Development of a recombinant anti-VEGFR2-EPCAM bispecific antibody to improve antiangiogenic efficiency.

Tumor progression and metastasis, especially in invasive cancers (such as triple-negative breast cancer [TNBC]), depend on angiogenesis, in which vascular epithelial growth factor (VEGF)/vascular epithelial growth factor receptor [1] has a decisive role, followed by the metastatic spread of cancer cells. Although some studies have shown that anti-VEGFR2/VEGF monoclonal antibodies demonstrated favorable results in the clinic, this approach is not efficient, and further investigations are needed to improve the quality of cancer treatment. Besides, the increased expression of epithelial cell adhesion molecule (EpCAM) in various cancers, for instance, invasive breast cancer, contributes to angiogenesis, facilitating the migration of tumor cells to other parts of the body. Thus, the main goal of our study was to target either VEGFR2 or EpCAM as pivotal players in the progression of angiogenesis in breast cancer. Regarding cancer therapy, the production of bispecific antibodies is easier and more cost-effective compared to monoclonal antibodies, targeting more than one antigen or receptor; for this reason, we produced a recombinant antibody to target cells expressing EpCAM and VEGFR2 via a bispecific antibody to decrease the proliferation and metastasis of tumor cells. Following the cloning and expression of our desired anti-VEGFR2/EPCAM sequence in E. coli, the accuracy of the expression was confirmed by Western blot analysis, and its binding activities to VEGFR2 and EPCAM on MDA-MB-231 and MCF-7 cell lines were respectively indicated by flow cytometry. Then, its anti-proliferative potential was indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis assay to evaluate inhibitory effects of the antibody on tumor cells. Subsequently, the data indicated that migration, invasion, and angiogenesis were inhibited in breast cancer cell lines via the bispecific antibody. Furthermore, cytokine analysis indicated that the bispecific antibody could moderate interleukin 8 (IL-8) and IL-6 as key mediators in angiogenesis progression in breast cancer. Thus, our bispecific antibody could be considered as a promising candidate tool to decrease angiogenesis in TNBC.

The PD-1/PD-L1 pathway in murine hair cycle transition: a potential anagen phase regulator.

Programmed cell death protein-1 (PD-1) is primarily recognized as an inhibitory receptor involved in the regulation of immunological tolerance. However, recent studies have indicated that PD-1/PD-L1 signaling could also regulate the functions of nonimmune cells and may be involved in regulating hair biology. In this study, we showed in a mouse model of depilation-induced hair cycling that PD-1/PD-L1 are expressed in the murine epidermis and hair follicle (HF) in a hair cycle-dependent manner. During HF morphogenesis, PD-1 expression was strongly decreased during the anagen phase compared with the catagen and telogen phases. PD-L1 expression was enhanced during the catagen phase compared with the anagen and telogen phases. Moreover, direct blockade of PD-L1 not only accelerated hair anagen phase onset but also delayed catagen progression. In conclusion, our findings indicated that PD-1/PD-L1 signaling may act as a negative regulator of hair cycle transition. Anti-PD-1/PD-L1 therapy may thus be a promising strategy for treating anagen-reduced hair loss.

The morphological basis of the development of the chick embryo immune system.

The chick immune system is a fundamental model in basic immunology. In birds, the bone marrow derived pluripotent stem cells after entering the circulation, migrate to bursa of Fabricius to benefit from a microenvironment which supports the differentiation and maturation of B lymphocytes by the help of its resident cells and tissues. Delivering sufficient functional B cells is required to maintain their peripheral population and normal peripheral humoral responses. Additionally, bursa acts as an active site for the generation of antibody diversity through gene conversion. Being consisted of 98% B lymphocytes, the organ is occupied by other cell types including T cells, macrophages, eosinophils and mast cells. Thymus, which is an epithelial organ is the main site of T cell development where positive and negative selections contribute to the development of functional and not autoreactive T cell repertoire. Bursectomy and thymectomy are surgical exercises through which the involvement of cells of specific immunity including B cells and T cells can be determined.

Development, ontogeny, and maintenance of TCRαß+ CD8αα IEL.

