the bone marrow. It is interesting that we observed that in the absence of GRK6, the G-CSF-induced increase in circulating neutrophils is profoundly impaired. Three days after injection of pegylated-G-CSF, significantly lower numbers of circulating neutrophils were observed in GRK6-/- as compared with wild-type (WT) mice. In addition, early/acute neutrophil mobilization in response to G-CSF (3 h after treatment) was also impaired in GRK6-/- mice. However, blood neutrophil levels in untreated GRK6-/- and WT mice were not different. Moreover, the percentage of neutrophils in the bone marrow after G-CSF treatment was increased to the same extent in WT and GRK6-/- mice, indicating that neutrophil production is normal in the absence of GRK6. However, the increased chemotactic sensitivity of GRK6-/- neutrophils to SDF-1 was retained after G-CSF treatment. In view of these data, we suggest that the impaired G-CSF-induced neutrophil mobilization in the absence of GRK6 may be a result of enhanced CXCR4-mediated retention of PMN in the bone marrow.

Objective: To investigate whether in rheumatoid arthritis (RA) patients the immunological changes induced by adrenaline are different from healthy controls (HC)., Methods: Fifteen female RA patients and 14 HC were infused with 1 micro g/kg adrenaline over 20 min. Blood was drawn before, immediately after, and 1 h after the end of infusion. Lymphocyte subpopulations, cytokine production and natural killer cell cytotoxicity were determined., Results: Subjects exhibited mild cardiovascular changes with no differences between patients and controls. CD16(+)CD56(+)CD3(-) NK cells increased by a factor of 5.7, CD3(+) T cells by 1.5, monocytes by 1.6 and PMN by 1.2 in both groups. The numbers of IL-8- and IL-10-producing monocytes were higher in patients and presented a larger increase after infusion. NK cytotoxic activity was higher in RA patients and increased after infusion in both groups. Activated monocytes and T cells were preferentially recruited in patients and controls. Values returned to baseline 1 h later., Conclusion: We describe an altered response to adrenaline in patients with RA with both pro- and anti-inflammatory effects. Additionally, activated T cells and monocytes recruited to the peripheral blood may influence disease activity.

Objective: To investigate whether oral administration of mycobacterial heat-shock protein 65 (HSP65) during adjuvant arthritis (AA) induces regulatory cells and cytokines., Methods: AA was induced in Lewis rats and from the time of disease onset HSP65 in the presence of soya bean trypsin inhibitor (STI) was administered orally every other day. The number of splenic CD4+CD25+ T cells and antigen-induced cytokine mRNA expression were determined., Results: Oral treatment with HSP65/STI reduced AA symptoms. After one feeding of HSP65/STI, the number of CD4+CD25+ splenic T cells increased and HSP65-specific T cells expressed increased levels of interferon gamma and interleukin 10. After two feedings, the expression of interleukin-10 mRNA remained increased, whereas there was low expression of interferon gamma mRNA. The number of CD4+CD25+ splenic T cells remained increased., Conclusions: Oral treatment with HSP65/STI after AA onset reduces disease symptoms via dynamic changes in the number of CD4+CD25+ splenocytes and in antigen-induced cytokine production.

To investigate the role of cell-mediated immunity during respiratory syncytial virus (RSV) infection, interferon (IFN)-gamma and interleukin (IL)-10 levels in nasopharyngeal secretions were measured in infants with lower respiratory tract infection (LRTI) caused by RSV. A novel technique was used to measure in vivo cytokine levels in nasopharyngeal aspirates (NPAs). Cytokine levels in the NPAs of 17 mechanically ventilated infants and 43 nonventilated hospitalized infants were compared. As expected, mechanically ventilated infants were significantly younger than nonventilated infants (7 vs. 14 weeks). IFN-gamma levels were above the limit of detection in the NPAs of 3 (18%) mechanically ventilated infants and in the NPAs of 26 (60%) nonventilated infants. IL-10 levels in the NPAs of mechanically ventilated and nonventilated infants were comparable. It is hypothesized that maturation-related mechanisms have a key role in the development of RSV LRTI that results in mechanical ventilation.

