Androgens Modulate the Immune Profile in a Mouse Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is associated with a low-grade inflammation, but it is unknown how hyperandrogenism, the hallmark of PCOS, affects the immune system. Using a PCOS-like mouse model, it is demonstrated that hyperandrogenism affects immune cell populations in reproductive, metabolic, and immunological tissues differently in a site-specific manner. Co-treatment with an androgen receptor antagonist prevents most of these alterations, demonstrating that these effects are mediated through androgen receptor activation.

MHC Class I-Dependent Shaping of the NK Cell Ly49 Receptor Repertoire Takes Place Early during Maturation in the Bone Marrow.

MHC class I (MHC I) expression in the host influences NK cells in a process termed education. The result of this education is reflected in the responsiveness of NK cells at the level of individual cells as well as in the repertoire of inhibitory MHC I-specific receptors at the NK cell system level. The presence of MHC I molecules in the host environment gives rise to a skewed receptor repertoire in spleen NK cells where subsets expressing few (one or two) inhibitory receptors are expanded whereas subsets with many (three or more) receptors are contracted.

NK- and T-cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti-CTLA-4 therapy.

Malignant mesothelioma (MM) is a highly aggressive form of cancer with limited treatment options. Although the role of NK cells has been studied in many solid tumors, the pattern of NK-cell subsets and their recognition of mesothelioma cells remain to be explored. We used RNA expression data of MM biopsies derived from the cancer genome atlas to evaluate the immune cell infiltrates.

NK cells control breast cancer and related cancer stem cell hematological spread.

The growth and recurrence of a number of cancers is driven by a scarce population of cancer stem cells (CSCs), which are resistant to most current therapies. It has been shown previously that natural killer (NK) cells recognize human glioma, melanoma, colon and prostate CSCs . We herein show that human and mouse breast CSCs are also susceptible to NK cytotoxic activity .

Dynamic Regulation of NK Cell Responsiveness.

Natural killer (NK) cells deliver cytotoxic granules and immunomodulatory cytokines in response to transformed and virally infected cells. NK cell functions are under the control of a large number of germline-encoded receptors that recognize various ligands on target cells, but NK cells also respond to cytokines in the surrounding environment. The interaction between NK cell receptors and their ligands delivers either inhibitory or activating signals.

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response.

Natural killer (NK) cells are most efficient if their targets do not express self MHC class I, because NK cells carry inhibitory receptors that interfere with activating their cytotoxic pathway. Clinicians have taken advantage of this by adoptively transferring haploidentical NK cells into patients to mediate an effective graft-versus-leukemia response. With a similar rationale, antibody blockade of MHC class I-specific inhibitory NK cell receptors is currently being tested in clinical trials.

A genetic defect in mice that impairs missing self recognition despite evidence for normal maturation and MHC class I-dependent education of NK cells.

In studies of a CD1d1-deficient mouse strain, we unexpectedly observed a severely impaired capacity for NK cell-mediated rejection of MHC class I-deficient (spleen or tumor) cells. Studies of another CD1-defective strain, as well as intercrosses with C57BL/6 mice, indicated that the impaired missing self rejection (IMSR) NK cell defect was a recessive trait, independent from the targeted CD1 locus. Studies with mixed bone marrow chimeras indicated that the defect is intrinsic to NK cells.

Accumulation and activation of natural killer cells in local intraperitoneal HIV-1/MuLV infection results in early control of virus infected cells.

Natural killer (NK) cells are important effectors in resistance to viral infections. The role of NK cells in the acute response to human immunodeficiency virus 1 (HIV-1) infected cells was investigated in a mouse model based on a HIV-1/murine leukemia virus (MuLV) pseudovirus. Splenocytes infected with HIV-1/MuLV were injected intraperitoneally and local immunologic responses and persistence of infected cells were investigated.

Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.

Background: A major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8(+) T cell attack, but may at the same time develop NK cell sensitivity, due to failure to express inhibitory ligands for Ly49 receptors. The extent of MHC class I downregulation needed on normal cells to trigger NK cell effector functions is not known.

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: maintained tolerance to normal cells even in the presence of IL-2.

Missing-self-reactivity can be mimicked by blocking self-specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab-mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self-tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H-2(b)) NK cells were blocked with F(ab')(2) fragments of the mAb 5E6.

NK cell activation by KIR-binding antibody 1-7F9 and response to HIV-infected autologous cells in viremic and controller HIV-infected patients.

Natural killer (NK) cells may be protective in HIV infection and are inhibited by killer cell immunoglobulin-like receptors (KIRs) interacting with MHC class I molecules, including HLA-C. Retention of HLA-C despite downregulation of other MHC class I molecules on HIV infected cells might protect infected cells from NK cell recognition in vitro. To assess the role of inhibitory HLA-C ligands in the capacity of NK cells to recognize autologous infected T cells, we measured NK cell degranulation in vitro in viremic patients, controllers with low viremia, and healthy donors.