The intestinal epithelium is the outermost cellular layer that separates the body from the gut lumen. The integrity of this protective mucosal barrier is crucial and maintained by specialized cells-intraepithelial lymphocytes (IEL). Much research has been conducted on these cells and our overall understanding of them is increasing rapidly. In this review we focus on the TCRαß+ subset of CD8αα IEL. We discuss recent studies that shed light on the development, ontogeny, maintenance, and functional characteristics of CD8αα IEL, and highlight yet unanswered questions for future studies.

Whole-mount Confocal Microscopy for Adult Ear Skin: A Model System to Study Neuro-vascular Branching Morphogenesis and Immune Cell Distribution.

Here, we present a protocol of a whole-mount adult ear skin imaging technique to study comprehensive three-dimensional neuro-vascular branching morphogenesis and patterning, as well as immune cell distribution at a cellular level. The analysis of peripheral nerve and blood vessel anatomical structures in adult tissues provides some insights into the understanding of functional neuro-vascular wiring and neuro-vascular degeneration in pathological conditions such as wound healing. As a highly informative model system, we have focused our studies on adult ear skin, which is readily accessible for dissection. Our simple and reproducible protocol provides an accurate depiction of the cellular components in the entire skin, such as peripheral nerves (sensory axons, sympathetic axons, and Schwann cells), blood vessels (endothelial cells and vascular smooth muscle cells), and inflammatory cells. We believe this protocol will pave the way to investigate morphological abnormalities in peripheral nerves and blood vessels as well as the inflammation in the adult ear skin under different pathological conditions.

Modificación ultraestructural de las membranas derivadas del retículo endoplasmático y morfogénesis del virus de la hepatitis C en muestras de hígado humano / Ultrastructural remodelling of e ndoplasmic reticulum-derived membranes and hepatitis C virus morphogenesis in human liver samples

Introducción: la infección por el virus de la hepatitis C es una de las causas principales de la enfermedad del hígado a nivel mundial. La utilización de la cepa del virus de la hepatitis C, JFH1 en cultivo de células de hepatoma ha permitido el avance de la comprensión del ciclo de vida viral. No obstante, se conoce poco sobre la morfogénesis del virus de la hepatitis C. Las dificultades para detectar el ensamblaje viral en este modelo de cultivo celular, así como los bajos niveles y complejidad de las partículas del virus de la hepatitis C en pacientes y chimpancés infectados limitan el estudio de la morfogénesis viral.Objetivo: estudiar las características ultraestructurales y los eventos de ensamblaje viral en hepatocitos de pacientes infectados con el virus de la hepatitis C.Métodos: se utilizaron muestras de biopsias de hígado de pacientes infectados, anticuerpos específicos para el virus de la hepatitis C y técnicas de microscopía e inmunomicroscopía electrónica.Resultados: la infección por el virus de la hepatitis C se relacionó con una modificación de las membranas derivadas del retículo endoplasmático y con diferentes microambientes citoplasmáticos en los hepatocitos de individuos infectados. La dilatación del retículo endoplasmático y la formación de diferentes vesículas de membrana son características que se asocian con los complejos de replicación viral. Resulta interesante destacar la detección del ensamblaje de partículas semejantes a la cápsida y al virus de la hepatitis C cerca de complejos de membrana con alta densidad electrónica y estructuras tubulares. Las proteínas estructurales del virus de la hepatitis C se detectaron en el retículo endoplasmático .Conclusiones: estos eventos sugieren que el proceso temprano de ensamblaje de las nucleocápsidas y del virión ocurre en las membranas del retículoendoplasmático que se asocian con estos microambientes citoplasmáticos en los hepatocitos humanos(AU)