Objective: To study whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) differ from healthy individuals in their immune responses to acute psychological stress., Methods: The phenotype and function of peripheral blood lymphocytes were analysed before and after stress exposure in patients and healthy subjects., Results: Natural killer (NK) cell numbers increased transiently in all groups under stress. NK activity, however, increased in healthy controls only. We observed a stress-induced increase in interleukin (IL)-4-producing (IL-4(+)) cells in SLE patients only, whereas interferon (IFN) gamma(+) cell numbers increased due to stress in all three groups. An analysis of supernatants from phytohaemagglutinin (PHA) cultures revealed increased IFN gamma and IL-10 levels in healthy subjects but not in SLE or RA patients after stress exposure., Conclusions: These data demonstrate that RA and SLE patients differ in their immune response to stress from healthy controls. Changes in cytokine patterns might be responsible for stress-induced exacerbation of disease activity in RA and SLE patients.

Decreased quality of sleep is frequently reported by chronic fatigue syndrome (CFS) patients. The pineal hormone melatonin is involved in regulation of sleep. We analyzed the nocturnal rise in melatonin in 13 adolescent CFS patients and 15 healthy age-matched controls. Saliva samples were collected at hourly intervals between 1700 and 0200 h. Nocturnal saliva melatonin levels were significantly higher in CFS patients, compared with controls, at midnight, 0100 h, and 0200 h (P < 0.001). No differences were observed in timing of melatonin increase in saliva between patients and controls. Time of sleep onset and duration of sleep did not differ significantly between patients and controls. However, all CFS patients and only one of the controls in our study group reported unrefreshing sleep. Our data demonstrate that sleep problems in adolescents with CFS are associated with increased melatonin levels during the first part of the night. Based on these data, we suggest that there is no indication for melatonin supplementation in adolescents with CFS.

The correlation of clinical and immunological parameters with the duration of respiratory failure was investigated to identify factors determining the clinical outcome of respiratory syncytial virus (RSV) bronchiolitis necessitating mechanical ventilation. At initiation of mechanical ventilation in 30 patients with RSV, production of interleukin (IL)-12 and IL-10 was measured in 48-h peripheral blood cell cultures that were stimulated with lipopolysaccharide and interferon-gamma. The ventilation index (VI)-an indicator of respiratory dysfunction that includes partial pressure of arterial CO2, peak airway pressure, and respiratory rate-correlated with the duration of mechanical ventilation (r=.47; P=.013). Age was not associated with the duration of mechanical ventilation. A highly significant inverse correlation was found between the duration of mechanical ventilation and the production of IL-12 at admission (r=-.62; P<.001). This correlation was independent of VI. No correlation was found between IL-10 production and the duration of mechanical ventilation. It is hypothesized that low monocyte IL-12 response during initial RSV infection adversely affects clinical outcome of patients with severe RSV bronchiolitis.

The present study was designed to investigate the interaction between neuroendocrine mediators and the immune system in chronic fatigue syndrome (CFS). We examined the sensitivity of the immune system to the glucocorticoid agonist dexamethasone and the beta2-adrenergic agonist terbutaline in 15 adolescent girls with CFS and 14 age- and sex-matched controls. Dexamethasone inhibits T-cell proliferation in healthy controls and in CFS patients. However, the maximal effect of dexamethasone on T-cell proliferation is significantly reduced in CFS patients as compared with controls. The beta2-adrenergic receptor agonist terbutaline inhibits tumor necrosis factor-alpha production and enhances interleukin-10 production by monocytes. Our data demonstrate that the capacity of a beta2-adrenergic agonist to regulate the production of these two cytokines is also reduced in CFS patients. We did not observe differences in baseline or CRH-induced cortisol and ACTH between CFS patients and controls. Baseline noradrenaline was similar in CFS and controls, whereas baseline adrenaline levels were significantly higher in CFS patients. We conclude that CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest CFS should be viewed as a disease of deficient neuroendocrine-immune communication.

