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Query: K01C8 .1
 572,118 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The effect of sensory neuropeptides and capsaicin on basal and stimulated tone of mouse bronchial smooth muscle has been evaluated. 2. In basal conditions neither sensory neuropeptides (substance P, neurokinin A or calcitonin gene-related peptide (CGRP) nor capsaicin exerted any contractile effects. However, when a tonic contraction was induced with carbachol (1 microM) a prompt relaxation was induced by substance P (1- 100 nM) and by neurokinin A (1- 100 nM), with substance P being more potent. A second application of substance P was without effect. CGRP (10 nM) produced only a very small and erratic relaxation. Relaxation was also induced by capsaicin (1 microM), and this response could be evoked only once in each preparation. In 4 out of 6 preparations a cross-desensitization between substance P and capsaicin was observed. 3. The selective NK1 tachykinin agonist, [Pro9]-SP sulphone (1 microM), exerted potent bronchodilator actions on carbachol-contracted mouse bronchial preparations. In contrast, neither [beta Ala8]-NKA (4-10) nor [MePhe7]-NKB (both at a concentration of 1 microM), selective synthetic agonists for NK2 and NK3 receptors, exerted significant relaxant effects. Furthermore, the selective NK1 tachykinin antagonist, (+/-)-CP 96,345 (1 microM), abolished substance P (1 nM)- but not isoprenaline (0.1 microM)-induced relaxations. 4. Application of electrical field stimulation (EFS) (20 Hz, supramaximal voltage, 0.5 ms for 10 s) to carbachol-contracted preparations evoked a transient contraction followed by a relaxation. The tetrodotoxin-sensitive slow component of this relaxation was reduced following capsaicin desensitization. 5. In the presence of indomethacin (5 microM) the relaxation induced by substance P, capsaicin or EFS was suppressed.6. In conclusion, the mouse main bronchus appears to be a monoreceptorial tissue containing only NK, receptors which subserve bronchodilator functions. Such receptors could be activated by exogenous or endogenously (capsaicin or EFS) released tachykinins and the consequent relaxation is probably mediated by the generation of prostanoids.
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PMID:Bronchodilatation by tachykinins and capsaicin in the mouse main bronchus. 138 Mar 76

The transplantable rat kidney carcinoma (RKC) provides an excellent experimental model for immunological and therapeutic studies of renal cell carcinoma. In this report, we define the biological characteristics of RKC and explore the interactions between RKC and natural killer (NK) cells. RKC, a transplantable tumor of spontaneous origin, grows progressively over a 12-week period and metastasizes to the lung when implanted orthotopically in the kidneys of female Lewis rats. Rats bearing RKC survived for an average of 10.5 +/- 1.5 (SD) weeks postimplantation. Lung metastases were visible between 7.5 and 8.5 weeks postimplantation, and by 9 to 10 weeks the incidence of metastases reached approximately 67%. Injection of the NK cell-specific monoclonal antibody 3.2.3 depleted Lewis rats of their NK activity for up to 14 days. Adherent lymphokine-activated killer cells generated from the spleens of 3.2.3-injected rats were significantly less lytic than those from control rats and contained a significantly lower percentage of 3.2.3+ cells when analyzed by flow cytometry. Groups of rats were implanted with RKC and received injections of 3.2.3 biweekly to maintain depletion of NK cells or of a control antibody, NK1.1, specific for mouse NK cells. At 10 weeks postimplantation, 3.2.3-injected rats had significantly (P < or = 0.005) larger tumors (104.4 +/- 20.1 g) than NK1.1-injected rats (75.4 +/- 13.9 g). Spleen cells and peripheral blood cells from uninjected, tumor-bearing rats had a slight but nonsignificant decrease in NK activity against 51Cr-labeled YAC-1 targets over the course of RKC progression. The activity of adherent lymphokine-activated killer cells from tumor-bearing rats was lower than that from normal rats, but not significantly. Cultured RKC cells were killed by both splenic NK cells and adherent lymphokine-activated killer cells. These data demonstrate that RKC is NK sensitive and that tumor growth does not abrogate NK activity. The RKC tumor provides a model system for the analysis of immunological factors in renal cell carcinoma growth and presents opportunities for testing therapeutic interventions in a system that closely mimics the human disease.
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PMID:Renal cell carcinoma and natural killer cells: studies in a novel rat model in vitro and in vivo. 142 74