Introduction: hepatitis C virus infection is considered as a leading cause of liver disease worldwide. Despite recent advances in understanding the hepatitis C virus life cycle using the highly replicative JFH1 strain in human hepatoma cells, little is known about hepatitis C virus morphogenesis. Low levels of hepatitis C virus assembly in this cell culture model as well as low levels and complexity of hepatitis C virus particles in infected humans and chimpanzees have hampered the study of hepatitis C virus morphogenesis in vivo.Objetivo: to study the ultrastructural features and viral assembly events in hepatocytes from HCV hepatitis C virus-infected patients.Methods: liver needle biopsies samples of patients with hepatitis C virus infection, specific antibodies against hepatitis C virus and transmission electron microscopy and immunoelectron microscopy analyses were used in this study.Results: ultrastructural studies in liver biopsies from hepatitis C virus-infected patients revealed that hepatitis C virus infection was related with remodelling of endoplasmic reticulum-derived membranes and with a variety of cytoplasmic microenvironments in hepatocytes. Dilated endoplasmic reticulum and formation of various membrane vesicles are features that have been associated with the viral replication complex. Interestingly, hepatitis C virus-like particles and core-like particles budding and assembly were observed near convoluted electron-dense membranes and tubular structures. Particularly, hepatitis C virus structural proteins localize to the endoplasmic reticulum.Conclusions: these events indicate that hepatitis C virus nucleocapsids and early virion assembly take place atendoplasmic reticulum membranes that are associated with these cytoplasmic microenvironments in human hepatocytes(AU)

Comparative ontogenetic development of two marine teleosts, gilthead seabream and European sea bass: New insights into nutrition and immunity.

Gilthead seabream and European sea bass are two of the most commonly farmed fish species. Larval development is critical to ensure high survival rates and thus avoid unacceptable economic losses, while nutrition and immunity are also important factors. For this reason this paper evaluates the ontogenetic development of seabream and sea bass digestive and immune systems from eggs to 73 days post-fertilisation (dpf) by assessing the expression levels of some nutrition-relevant (tryp, amya, alp and pept1) and immune-relevant (il1b, il6, il8, tnfa, cox2, casp1, tf, nccrp1, ighm and ight) genes. The results point to similar ontogenetic development trends for both species as regard nutrition and differences in some immunity related genes.

Función barrera intestinal y su implicación en enfermedades digestivas / The intestinal barrier function and its involvement in digestive disease

La superficie de la mucosa del tracto gastrointestinal está revestida de células epiteliales que establecen una barrera efectiva, mediante uniones intercelulares, entre el medio interno y el medio externo, impidiendo el paso de sustancias potencialmente nocivas. Sin embargo las células epiteliales también son responsables de la absorción de nutrientes y electrolitos, por lo que se requiere una barrera semipermeable que permita el paso selectivo a ciertas sustancias, mientras que evite el acceso a otras. Para ello, el intestino ha desarrollado la “función barrera intestinal”, un sistema defensivo compuesto por diferentes elementos, tanto extracelulares como celulares, que actúan de forma coordinada para impedir el paso de antígenos, toxinas y productos microbianos y, a la vez, mantiene el correcto desarrollo de la barrera epitelial, el sistema inmunitario y la adquisición de tolerancia hacia los antígenos de la dieta y la microbiota intestinal. La alteración de los mecanismos que componen la función barrera favorece el desarrollo de respuestas inmunitarias exageradas, y, aunque se desconoce su implicación exacta, la alteración de la función barrera intestinal se ha asociado al desarrollo de enfermedades inflamatorias en el tracto digestivo. En esta revisión se detallan los diferentes elementos que componen la función barrera intestinal y las alteraciones moleculares y celulares más características descritas en enfermedades digestivas asociadas a la disfunción de este mecanismo de defensa

The gastrointestinal mucosal surface is lined with epithelial cells representing an effective barrier made up with intercellular junctions that separate the inner and the outer environments, and block the passage of potentially harmful substances. However, epithelial cells are also responsible for the absorption of nutrients and electrolytes, hence a semipermeable barrier is required that selectively allows a number of substances in while keeping others out. To this end, the intestine developed the “intestinal barrier function”, a defensive system involving various elements, both intra- and extracellular, that work in a coordinated way to impede the passage of antigens, toxins, and microbial byproducts, and simultaneously preserves the correct development of the epithelial barrier, the immune system, and the acquisition of tolerance against dietary antigens and the intestinal microbiota. Disturbances in the mechanisms of the barrier function favor the development of exaggerated immune responses; while exact implications remain unknown, changes in intestinal barrier function have been associated with the development of inflammatory conditions in the gastrointestinal tract. This review details de various elements of the intestinal barrier function, and the key molecular and cellular changes described for gastrointestinal diseases associated with dysfunction in this defensive mechanism

Global analysis of fungal morphology exposes mechanisms of host cell escape.