Insulin-like growth factor-I and -II (IGF-I and IGF-II), both of which bind to type I IGF receptors, can modulate certain functions of the immune system. We, therefore, studied the expression of type I IGF receptors on purified subpopulations of peripheral blood mononuclear cells. Using two-color flow cytometry, specific binding of a monoclonal antibody directed against the type I IGF receptor (alpha IR3) was found in every subpopulation. Relatively high numbers of receptors were detected on monocytes, natural killer cells, and CD4+ T-helper cells, an intermediate number of receptors on CD8+ suppressor/cytotoxic T-cells, and a relatively low number of receptors on B-cells. The presence of these receptors was confirmed by specific binding of [125I] IGF-I to purified subpopulations. alpha IR3 inhibited the binding of [125I] IGF-I. The specific binding of [125I]IGF-I to monocytes could be completely inhibited by IGF-II and insulin, but higher doses of these peptides were needed than of IGF-I. Scatchard analysis revealed the presence of 734 +/- 426 receptors/monocyte, with a Kd of 0.23 +/- 0.05 nM. A lower number of receptors (230 +/- 52), but with a higher affinity (Kd = 0.05 +/- 0.02 nM), was found on purified T-cells. The positive effect of IGF-I on natural killer cell cytotoxicity indicates that the type I IGF receptors on this cell type are functional. The possibility that IGF-I mediates hormonal effects on the immune system is discussed.

Lymphocytes are now recognized as an extrapituitary source of neuropeptides, such as the opioid peptide beta-endorphin. In the present paper the intracellular signalling pathways involved in regulation of the secretion of immunoreactive (ir) beta-endorphin by human peripheral blood mononuclear cells are described. Activation of protein kinase-C with a phorbol ester rapidly induces secretion of ir-beta-endorphin by T-cells as well as by the non-T cell fraction. Stimulation of protein kinase-A by the addition of (Bu)2cAMP to T-cells or non-T-cells can also induce the secretion of ir-beta-endorphin by these cells. Investigation of the effect of different mitogens or antigen on ir-beta-endorphin secretion by lymphocytes revealed that the nature of the stimulus determines the kinetics of the response and the responding cell type. Induction of ir-beta-endorphin secretion by T-cells after stimulation with a T-cell mitogen is relatively fast; it can be observed within 3 h. In contrast, the response of the non-T-cell fraction to, for example, stimulation with (Bu)2cAMP can only be observed after 18 h of culture. Evidence will be presented that the fast response is mediated via protein kinase-C activation. The response observed after 18 h can be mediated via protein kinase-C as well as protein kinase-A activation.

The immune system and the neuroendocrine system have been shown to be functionally interactive. The neuroendocrine system can modulate the immune response and immune mediators can influence the neuroendocrine system. The present paper focuses on the capacity of lymphocytes to produce and secrete neuroendocrine substances. Lymphocytes can secrete the neuropeptide beta-endorphin in response to activation with mitogen or antigen. Moreover, mediators that are involved in the adaptation to stress have also been shown to induce the release of immunoreactive-beta-endorphin by lymphocytes. It is shown here that stimulation of human peripheral blood mononuclear cells with the beta-adrenergic agonist isoprenaline induces beta-endorphin secretion. The effect of isoprenaline can be mimicked by elevation of the intracellular concentration of cAMP with forskolin or (Bu)2cAMP. Inhibition of cAMP-dependent protein kinase PKA by the antagonist N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide abrogates isoprenaline-induced secretion of immunoreactive-beta-endorphin by peripheral blood mononuclear cells. The present data give evidence that, beta-adrenergic activation activation of lymphocytes stimulates the secretion of ir-beta-endorphin via a protein kinase A-dependent mechanism. Both beta-adrenergic agonists as well as beta-endorphin have been shown to modulate the immune response. The data presented here are indicative for a role of beta-endorphin in the modulation of the immune response after beta-adrenergic activation.

