| 1. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 2. |
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| 3. |
- Persson, Marie
(författare)
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Immune regulation during pregnancy in relation to allergy and in women undergoing in vitro fertilization
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During pregnancy, the fetus expresses both maternal and paternal antigens. To the mother, the paternal antigens are foreign, providing her immune system with an interesting challenge. The fact that the fetus is not normally attacked and rejected implies that mechanisms of tolerance must exist. Pregnancy has long been considered to cause a redirection of the maternal immune responses towards a less aggressive type. Allergic disease has also been associated with that same redirection of immune responses, suggesting that this deviation may be more pronounced in allergic women during pregnancy. Several observations support the concept of a role of the immune system in the etiology of unexplained infertility, associating a redirection of the immune responses towards a more aggressive type with pregnancy loss and pregnancy failure.The aim of this thesis was to investigate the immune responses during pregnancy in allergic and non-allergic women, and in infertile women undergoing IVF treatment. We hypothesized that allergic women would have a more pronounced Th2-deviation than non-allergic women towards paternal antigens during pregnancy and that an unsuccessful outcome of IVF treatment would be associated with aberrations in circulating leukocyte populations and a paternal antigen-specific Th1 and Th17 bias.An increased number of both spontaneous and paternal antigen-induced Th2-like cytokine-secreting cells in peripheral blood was associated with pregnancy in 54 women with pregnancies defined as normal. The allergic pregnant women did not have a more pronounced Th2-deviation than the non-allergic women, as measured by numbers of cytokine-secreting cells. However, when analyzing cytokine levels in cell supernatants, we did observe lower Th1 responses towards paternal antigens in the allergic compared with non-allergic women. Additionally, allergy was associated with a reduced capacity to induce anti-inflammatory IL-10 responses towards paternal antigens.In 25 infertile women undergoing IVF, the peak levels of the majority of paternal antigen-induced cytokines and leukocyte populations investigated coincided with the maximal levels of gonadotropins administered during IVF treatment, suggesting that controlled ovarian hyper-stimulation has a general stimulatory effect on the immune system and that it may be regarded as an inflammatory state. During the treatment, no differences were found regarding cytokine responses to paternal antigens in peripheral blood or the numbers or proportions of circulating leukocyte populations between women with a successful or unsuccessful outcome of IVF. We did see higher numbers of Th2-associated cytokine secreting cells and a lower proportion of lymphocytes in the pregnant compared with the non-pregnant women four weeks after embryo transfer, however, in line with previous findings of immune modulation during pregnancy.In conclusion, normal pregnancy seems to be characterized by a less aggressive type of immune responses, possibly more pronounced in allergic women. This may be of importance for the in utero influences on childhood allergy development. An unsuccessful outcome of IVF does not appear to be associated with a more aggressive type of immune responses towards paternal antigens or aberrations in circulating leukocyte populations, although this should be confirmed in a larger study. The results in this thesis also indicate that the hormonal therapy during IVF treatment has a stimulatory effect on the immune system, generating an inflammatory state.
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| 4. |
- Persson, Marie, et al.
(författare)
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Immunological status in patients undergoing in vitro fertilisation : responses to hormone treatment and relationship to outcome
- 2012
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Ingår i: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 96:1-2, s. 58-67
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to prospectively investigate the paternal antigen-induced cytokine secretion by peripheral blood mononuclear cells (PBMCs) in response to hormone treatment in women undergoing in vitro fertilisation (IVF) and to examine the predictive value of the cytokine secretion profile in the outcome of IVF treatment, in a pilot study. Twenty-five women were included and IVF treatment was successful for six and unsuccessful for 19 women. Blood samples were collected before IVF treatment, on four occasions during IVF and four weeks after embryo transfer. The numbers of Th1-, Th2- and Th17-associated cytokine-secreting cells and cytokine levels in cell supernatants were analysed by enzyme-linked immunospot-forming (ELISpot), enzyme-linked immune-sorbent (ELISA) or Luminex assay. None of the cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, TNF and GM-CSF) had any predictive value regarding IVF outcome. The majority of the cytokines reached their peak levels at ovum pick-up, suggesting an enhancing influence of the hormonal stimulation. Pregnancy was associated with a high number of IL-4-, IL-5- and IL-13-secreting cells four weeks after ET. In conclusion, the results do not support our hypothesis of a more pronounced peripheral Th1 and Th17 deviation towards paternal antigens in infertile women with an unsuccessful IVF outcome, although this is based on a small number of observations. A larger study is required to confirm this conclusion. Higher numbers of Th2-associated cytokine-secreting cells in pregnant women four weeks after ET do corroborate the hypothesis of a Th2 deviation during pregnancy.
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| 5. |
- Persson, Marie, et al.