The purpose of the present study was to further delineate the role of natural killer (NK) cells in the early stages of resistance to infection by Pseudomonas aeruginosa, strain PAO1. Intravenous injection of the monoclonal antibody alpha-NK1.1 resulted in an 82% reduction in NK cell activity of normal mice, as measured by a standard 4-hour 51Cr release assay. Splenic bacterial clearance was examined in mice treated with this antibody 12 h prior to infection with a sublethal dose (10(6)) of PAO1. At 2, 4, and 6 h postinfection there was significant enhancement (up to 10-fold) of clearance in mice treated with alpha-NK1.1 when compared to untreated infected control animals. Interestingly, the enhanced clearance of PAO1 in the spleens of NK-depleted mice was found to be coupled to a significant increase in neutrophils. Normal murine spleens were found to contain 1-2% neutrophils, which increased to 6-7% following sublethal infection. However, in mice treated with alpha-NK1.1 and infected, splenic neutrophils increased up to 15% during the early stages of infection. The data presented here suggests that NK cells do not have direct bactericidal activity against Pseudomonas, but may regulate other effector cells, such as neutrophils-an indirect role for natural killer cells, probably mediated in vivo by their production and secretion of cytokines.
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PMID:Enhanced splenic bacterial clearance and neutrophilia in anti-NK1.1-treated mice infected with Pseudomonas aeruginosa. 147 96

In mice, the NK1.1 alloantigen is expressed on all NK cells and it initiates transmembrane signals that activate cytotoxicity. NK1.1 has been mapped to a chromosomal region that encodes two families of receptor-like molecules, the NKR-P1 family and the Ly-49 family. Both of these gene families encode type II integral membrane proteins whose extracellular domains are homologous with known C-type lectins. We have isolated and expressed a member of the NKR-P1 gene family (mNKR-P1.9) and have demonstrated both by immunofluorescence and by immunoprecipitation that this cDNA encodes NK1.1. These findings, which demonstrate the receptor-like structure of NK1.1, will facilitate studies regarding the role of NK1.1 in natural killing and regarding the identification of possible NK1.1 ligands.
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PMID:Molecular cloning of the NK1.1 antigen, a member of the NKR-P1 family of natural killer cell activation molecules. 150 85

NK cells are able to lyse a variety of virally infected and neoplastic cells in an MHC-unrestricted manner. The cell-surface protein NKR-P1 is thought to play a key role in this process. NKR-P1, initially identified in rat IL-2 activated NK cells, is encoded in the mouse by at least three similar, but not identical, genes. We previously reported the isolation and characterization of three different NKR-P1 cDNA, termed cDNA 2, 34, and 40, from IL-2 activated mouse NK cells. This report describes the structure of the gene encoding NKR-P1 cDNA 2, the smallest of these three cDNA. Gene 2 is composed of six exons spanning approximately 14 kb of genomic DNA. The first exon encodes the N-terminal intracellular domain, and exons 4, 5, and 6 contain the sequences coding for the CRD. This organization is similar to that of other genes that encode C-type animal lectins. The expression of the NKR-P1 genes in A-LAK cells from 13 mouse strains was examined by Northern blot analysis. NKR-P1 expression appears to coincide with that of the NK1.1 Ag. This observation further supports the hypothesis that the NK1.1 Ag is encoded by one of the NKR-P1 genes. Nucleotide sequence analysis of the promoter region of the three NKR-P1 genes in BALB/c and C57BL/6 mice suggests that differences in the level of expression probably do not result from alterations in the upstream regions of these genes, but may be caused by the expression of strain-specific transacting factors.
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PMID:Genomic structure and strain-specific expression of the natural killer cell receptor NKR-P1. 151 65