Mapping of quantitative trait loci determining NK cell-mediated resistance to MHC class I-deficient bone marrow grafts in perforin-deficient mice.

NK cells reject allogeneic and MHC class I-deficient bone marrow (BM) grafts in vivo. The mechanisms used by NK cells to mediate this rejection are not yet thoroughly characterized. Although perforin plays a major role, perforin-independent mechanisms are involved as well.

The dynamics of natural killer cell tolerance.

Natural killer (NK) cells are important mediators of resistance against tumor growth and metastasis. NK cell reactivity is regulated by a balance of signals from activating and inhibitory receptors. While reactivity against tumor cells is beneficial, it is essential that NK cells do not attack normal tissue.

Synthesis and characterization of molybdenum oxo complexes of two tripodal ligands: reactivity studies of a functional model for molybdenum oxotransferases.

Reaction of the tetradentate ligand N-(2-hydroxybenzyl)-N,N-bis(2-pyridylmethyl)amine (L-OH) with MoO2Cl2 in methanol in the presence of NaOMe and PF6- results in the formation of [MoO2(L-O)]PF6. Similarly, the reaction of N-(2-mercaptobenzyl)-N,N-bis(2-pyridylmethyl)amine (L-SH) with MoO2(acac)2 leads to the formation of [MoO2(L-S)]+. The dioxo-molybdenum complex [MoO2(L-O)]+ reacts with phosphines in methanol to afford phosphine oxides and an air-sensitive molybdenum complex, tentatively identified as [Mo(IV)O(L-O)(OCH3)].

Computational modeling of human natural killer cell development suggests a selection process regulating coexpression of KIR with CD94/NKG2A.

Natural killer cells fail to lyse target cells expressing sufficient levels of self MHC class I molecules, providing one mechanism to secure self tolerance. Inhibition of lysis is mediated by inhibitory receptors expressed by NK cells, such as the murine Ly49 receptors, human KIR receptors and CD94/NKG2A, expressed by both species. To ensure that most, if not all, NK cells express at least one inhibitory receptor for self MHC class I, selection processes have been postulated for murine NK cells regulating the number and identity of inhibitory receptors expressed by each cell.

Structural and mechanistic look at the orthoplatination of aryl oximes by dichlorobis(sulfoxide or sulfide)platinum(II) complexes.

Structural and mechanistic aspects of orthoplatination of acetophenone and benzaldehyde oximes by the platinum(II) sulfoxide and sulfide complexes [PtCl(2)L(2)] (2, L = SOMe(2) (a), rac-SOMePh (b), R-SOMe(C(6)H(4)Me-4) (c), and SMe(2) (d)) to afford the corresponding platinacycles cis-(C,S)-[Pt(II)(C(6)H(3)-2-CR'=NOH-5-R)Cl(L)] (3, R, R' = H, Me) have been investigated. The reaction of acetophenone oxime with sulfoxide complex 2a in methanol solvent occurs noticeably faster than with sulfide complex 2d due to the fact that the sulfoxide is a much better platinum(II) leaving ligand than the sulfide. Evidence is presented that the orthoplatination is a multistep process.

Structures of trans-[PtCl(2)(PBz(3))(2)], trans-[PtI(2)(PBz(3))(2)], trans-[Pt(NCS)(2)(PBz(3))(2)].0.5C(6)H(6) and trans-[PdI(2)(PBz(3))(2)].

A series of structures of trans-[MX(2)(PBz(3))(2)] [M = Pt, X = Cl(-); PBz(3) = tribenzylphosphine (1), I(-), trans-diiodobis(tribenzylphosphine)platinum(II) (2), and NCS(-), trans-di(thiocyanate)bis(tribenzylphosphine)platinum(II) (3); M = Pd, X = I(-), trans-diiodobis(tribenzylphosphine)palladium(II) (4)] have been characterized by X-ray crystallography. In all compounds each tribenzylphosphine has one benzylcarbon close to the coordination plane. In (1), (2) and (4) those (in-plane) C atoms, from the two different PBz(3), exhibit an anti conformation along the P-P axis, while (3) has the gauche conformation.

Tetrakis(dimethyl sulfide)palladium(II) bis(tetrafluoroborate) and tetrakis(1,4-oxathiane-kappaS)palladium(II) bis(tetrafluoroborate).

Tetrakis(dimethyl sulfide)palladium(II) bis(tetrafluoroborate), [Pd(C(2)H(6)S)(4)](BF(4))(2), (I), and tetrakis(1,4-oxathiane-kappaS)palladium(II) bis(tetrafluoroborate), [Pd(C(4)H(8)OS)(4)](BF(4))(2), (II), both crystallize as mononuclear square-planar complexes with tetrafluoroborate as the counter-ions. The Pd atom accepts four S-donor atoms and is positioned at an inversion centre in both compounds. The two unique S atoms in the dimethyl sulfide complex, (I), are disordered.