Developmental transitions between single-cell yeast and multicellular filaments underpin virulence of diverse fungal pathogens. For the leading human fungal pathogen Candida albicans, filamentation is thought to be required for immune cell escape via induction of an inflammatory programmed cell death. Here we perform a genome-scale analysis of C. albicans morphogenesis and identify 102 negative morphogenetic regulators and 872 positive regulators, highlighting key roles for ergosterol biosynthesis and N-linked glycosylation. We demonstrate that C. albicans filamentation is not required for escape from host immune cells; instead, macrophage pyroptosis is driven by fungal cell-wall remodelling and exposure of glycosylated proteins in response to the macrophage phagosome. The capacity of killed, previously phagocytized cells to drive macrophage lysis is also observed with the distantly related fungal pathogen Cryptococcus neoformans. This study provides a global view of morphogenetic circuitry governing a key virulence trait, and illuminates a new mechanism by which fungi trigger host cell death.

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons.

The central nervous system is recognized as an immunoprivileged site because peripheral immune cells do not typically enter it. Microglial cells are thought to be the main immune cells in brain. However, recent reports have indicated that neurons express the key players of innate immunity, including Toll-like receptors (TLRs) and their adaptor proteins (Sarm1, Myd88, and Trif), and may produce cytokines in response to pathogen infection. In the absence of an immune challenge, neuronal TLRs can detect intrinsic danger signals and modulate neuronal morphology and function. In this article, we review the recent findings on the involvement of TLRs and Sarm1 in controlling neuronal morphogenesis and neurodegeneration. Abnormal behaviors in TLR- and Sarm1-deficient mice are also discussed.

Sexual variability in Histoplasma capsulatum and its possible distribution: What is going on? / Variabilidad sexual de Histoplasma capsulatum y su posible distribución: fundamento

Histoplasma capsulatum is a dimorphic fungal pathogen naturally found in the soil. Inhalation of conidia can result in pulmonary histoplasmosis and, in some cases, causes severe disseminated disease and death. This fungus is an ascomycete that has an anamorphic or asexual stage and a teleomorphic or sexual stage, known as Ajellomyces capsulatus, which results from (+) and (−) mating types. Sexual reproduction is regulated by a specialized genomic region known as the mating-type (MAT1) locus. The mating process in this heterothallic species is represented by isolates that contain only one of the two different MAT1 locus idiomorphs (MAT1-1 or MAT1-2) that have unrelated sequences encoding different transcription factors. In medically important dimorphic pathogens and in most ascomycete molds, one MAT locus idiomorph encodes a high-mobility-group (HMG) box-domain transcription factor, and the other idiomorph encodes an alpha-box domain transcription factor. There is scarce molecular information about H. capsulatum mating type although recombinant population structures have been reported that could occur in nature and this process has been documented in distinct models such as parasites and other fungi. In this review, we shall focus on published studies on H. capsulatum sexuality, and outline the distribution of the two H. capsulatum mating types in Latin America (AU)