Cells of the immune system can be stimulated to secrete POMC-derived peptides such as beta-endorphin and ACTH. Recently, it has been reported that CRF induces beta-endorphin secretion by human peripheral blood mononuclear cells in vitro (1). It has been shown that interleukin-1 (IL-1) mediates the CRF-induced secretion of beta-endorphin by lymphocytes in vitro. In the present report it is demonstrated that sc administration of CRF to rats can also induced beta-endorphin secretion by lymphocytes from spleen and mesenteric lymph nodes. Moreover, this CRF-induced secretion of beta-endorphin coincides with enhanced secretion of IL-1 by macrophages. Previously, we reported that IL-1 can activate CRF neurons in the hypothalamus of the brain. Our data indicate the existence of an intricate relationship between CRF and IL-1, peptides that can be viewed as playing a pivotal role in the interaction between the central nervous system and the immune system.

Human peripheral blood B lymphocytes, when cultured for 6 days with ovalbumin in the presence of T cells and monocytes, can differentiate into plaque-forming cells (PFC) secreting small amounts of antigen-specific IgM. Phenotype analysis using Ig-isotype and B-cell specific monoclonal antibodies revealed that the PFC precursor is a sIgM+ IgD+IgG- B lymphocyte. The PFC itself also carries the B-cell specific membrane antigens B1 and BA-1; it expresses only IgM on its surface. When apart from the antigen a Concanavalin A-induced, T-cell derived growth factor preparation was added to the cultures, we observed the disappearance of sIgM from the membrane. Furthermore, it was demonstrated by means of density gradient centrifugation that the differentiation of the PFC-precursor into a PFC is accompanied by a decrease in cellular density. Finally, it was shown using hydroxyurea as an inhibitor of DNA-synthesis, that the PFC-precursor passes several cycles of cell division during the process of differentiation into a PFC.

The investigation described here is concerned with the T cell regulation of the antigen-specific antibody response which has been studied in patients suffering from systemic lupus erythematosus (SLE). Apart from the fact that T helper cell activity was found to be less efficient, it appeared that the peripheral blood leucocytes (PBL) of patients in an active stage of the disease did not contain the suppressor precursor cells, which functions as the target cell for the inductive signal of T mu+ suppressor inducer cells. The absence of the suppressor precursor cells in SLE patients coincided with the absence of T gamma+ suppressor effector cells. Characterization of the (post-thymic) precursor cells (derived from normal donors) with the aid of monoclonal antibodies of the OKT series and several other markers pointed out that this population contains OKT4+ as well as OKT8+ cells. Further experiments demonstrated that the cells are capable of rosetting with autologous erythrocytes, and do not bear Fc receptors for IgM or IgG. Considering the various findings as a whole the conclusion is warranted that the post-thymic suppressor precursor T cell can differentiate into a suppressor effector cell only after interaction with T suppressor inducer cells.

Phagocytic cells of patients with chronic granulomatous disease (CGD) are severely impaired in the killing process, on the basis of defective oxygen metabolism. In this study we investigated the antigen-presenting function of monocytes (i.e. adherent cells) of CGD patients. Adherent cells of CGD patients were investigated for their capacity to present ovalbumin (OA) in such a way that T helper cells are activated and OA-specific IgM-plaque forming cells (PFC) are generated. The results showed that the dose of OA required for optimal PFC responses was 20-25 times higher than the dose of antigen which is necessary for induction of PFCs from peripheral blood mononuclear cells of normal donors. We could show that the CGD monocytes were responsible for the observed shift which indicates peculiar antigen-presenting capacities. The finding could be mimicked in normal donors by treating adherent cells with phenylbutazone, a drug known to interfere with oxygen-dependent degradation of micro-organisms. Moreover, our results suggested that CGD monocytes and phenylbutazone-treated monocytes of normal donors absorb OA but do not re-express the processed antigen on the membrane. We conclude that our system used to study antigen presentation allowed the discovery of altered antigen presentation of CGD monocytes most probably on the basis of defective antigen processing. However, antigen presentation is not entirely absent, since relatively high doses of OA induced normal PFC responses in CGD mononuclear cells.