(författare)
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Leukocyte populations in patients undergoing in vitro fertilization: responses to hormone treatment and relation to outcome
- 2012
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We aimed to prospectively investigate circulating leukocyte populations in infertile women undergoing IVF treatment and to determine whether any differences in cell proportions were associated with the IVF outcome. We also assessed the effect of IVF-based ovarian stimulation on the leukocyte populations. Twenty-five women were included and IVF treatment was successful in six and unsuccessful in 19 women. Blood samples were collected before IVF treatment, at the time of embryo transfer and four weeks after embryo transfer. The numbers and proportions of lymphocytes, T cells, NK cells, monocytes and granulocytes were analysed by flow cytometry, as well as the following lymphocyte subpopulations: CD3+HLA-DR+, CD4+CD45RA+, CD4+CD45R0+, CD8+CD45RA+, CD8+CD45R0+, CD4+CD25+, CD4dimCD25bright regulatory T cells, CD3-CD56bright and CD3-CD56dim NK cells. The proportions and numbers of leukocytes during IVF treatment were not related to the IVF outcome, although pregnant women (four weeks after ET) had a lower proportion of lymphocytes than the non-pregnant women. The absolute counts of lymphocytes, T cells, granulocytes and monocytes, as well as the proportions of granulocytes and T cells, increased at the time of ET, coinciding with high FSH and hCG levels. In conclusion, the proportions and numbers of leukocyte populations were not associated with the IVF outcome, although a larger study should be conducted to confirm this conclusion. Changes in both proportions and numbers of several leukocyte populations were observed during the course of IVF treatment, suggesting a stimulatory effect of the hormonal influence.
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| 6. |
- Persson, Marie, et al.
(författare)
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Reduced IFN-γ and IL-10 responses to paternal antigens during and after pregnancy in allergic women
- 2012
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Ingår i: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 95:1-2, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the current study, we hypothesized that paternal antigen-induced cytokine responses during pregnancy would be deviated toward Th2 and an anti-inflammatory profile, and that the Th2 deviation would be more pronounced in allergic pregnant women. Blood samples were collected longitudinally on three occasions during pregnancy and two occasions post partum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Twelve women fulfilled the criteria for allergy (allergic symptoms and circulating immunoglobulin [Ig] E antibodies to inhalant allergens) and 20 were non-allergic (nonsensitized without symptoms). The levels of Th1- and Th2-associated cytokines and chemokines, the Th17 cytokine IL-17 and the anti-inflammatory cytokine IL-10 of the groups were compared. Paternal antigen-induced IL-4 and IL-10 responses increased between the first and the third trimester. Allergy was associated with decreased paternal antigen-induced IFN-γ and CXCL10 secretion in the nonpregnant state (one year pp) and also decreased IFN-γ/IL-4 and IFN-γ/IL-13 ratios during pregnancy. We also observed a decreased paternal antigen-induced IL-10 response in allergic compared with non-allergic women during pregnancy, along with a decreased IL-10/IL-13 ratio. In conclusion, our findings support the hypothesis of lower Th1 responses toward paternal antigens in allergic than in non-allergic women, but also indicate that allergy is associated with a lower capacity to induce anti-inflammatory IL-10 responses after paternal antigen stimulation during pregnancy.
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| 7. |
- Skogman, Barbro H, et al.
(författare)
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Adaptive and Innate Immune Responsiveness to Borrelia burgdorferi sensu lato in Exposed Asymptomatic Children and Children with Previous Clinical Lyme Borreliosis
- 2012
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Ingår i: Clinical & Developmental Immunology. - : Hindawi Publishing Corporation. - 1740-2522 .- 1740-2530. ; 2012:294587
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Tidskriftsartikel (refereegranskat)abstract
- Why some individuals develop clinical manifestations in Lyme borreliosis (LB) while others remain asymptomatic is largely unknown. Therefore, we wanted to investigate adaptive and innate immune responsiveness to Borrelia burgdorferi sensu lato in exposed Borrelia-antibody-positive asymptomatic children (n = 20), children with previous clinical LB (n = 24), and controls (n = 20). Blood samples were analyzed for Borrelia-specific interferon (IFN)-gamma, interleukin (IL)-4, and IL-17 secretion by ELISPOT and Borrelia-induced IL-1 beta, IL-6, IL-10, IL-12(p70), and tumor necrosis factor (TNF) secretion by Luminex. We found no significant differences in cytokine secretion between groups, but a tendency towards an increased spontaneous secretion of IL-6 was found among children with previous clinical LB. In conclusion, the adaptive or innate immune responsiveness to Borrelia burgdorferi sensu lato was similar in Borrelia-exposed asymptomatic children and children with previous clinical LB. Thus, the immunological mechanisms of importance for eradicating the spirochete effectively without developing clinical manifestations of LB remain unknown.
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