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Context: In nonallergic (naive) mice, type I cysteinyl-leukotriene receptors (CysLT1R) mediate the stimulatory effects of cytokines (eotaxin/CCL11, interleukin[IL] - 13), and nonsteroidal anti-inflammatory drugs (NSAID; indomethacin, aspirin) on eosinophil production by IL-5-stimulated bone-marrow. In ovalbumin (OVA)-sensitized mice, airway challenge-induced bone-marrow eosinophilia and eosinopoiesis are prevented by pretreatment with blockers of adrenal glucocorticoid signaling (RU486, metyrapone) or cysteinyl-leukotriene (CysLT) signaling (montelukast).Objective: To define whether allergen challenge modifies subsequent bone-marrow responses to CysLT, NSAID, and cytokines which act through type 1 CysLT receptor (CysLT1R).Methods: We examined the effects of sensitization/challenge, and of in vivo blockade of endogenous glucocorticoid or CysLT signaling, on ex vivo responses to CysLT1R-dependent stimuli.Results and discussion: Challenge abolished the stimulatory ex vivo responses to CysLT1R-dependent agents in the eosinophil lineage. In cultured bone-marrow of naive, sensitized and sensitized/challenged mice, responses to leukotriene D4 (LTD4) in eosinophil differentiation ex vivo shifted from stimulatory (without challenge) to suppressive (following challenge). Both stimulatory and suppressive LTD4 effects were blocked by montelukast. The suppressive LTD4 effect was accounted for by accelerated maturation followed by apoptosis of eosinophils. RU486/metyrapone or montelukast pretreatments before challenge prevented the challenge-induced change in subsequent responses to all these agents. Hence, allergen challenge has two separate effects on bone-marrow: (a) it enhances eosinopoiesis in vivo and upregulates ex vivo responses to IL-5; (b) it promotes a faster, but self-limiting, response to LTD4 and CysLT1R-dependent stimuli.Conclusion: Allergen challenge modifies eosinopoiesis through systemic (glucocorticoid- and CysLT1R-dependent) mechanisms, increasing responses to IL-5 but restricting responses to subsequent CysLT1R stimulation.
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Alérgenos/inmunología , Antiinflamatorios no Esteroideos/farmacología , Médula Ósea/efectos de los fármacos , Citocinas/farmacología , Leucotrieno D4/farmacología , Ovalbúmina/inmunología , Receptores de Leucotrienos/inmunología , Animales , Antiinflamatorios no Esteroideos/inmunología , Médula Ósea/inmunología , Citocinas/inmunología , Eosinófilos/citología , Eosinófilos/inmunología , Femenino , Glucocorticoides/inmunología , Glucocorticoides/metabolismo , Hipersensibilidad/inmunología , Leucotrieno D4/inmunología , Masculino , Ratones Endogámicos BALB C , Receptores de Leucotrienos/metabolismo , Transducción de SeñalRESUMEN
The mild neuroinflammation hypothesis of schizophrenia was introduced by Bechter in 2001. It has been hypothesized that a hypofunction of glutamatergic signaling via N-methyl-D-aspartate receptors (NMDARs) and hyperactivation of dopamine D2 receptors play a role in schizophrenia. The triplet puzzle theory states that sets of triplet amino acid homologies guide two different receptors toward each other and contributes to the formation of a receptor heteromer. It is, therefore, proposed that putative NMDAR-C-C chemokine receptor type 2 (CCR2), NMDAR-C-X-C chemokine receptor type 4 (CXCR4), and NMDAR- interleukin 1 receptor type II (IL1R2) heteromers can be formed in the neuronal networks in mild neuroinflammation due to demonstration of Gly-Leu-Leu (GLL), Val-Ser-Thr (VST), and/or Ser-Val-Ser (SVS) amino acid homologies between these receptor protomers. This molecular process may underlie the ability to produce symptoms of schizophrenia in mild neuroinflammation. In this state, volume transmission (VT) is increased involving increased extracellular vesicle-mediated VT from microglia and astroglia. These vesicles may contain CCR2, CXCR4, and/or IL1R2 as well as their ligands and upon internalization by endocytic pathways into neurons can form heteroreceptor complexes with NMDAR in the plasma membrane with pathological allosteric receptor-receptor interactions involving increased internalization and reduced NMDAR signaling. The triplet puzzle theory also suggests the formation of putative D2R-CCR2, D2R-CXCR4, and D2R-IL1R2 heteromers in mild neuroinflammation in view of their demonstrated sets of Leu-Tyr-Ser (LYS), Leu-Pro-Phe (LPF), and/or Ser-Leu-Ala (SLA) triplet homologies. These D2R heteroreceptor complexes may also contribute to schizophrenia-like symptoms in mild neuroinflammation by enhancing D2R protomer function.
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Cell damage and death releases alarmins, self-derived immunomodulatory molecules that recruit and activate the immune system. Unfortunately, numerous processes critical to the transplantation of allogeneic materials result in the destruction of donor and recipient cells and may trigger alarmin release. Alarmins, often described as damage-associated molecular patterns, together with exogenous pathogen-associated molecular patterns, are potent orchestrators of immune responses; however, the precise role that alarmins play in alloimmune responses remains relatively undefined. We examined evolving concepts regarding how alarmins affect solid organ and allogeneic hematopoietic cell transplantation outcomes and the mechanisms by which self molecules are released. We describe how, once released, alarmins may act alone or in conjunction with nonself materials to contribute to cytokine networks controlling alloimmune responses and their intensity. It is becoming recognized that this class of molecules has pleotropic functions, and certain alarmins can promote both inflammatory and regulatory responses in transplant models. Emerging evidence indicates that alarmins and their receptors may be promising transplantation biomarkers. Developing the therapeutic ability to support alarmin regulatory mechanisms and the predictive value of alarmin pathway biomarkers for early intervention may provide opportunities to benefit graft recipients.