Histoplasma capsulatum es un patógeno fúngico, dimórfico que habita en suelos ricos en materia orgánica. La inhalación de los conidios puede inducir histoplasmosis pulmonar y, en algunos casos, enfermedad diseminada grave y la muerte. Este ascomiceto caracterizado por un estadio anamórfico asexual y un estado teleomórfico o sexual, conocido como Ajellomyces capsulatus, que es consecuencia de los tipos de apareamiento (MAT+ y MAT−) (mating-type, por sus siglas en inglés). La reproducción sexual está regulada por una región genómica especializada, conocida como locus MAT1. El proceso de apareamiento en esta especie heterotálica (o autoincompatible) está representado por aislamientos que solo contienen uno de los 2 diferentes idiomorfos del locus MAT1 (MAT1-1 y MAT1-2), que tienen secuencias muy distintas que codifican diferentes factores de transcripción. En los patógenos dimórficos importantes desde un punto de vista médico y en la mayoría de los ascomicetos filamentosos, un idiomorfo del locus MAT codifica el dominio-caja HMG (high-mobility-group, por sus siglas en inglés) de un factor de transcripción, y el otro idiomorfo codifica el dominio-caja alfa de otro factor de transcripción. Apenas disponemos de información molecular sobre el mating type de H. capsulatum, aunque se ha descrito que en la naturaleza podrían estar presentes estructuras de población recombinante. Este proceso se ha documentado en distintos modelos como parásitos y otros hongos. En esta revisión nos hemos centrado en los estudios publicados sobre la sexualidad de H. capsulatum, y hemos abordado la distribución de los 2 mating type de H. capsulatum en Sudamérica (AU)

Expression of immune system-related genes during ontogeny in experimentally wounded common carp (Cyprinus carpio) larvae and juveniles.

We investigated the effect of full-thickness incisional wounding on expression of genes related to the immune system in larvae and juveniles of common carp (Cyprinus carpio). The wounds were inflicted by needle puncture immediately below the anterior part of the dorsal fin on days 7, 14, 28 and 49 after fertilization. We followed the local gene expression 1, 3 and 7 days after wounding by removing head and viscera before extracting RNA from the remaining part of the fish, including the wound area. In addition, we visually followed wound healing. Overall the wounds had regenerated to a point where they were microscopically indistinguishable from normal tissue by day 3 post-wounding in all but the juvenile carp wounded on day 49 post-fertilization. In these juveniles the wounded area was still visible even 7 days post-wounding. On the transcriptional level a very limited response was observed in the investigated genes as a result of the wounding. HSP70 was downregulated 1 and 3 days post-wounding in the smallest larvae. However, HSP70 was differentially expressed at different time-points in a similar manner in wounded and mock-wounded groups, thus suggesting a stress effect of the handling, which may have overshadowed some transcriptional effects of the wounding. MMP-9, TGF-ß1 and IgZ1 were slightly but significantly upregulated at few time-points, while no effect of wounding was detected on the expression of IgM, C3, IL-1ß and IL-6 family member M17.

Contribution of the urodele amphibian Pleurodeles waltl to the analysis of spaceflight-associated immune system deregulation.

Immune system deregulation has been demonstrated to occur during and immediately following spaceflight. Several animal models have been used to study this phenomenon because of the limited availability of human subjects in space as well as of the need to carry out experiments requiring samples and experimental conditions that cannot be performed using humans. Here, we review major spaceflight-induced microbial and immunological modifications, some of the existing hardware developed to host amphibians in a space station and immunological information provided by space experiments performed with Pleurodeles waltl as an animal model. These data show that the urodele amphibian P. waltl fulfills many technical requirements associated with spaceflight experimentation and that this model is interesting to improve our understanding of the immunosuppressive effects of spaceflight, data required for the preparation of future deep-space missions.

Insight into lymphoid tissue morphogenesis.

Secondary lymphoid organs (SLO) are crucial structures for immune-surveillance and rapid immune responses allowing resident lymphocytes to encounter antigen-presenting cells that carry antigens from peripheral tissues. These structures develop during embryonic life through a tightly regulated process that involves interactions between haematopoietic and mesenchymal cells. Importantly, this morphogenesis potential is maintained throughout life since in chronic inflammatory conditions novel "tertiary lymphoid organs" can be generated by processes that are reminiscent of embryonic SLO development. In this review we will discuss early events in SLO morphogenesis, focusing on haematopoietic and mesenchymal cell subsets implicated on the development of lymphoid organs.

Complement in animal development: unexpected roles of a highly conserved pathway.