We have recently demonstrated that high-dose IL-2, when begun on the day of bone marrow transplantation, has a potent protective effect against graft-vs.-host disease mortality, especially when coadministered with T cell-depleted syngeneic bone marrow cells. Because several groups of investigators have demonstrated that lymphokine-activated killer cells can mediate GVHD protection, we hypothesized that the mechanism of protection by IL-2 administration might involve the in vivo activation of natural killer and/or LAK cells. In order to test this hypothesis, we evaluated the effect of IL-2 administration on the number of NK1+ cells and on NK-mediated cytotoxic activity in recipients of GVHD-producing inocula. Furthermore, we evaluated the effects on IL-2-induced GVHD protection of depleting NK cells and LAK precursor cells in vivo with mAb against NK1.1 or antiserum against asialo GM1. The results demonstrate that: (1) The number of NK1+ cells is not increased in spleens of IL-2-treated compared with control recipients of GVHD-producing inocula; (2) NK activity is not increased in IL-2-treated compared with control recipients of GVHD-producing inocula during or immediately following the period of IL-2 administration; (3) depletion of NK cells and LAK precursors from the donor and host influenced the time course of GVHD-related mortality in a complex fashion; and (4) IL-2-induced GVHD protection is largely independent of the activity of an NK or LAK cell population of donor or host origin. IL-2-induced GVHD protection therefore reflects primarily the activity of non-LAK protective cell populations, or it may be a direct inhibitory effect on responding donor cell populations as they encounter host antigen.
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PMID:The mechanism of IL-2-mediated protection against GVHD in mice. II. Protection occurs independently of NK/LAK cells. 153 68

The mechanisms by which non-oncogene bearing, slowly transforming T-cell-tropic retroviruses induce leukemia is not well understood. Viruses such as the murine radiation leukemia virus (RadLV) induce oncogenic transformation of T-cells in the thymus only in vivo and after a long latency. The capacity of RadLV to induce proliferation of lymphoid cells in vitro has been analysed here as a first attempt at mapping oncogenic transformation. Autonomously replicating cell lines have been isolated following exposure of splenic lymphocytes to two different isolates of RadLV, following in vitro culture in the presence of T-cell growth factors. Cells of similar precursor lymphoid morphology and phenotype have been isolated and cloned from cultures established from different animals. These cell lines all grow independently of exogenous growth factors in vitro, but are not tumorigenic in mice. Exposure to RadLV under the culture conditions provided has allowed integration of a new retroviral genome into each cell line, but no active replication of virus has been detected in any of the cell lines analysed. A common cell type resembling a lymphoid precursor has been induced to proliferate. These cell lines express cell surface markers attesting to their bone marrow origin, such as CD44 (Pgp-1), Gr-1, B220 and NK1.1, but they do not show the characteristics of T cells which have undergone differentiation within the thymus. They do not express the Thy-1 marker, nor show rearrangement involving any of the T-cell receptor (TCR) alpha, beta gamma or sigma genes. These cells bind several antibodies specific for the CD3-epsilon and TCR-alpha beta structures, and there appears to be aberrant expression of TCR proteins in cells bearing fully rearranged TCR genes. Precursor lymphoid cells and not mature T-cells in spleen, appear to be appropriate targets for RadLV-induced proliferation/immortalisation in vitro. Oncogenic transformation induced by RadLV in vivo may occur within precursor lymphoid cells and must be a complex process dependent on both the differentiation events which occur within the thymus, as well as the thymic environment of stromal cells.
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PMID:Unique lymphoid cell subset target to infection and proliferation induced in vitro by a murine leukemia virus. 158 90

We studied the effect of depleting NK1.1+ cells from an allograft of lymph node and spleen cells on the outcome of GVH disease in the parent----F1-hybrid combination C57BL/6----(C57BL/6xDBA/2)F1. Four treatment groups were established: group I mice were transplanted with an unmodified graft from normal donors; group II mice were transplanted with an NK1.1-depleted graft that had been harvested from normal donors; group III mice received grafts from donors that had been injected with Poly I:C (100 micrograms i.p.) 18 hr prior to harvesting (These grafts were incubated with complement, but no antibody.); group IV mice were transplanted with depleted grafts harvested from donors that had received Poly I:C. Recipients in each group were monitored for splenomegaly, mitogen responsiveness, NK and CTL activity, histopathology, weight loss, and mortality. Results showed that recipients in all four groups developed splenomegaly and unresponsiveness to LPS, PHA, and Con A by day 12. Augmented host-derived NK activity and graft-derived antihost CTL activity was also demonstrated. Group IV showed little or no weight loss, minimal histopathological changes and a marked reduction in mortality. Recipients in all other groups developed features characteristic of GVH disease and exhibited a steady decline in body weight beginning by day 12. Mortality generally began on day 18 and reached 75-90% by day 60. We postulate that anti-NK1.1 depletes cells from the graft are intimately connected with the effector mechanism in acute GVH disease.
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PMID:Prevention of acute lethal graft-versus-host disease in F1 hybrid mice by pretreatment of the graft with anti-NK-1.1 and complement. 163 23