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Alarminas/metabolismo , Enfermedad Injerto contra Huésped/inmunología , Receptores Inmunológicos/metabolismo , Animales , Humanos , Trasplante HomólogoRESUMEN
Natural killer (NK) cells are key components of the innate immune system. In murine cardiac transplant models, donor-specific antibodies (DSA), in concert with NK cells, are sufficient to inflict chronic allograft vasculopathy independently of T and B cells. In this study, we aimed to determine the effector mechanism(s) required by NK cells to trigger chronic allograft vasculopathy during antibody-mediated rejection. Specifically, we tested the relative contribution of the proinflammatory cytokine interferon gamma (IFN-γ) versus the contact-dependent cytotoxic mediators of perforin and the CD95/CD95L (Fas/Fas ligand [FasL]) pathway for triggering these lesions. C3H/HeJ cardiac allografts were transplanted into immune-deficient C57BL/6 rag-/- γc-/- recipients, who also received monoclonal anti-major histocompatibility complex (MHC) class I DSA. The combination of DSA and wild-type NK cell transfer triggered aggressive chronic allograft vasculopathy. However, transfer of IFN-γ-deficient NK cells or host IFN-γ neutralization led to amelioration of these lesions. Use of either perforin-deficient NK cells or CD95 (Fas)-deficient donors alone did not alter development of vasculopathy, but simultaneous disruption of NK cell-derived perforin and allograft Fas expression resulted in prevention of these abnormalities. Therefore, both NK cell IFN-γ production and contact-dependent cytotoxic activity are rate-limiting effector pathways that contribute to this form of antibody-induced chronic allograft vasculopathy.
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Anticuerpos Monoclonales/inmunología , Rechazo de Injerto/inmunología , Trasplante de Corazón , Interferón gamma/metabolismo , Células Asesinas Naturales/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Citocinas/metabolismo , Proteína Ligando Fas/inmunología , Femenino , Antígenos de Histocompatibilidad Clase I/metabolismo , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Perforina/inmunología , Trasplante Homólogo , Receptor fas/inmunologíaRESUMEN
Increasing evidence from small animal models shows that myeloid-derived suppressor cells (MDSCs) can play a crucial role in inhibiting allograft rejection and promoting transplant tolerance. We identified CD3(-)CD20(-)HLA-DR(-)CD14(+)CD33(+)CD11b(+) cells in peripheral blood of healthy rhesus macaques. These putative monocytic MDSCs constituted 2.1% ± 1.7% of lin(-)HLA-DR(-) peripheral blood mononuclear cells. Administration of granulocyte-macrophage colony-stimulating factor (CSF) and granulocyte CSF increased their incidence to 5.3% ± 3.4%. The total number of MDSCs that could be flow sorted from a single whole rhesus leukapheresis product was 38 ± 13 × 10(6) (n = 10 monkeys). Freshly isolated or cryopreserved MDSCs from mobilized monkeys incorporated in cultures of anti-CD3- and anti-CD28-stimulated autologous T cells markedly suppressed CD4(+) and CD8(+) T cell proliferation and cytokine secretion (interferon γ, IL-17A). Moreover, these MDSCs enhanced CD4(+)CD25(hi)Foxp3(+) regulatory T cell (Treg) expansion while inhibiting proliferation of activated memory T cells and increasing Treg relative to effector and terminally differentiated memory T cells. Inhibition of arginase-1, but not inducible nitric oxide synthase activity, partially reversed the inhibitory effect of the MDSCs on CD8(+) T cell proliferation. Consequently, functional MDSCs can be isolated from nonhuman primates for prospective use as therapeutic cellular vaccines in transplantation.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Monocitos/inmunología , Células Mieloides/inmunología , Linfocitos T Reguladores/inmunología , Animales , Arginasa/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Citocinas/metabolismo , Estudios de Factibilidad , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Leucaféresis , Activación de Linfocitos , Macaca mulatta , Masculino , Monocitos/metabolismo , Células Mieloides/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
Elevated serum soluble (s) suppressor of tumorigenicity-2 is observed during cardiovascular and inflammatory bowel diseases. To ascertain whether modulated ST2 levels signify heart (HTx) or small bowel transplant (SBTx) rejection, we quantified sST2 in serially obtained pediatric HTx (n = 41) and SBTx recipient (n = 18) sera. At times of biopsy-diagnosed HTx rejection (cellular and/or antibody-mediated), serum sST2 was elevated compared to rejection-free time points (1714 ± 329 vs. 546.5 ± 141.6 pg/mL; p = 0.0002). SBTx recipients also displayed increased serum sST2 during incidences of rejection (7536 ± 1561 vs. 2662 ± 543.8 pg/mL; p = 0.0347). Receiver operator characteristic (ROC) analysis showed that serum sST2 > 600 pg/mL could discriminate time points of HTx rejection and nonrejection (area under the curve [AUC] = 0.724 ± 0.053; p = 0.0003). ROC analysis of SBTx measures revealed a similar discriminative capacity (AUC = 0.6921 ± 0.0820; p = 0.0349). Quantitative evaluation of both HTx and SBTx biopsies revealed that rejection significantly increased allograft ST2 expression. Pathway and Network Analysis of biopsy data pinpointed ST2 in the dominant pathway modulated by rejection and predicted tumor necrosis factor-α and IL-1ß as upstream activators. In total, our data indicate that alloimmune-associated pro-inflammatory cytokines increase ST2 during rejection. They also demonstrate that routine serum sST2 quantification, potentially combined with other biomarkers, should be investigated further to aid in the noninvasive diagnosis of rejection.