The complement pathway is most famous for its role in immunity, orchestrating an exquisitely refined system for immune surveillance. At its core lies a cascade of proteolytic events that ultimately serve to recognise microbes, infected cells or debris and target them for elimination. Mounting evidence has shown that a number of the proteolytic intermediaries in this cascade have, in themselves, other functions in the body, signalling through receptors to drive events that appear to be unrelated to immune surveillance. It seems, then, that the complement system not only functions as an immunological effector, but also has cell-cell signalling properties that are utilised by a number of non-immunological processes. In this review we examine a number of these processes in the context of animal development, all of which share a requirement for precise control of cell behaviour in time and space. As we will see, the scope of the complement system's function is indeed much greater than we might have imagined only a few years ago.

Identification of infection- and defense-related genes via a dynamic host-pathogen interaction network using a Candida albicans-zebrafish infection model.

Candida albicans infections and candidiasis are difficult to treat and create very serious therapeutic challenges. In this study, based on interactive time profile microarray data of C. albicans and zebrafish during infection, the infection-related protein-protein interaction (PPI) networks of the two species and the intercellular PPI network between host and pathogen were simultaneously constructed by a dynamic interaction model, modeled as an integrated network consisting of intercellular invasion and cellular defense processes during infection. The signal transduction pathways in regulating morphogenesis and hyphal growth of C. albicans were further investigated based on significant interactions found in the intercellular PPI network. Two cellular networks were also developed corresponding to the different infection stages (adhesion and invasion), and then compared with each other to identify proteins from which we can gain more insight into the pathogenic role of hyphal development in the C. albicans infection process. Important defense-related proteins in zebrafish were predicted using the same approach. The hyphal growth PPI network, zebrafish PPI network and host-pathogen intercellular PPI network were combined to form an integrated infectious PPI network that helps us understand the systematic mechanisms underlying the pathogenicity of C. albicans and the immune response of the host, and may help improve medical therapies and facilitate the development of new antifungal drugs.

Ancestral gene and "complementary" antibody dominate early ontogeny.

According to N.K. Jerne the somatic generation of immune recognition occurs in conjunction with germ cell evolution and precedes the formation of the zygote, i.e. operates before clonal selection. We propose that it is based on interspecies inherent, ancestral forces maintaining the lineage. Murine oogenesis may be offered as a model. So in C57BL/10BL sera an anti-A reactive, mercapto-ethanol sensitive glycoprotein of up to now unknown cellular origin, but exhibiting immunoglobulin M character, presents itself "complementary" to a syngeneic epitope, which encoded by histocompatibility gene A or meanwhile accepted ancestor of the ABO gene family, arises predominantly in ovarian tissue and was detected statistically significant exclusively in polar glycolipids. Reports either on loss, pronounced expressions or de novo appearances of A-type structures in various conditions of accelerated growth like germ cell evolution, wound healing, inflammation and tumor proliferation in man and ABO related animals might show the dynamics of ancestral functions guarantying stem cell fidelity in maturation and tissue renewal processes. Procedures vice versa generating pluripotent stem cells for therapeutical reasons may indicate, that any artificially started growth should somehow pass through the germ line from the beginning, where according to growing knowledge exclusively the oocyte's genome provides a completely channeling ancestral information. In predatory animals such as the modern-day sea anemone, ancestral proteins, particularly those of the p53 gene family govern the reproduction processes, and are active up to the current mammalian female germ line. Lectins, providing the dual function of growth promotion and defense in higher plants, are suggested to represent the evolutionary precursors of the mammalian immunoglobulin M molecules, or protein moiety implying the greatest functional diversity in nature. And apart from any established mammalian genetic tree, a common vetch like Vicia cracca, may represent an ancient model of protected reproduction mirroring A-reactive "complementarity" already in a plant. The in its seeds developed, and from the number of chromosomes depending amount of an anti-A(1) specific glycoprotein suggests promotion of germination while simultaneously exerting protection from a soil bacterium, which intriguingly is immobilized by human anti-A immunoglobulin as well. Moreover, in a mammalian ovary the lectin of Dolichos biflorus detects again histo (blood) group A-determining N-acetyl-d-galactosamine epitopes, here signalizing activity of embryonic stem cells. So apparently based on identical, ancestral structures, the dual function of growth promotion and defense, predetermined in a plant genome, might be preserved right up to dominate early mammalian ontogeny.

Natural killer cell-triggered vascular transformation: maternal care before birth?