1. The interaction at tachykinin receptors of a series of novel cyclic hexapeptides has been examined by use of radioligand binding assays (NK1 and NK3 sites in rat cortex, NK2 sites in hamster urinary bladder) and functional pharmacological assays (guinea-pig ileum, rat vas deferens and rat portal vein for NK1, NK2 and NK3 receptors, respectively). 2. The compounds cyclo(GlnTrpPhe(R)Gly[ANC-2]LeuMet) (L-659,837) and cyclo(GlnTrpPheGly-LeuMet) (L-659,877) were powerful and selective displacers of NK2 binding (pIC50 6.9 and 8.0, respectively), and were competitive antagonists of responses to stimulation of NK2 receptors in rat vas deferens (pKB for antagonism of responses to eledoisin 6.7 and 8.1, respectively). Responses in the NK1 and NK3 pharmacological assays were blocked only weakly, if at all. 3. In the longitudinal muscle of the small intestine of the rat, responses to stimulation of the putative NK2 receptor by eledoisin, neurokinin A or neurokinin B were antagonized by both cyclo(GlnTrpPhe(R)-Gly[ANC-2]LeuMet) and cyclo (GlnTrpPheGlyLeuMet) in a manner consistent with the presence in this tissue of a uniform population of receptors, indistinguishable from the NK2 receptor of the rat vas deferens. 4. The compounds cyclo(GlnTrpPheGlyLeuMet) and the lactam-containing analogue are among the most selective antagonists for the NK2 receptor that have been described; their availability should be of value in the characterization of the receptors mediating responses to tachykinins, and in elucidating the physiological functions of the tachykinin receptors.
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PMID:Pharmacological specificity of novel, synthetic, cyclic peptides as antagonists at tachykinin receptors. 166 32

The population dynamics of "null" small lymphocytes lacking B and T lineage markers in mouse bone marrow have been examined using a combination of immunolabeling and hydroxyurea (HU) deletion techniques. The binding of the B lineage-associated mAb, 14.8, and anti-Thy1.2 to bone marrow cells has been detected radioautographically. Null cells lacking 14.8 and Thy1.2 determinants (14.8- Thy1-) formed a substantial subset (12-14%) of bone marrow small lymphocytes, representing 0.5 x 10(6) cells per femur (2-3% of nucleated cells). HU treatment revealed an exceptionally rapid turnover of the null small lymphocyte population (T1/2, 7.5 hr) compared with 14.8+ cells (T1/2, 20.5 hr) and Thy1+ cells (T1/2, 53 hr). Small lymphocytes bearing low intensities of Thy1 (Thy1lo) were also rapidly renewed (T1/2, 28 hr) whereas those with high intensities of Thy1 (Thy1hi) were renewed only slowly (T1/2, 123 hr). During ontogeny, null small lymphocytes first appeared in the fetal liver by Day 11 and the fetal spleen by Day 16, but increased rapidly in the bone marrow in early postnatal life. Double immunolabeling techniques demonstrated that 10% of null small lymphocytes in the bone marrow expressed NK1.1 antigen, while larger proportions bound to tumor (YAC.1) cells in vitro and displayed Fc receptors. The NK1.1-bearing fraction of null small lymphocytes in bone marrow was depleted by HU treatment only after an initial delay. NK1.1 was also expressed on subsets of Thy1lo cells and Thy1hi cells. The results have revealed the continuous production in mouse bone marrow of null and Thy1lo small lymphocytes, totaling 1-3 x 10(7) cells/day and 1.2 x 10(6) cells/day, respectively. The findings suggest that the large-scale production of null lymphocytes in mouse bone marrow includes the genesis of NK lineage cells which express NK1.1 and Thy1lo during a period of terminal maturation.
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PMID:Population dynamics of "null" and Thy1lo lymphocytes in mouse bone marrow: genesis of cells with natural killer cell lineage characteristics. 167 34


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