Nude mice--a model system for studying the cellular basis of the humoral immune response.
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Biomedical subjects
B A Croy
Publications and source records attributed to B A Croy.
Nude mice and the mixed leukocyte reaction.
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Can murine uterine natural killer cells give insights into the pathogenesis of preeclampsia?
These studies aimed to advance understanding of the functions of pregnancy-associated uterine lymphocytes of the natural killer (NK) cell lineage. The approach was morphometric analysis of implantation sites from timed pregnancies in genetically modified mice deficient in NK cells or in signaling associated with their major product, the cytokine interferon-gamma. In four different strains of pregnant, NK cell--deficient mice, the major decidual arterioles failed to undergo modifications to their smooth-muscle coats and displayed endothelial cell damage. Decidua lacked normal cell density. This pathology was observed by the end of the first trimester, before placental differentiation. By midgestation in these strains, placentas were smaller than in control strains. In normal mice, many uterine NK cells are perivascular in location and appear to be activated because they are the major sources of interferon-gamma and of the interferon-gamma--regulated enzyme inducible nitric oxide synthase. During pregnancy in mice genetically ablated for interferon-gamma, the interferon-gamma receptor chain-alpha or the transcription factor interferon regulatory factor-1, uterine NK cells differentiate but appear to be abnormal both morphologically and functionally. In these three strains, failure of pregnancy-induced vascular modifications and overt necrosis of decidua occur. Thus, in mice, lymphocytes of the NK cell lineage make specialized contributions to pregnancy-associated modification of the uterine vasculature and to maintenance of decidua. These contributions are achieved through interferon-gamma--mediated gene regulation and appear to enhance subsequent placental growth. Human CD56 bright decidual lymphocytes may have analogous functions. If so, changes in numbers or levels of activity of human uterine NK cells or mutations in genes regulated by uterine interferon-gamma could contribute to initiation of preeclampsia.
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Immune competence involving the natural killer cell lineage promotes placental growth.
Very small placentae and absence of uterine natural killer (uNK) cells are amongst the reproductive deficits found in the natural killer (NK) cell and thymus-derived (T) cell immunodeficient mouse tgepsilon26. These defects can be reversed by grafting of adult tgepsilon26 females with bone marrow from T and B cell immunodeficient scid/scid donors. We report here that a second protocol, grafting of neonatal tgepsilon26 females with immunocompetent bone marrow pretreated with antibody to Thy-1, successfully established the uNK cell lineage and ameliorated the phenotype. Further, comparisons of mid-gestation (days 10-16) placental area measurements from tgepsilon26 and seven other immunodeficient strains to time-matched tissues from four strains of immunocompetent mice indicate that lymphocytes of the NK but not the T or B cell lineages are able to influence placental size during normal gestation and that this action is independent of interleukin 2. Area measurements of placentae produced in manipulated tgepsilon26 pregnancies (maternal bone marrow engraftment, outcrossing to immunocompetent males and reciprocal embryo transfers with an immunocompetent strain) suggest that NK cell competence is required in each of the maternal and fetal compartments to optimize placental growth.
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Transplantation into genetically alymphoid mice as an approach to dissect the roles of uterine natural killer cells during pregnancy--a review.
Mice genetically deficient in the natural killer (NK) cell lineage lack uterine (uNK cells) and demonstrate morphometrically-quantifiable histopathology within their implantation sites. Two particular mouse strains, tg(epsilon),26 and RAG-2 null x gamma(c) null, have been used successfully as transplant recipients to address questions relating to the biology of uNK cells. uNK cells did not differentiate within decidualized uterine graft segments from normal mice, which were anastomosed orthotopically into immunodeficient hosts. uNK cells did appear in similar grafts placed into immunocompetent hosts, indicating that uNK cells or their progenitors must home to the uterus. This was confirmed by splenocyte transplantation into pregnant uNK cell deficient recipients. Only splenocytes from pregnant donors, not those from non-pregnant donors, homed to the uterus. Homing in this in vivo assay was independent of the CC-chemokine receptors, CCR-2 and CCR-5. Longer-term bone marrow cell reconstitution of neonatal or virgin adult uNK cell-deficient mice has identified a functional role for uNK cells in modification of the decidual arterioles which is mediated by IFN-gamma. By utilizing mutant and gene-ablated mice as donors for tissue or haematopoietic cell transplants to uNK cell deficient mice, it should be possible to fully characterize the in vivo regulation and functions of these pregnancy-specific uterine lymphocytes.
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Uterine natural killer cells: insights into lineage relationships and functions from studies of pregnancies in mutant and transgenic mice.
Mice expressing genetic alterations have been extremely valuable in providing insights into both the lineage relationships and functions of lymphohematopoietic cells. This approach has been applied to granulated lymphocytes that localize to implantation sites in the rodent uterus during pregnancy. Histological analyses of implantation sites collected from various mutant and transgenic mice over the course of gestation strongly support the conclusions that these granulated lymphocytes, previously named granulated metrial gland (GMG) cells, are natural killer (NK) cells and that they are essential for normal development of the placenta. Pregnancy-associated uterine NK (uNK) cells have limited lytic activity suggesting that their secretory products, particularly cytokines and matrix proteins, may be critical for normal placental maturation. This review will highlight information collected from pregnancies in mutant and transgenic mice that have contributed to the current understanding of functions of uNK cells during gestation.
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