Natural killer (NK) cells are found in lymphoid and non-lymphoid organs. In addition to important roles in immune surveillance, some NK cells contribute to angiogenesis and circulatory regulation. The uterus of early pregnancy is a non-lymphoid organ enriched in NK cells that are specifically recruited to placental attachment sites. In species with invasive hemochorial placentation, these uterine natural killer (uNK) cells, via secretion of cytokines, chemokines, mucins, enzymes and angiogenic growth factors, contribute to the physiological change of mesometrial endometrium into the unique stromal environment called decidua basalis. In humans, uNK cells have the phenotype CD56(bright)CD16(dim) and they appear in great abundance in the late secretory phase of the menstrual cycle and early pregnancy. Gene expression studies indicate that CD56(bright)CD16(dim) uterine and circulating cells are functionally distinct. In humans but not mice or other species with post-implantation decidualization, uNK cells may contribute to blastocyst implantation and are of interest as therapeutic targets in female infertility. Histological and genetic studies in mice first identified triggering of the process of gestation spiral arterial modification as a major uNK cell function, achieved via interferon (IFN)-γ secretion. During spiral arterial modification, branches from the uterine artery that traverse the endometrium/decidua transiently lose their muscular coat and ability to vasoconstrict. The expression of vascular markers changes from arterial to venous as these vessels dilate and become low-resistance, high-volume channels. Full understanding of the vascular interactions of human uNK cells is difficult to obtain because endometrial time-course studies are not possible in pregnant women. Here we briefly review key information concerning uNK cell functions from studies in rodents, summarize highlights concerning human uNK cells and describe our preliminary studies on development of a humanized, pregnant mouse model for in vivo investigations of human uNK cell functions.

Transmisión oral de la enfermedad de chagas: con especial referencia a la patología de los casos del año 2009 / Oral transmission of chagas disease due to oral: with special reference to the pathology of the cases from the year 2009

La transmisión oral de la enfermedad de Chagas habitual en el ciclo selvático es una forma rará en el ser humano. En este último, se debe a la contaminación de las heces con Trypanosoma cruzi (Tcruzi) en los alimentos o a la manipulación infectada de los mismos. Más raramente a la ingesta de carne de reservorios infectados. En esta comunicación, se ponen en el tapete, los trabajos experimentales y naturales del investigador Díaz-Ungría quien demostró el importante papel que juega la mosca doméstica en la contaminación de los alimentos con las heces infectadas de los vectores. Igualmente, se destaca la importancia del perro como reservorio doméstico, todos los cuales podrían ser factores determinantes en la causa de los brotes agudos presentados en los dos últimos años en nuestro país. Se exponen las características de la miocarditis aguda chagásica como la expresión más constante de la forma aguda de la enfermedad por transmisión oral. Se destacan las medidas de prevención efectuadas por las autoridades sanitarias en estas circunstancias

Oral transmission of Chagas disease is common in the forest'cycle and is a rare form in humans. In the human is due to contamination of the stool with T.cruzi in food or infected by their manipulation. More rarely due to reservoirs infected T.cruzi meat intake. In this communication we described the natural and experimental works of the Díaz-Ungría researcher who demonstrated the important role played bi the house fly in the contamination of food with vectors infected faeces. It also highlights the importance of the dog as domestic reservoir, all of which could be determining factors in the cause of acute outbreaks in the past two years in our country. The features of acute Chagasic'myocarditis are exposed as the constant expression of the acute form of the disease by oral transmission. The prevention measures carried out by the health authorities in these circunstances are high lighted

The ontogeny of the porcine immune system.

Cellular and humoral aspects of the immune response develop sequentially in the fetus. During the ontogeny, the pluripotent stem cells emerge and differentiate into all hematopoietic lineages. Basic questions including the identification of the first lympho-hematopoietic sites, the origin of T and B lymphocytes, the development of different subpopulations of alphabeta T, gammadelta T and B lymphocytes as well as development of innate immunity and the acquisition of full immunological capacities are discussed here for swine and compared with other species. The description of related topics such as fertilization, morphogenesis, maternal-fetal-neonatal physiology and early neonatal development are also discussed.