Cancer,aging and immunotherapy: lessons learned from animal models

Aging of the immune system is associated with a dramatic reduction in responsiveness as well as functional dysregulation. This deterioration of immune function with advancing age is associated with an increased incidence of cancer. Although there is a plethora of reports evaluating the effect of immunotherapy in stimulating antitumor immune responses, the majority of these studies do not pay attention to the effect aging has on the immune system. Studies from our group and others indicate that immunotherapies could be effective in the young, are not necessarily effective in the old. To optimally stimulate an antitumor immune response in the old, it is necessary to (1) identify and understand the intrinsic defects of the old immune system and (2) use relevant models that closely reflect those of cancer patients, where self-tolerance and aging are present simultaneously. The present review summarizes some defects found in the old immune system affecting the activation of antitumor immune responses, the strategies used to activate stronger antitumor immune response in the old and the use of a tolerant animal tumor model to target a self-tumor antigen for the optimization of immunotherapeutic interventions in the old.     

Anidulafungin: experimental therapy of fungal infections in animal models

We have reviewed the existing data on the efficacy of anidulafungin, which is the most recent echinocandin in the experimental treatment of fungal infections. The scarce published data practically only refers to disseminated and pulmonary aspergillosis and to disseminated candidiasis. Anidulafungin shows fungistatic activity against Aspergillus fumigatus, and fungicidal activity against Candida albicans and Candida glabrata.     

The core-binding factor leukemias: lessons learned from murine models

The recent development of murine models of core-binding factor leukemias has provided important insights into the underlying molecular pathology of this common subtype of acute myeloid leukemia. Evidence from these models supports the idea that acute myeloid leukemia 1/core-binding factor beta-subunit (AML1/CBFbeta) has a critical role in the control of the self-renewal capacity of hematopoietic stem cells and their progeny. Moreover, the accumulated data demonstrate that the expression of translocation-encoded AML1 or CBFbeta fusion proteins are insufficient by themselves to induce a full leukemic phenotype. The models that have been developed should prove to be of value for defining the range of mutations that can cooperate with AML1/CBFbeta fusion proteins, and for assessing novel therapies targeted toward the pathways that are altered by the expression of these fusion proteins.     

Regulation of immunity to malaria: valuable lessons learned from murine models

A major advance in immunology has been the establishment of a framework for analysing how certain immune responses dominate following exposure to a particular pathogen or antigen. CD4(+) T helper (Th) cells can be separated into two major subsets which mediate qualitatively distinct cell-mediated (Th1) and humoral (Th2) immune responses. Immunity to most pathogens can be broadly categorized into a predominant protective response of either type. A characteristic of murine malarias is that primary infections with asexual erythrocytic parasites (the pathogenic stage of the malaria life cycle) generate a host protective immune response with a broad spectrum of Th1- and Th2-type CD4(+) T-cell involvement and so can be examined as models of the interaction of Th1 and Th2 cells during an immune response to an infectious agent. Andrew Taylor-Robinson here describes recent events in the dissection of the mechanisms responsible for the generation of protective immunity to Plasmodium chabaudi chabaudi and other experimental malarias in mice.     

Exploring molecular genetics of bladder cancer: lessons learned from mouse models

Urothelial cell carcinoma (UCC) of the bladder is one of the most common malignancies worldwide, causing considerable morbidity and mortality. It is unusual among the epithelial carcinomas because tumorigenesis can occur by two distinct pathways: low-grade, recurring papillary tumours usually contain oncogenic mutations in FGFR3 or HRAS, whereas high-grade, muscle-invasive tumours with metastatic potential generally have defects in the pathways controlled by the tumour suppressors p53 and retinoblastoma (RB). Over the past 20 years, a plethora of genetically engineered mouse (GEM) models of UCC have been developed, containing deletions or mutations of key tumour suppressor genes or oncogenes. In this review, we provide an up-to-date summary of these GEM models, analyse their flaws and weaknesses, discuss how they have advanced our understanding of UCC at the molecular level, and comment on their translational potential. We also highlight recent studies supporting a role for dysregulated Wnt signalling in UCC and the development of mouse models that recapitulate this dysregulation.     

Diabetic embryopathy and fuel-mediated organ teratogenesis: lessons from animal models

The growing recognition that faulty maternal metabolism during early organogenesis may be implicated in the increased incidence of birth defects in pregnancies complicated by diabetes has prompted worldwide efforts to institute improved preconceptional metabolic regulation. However, the failure to identify the periods of greatest risk for diabetic embryopathy, the mediating teratogen(s), and the underlying mechanisms have complicated attempts to establish precise therapeutic guidelines and targets. Some of the reported in vivo and in vitro experiences with rodent models have been reviewed to derive relevant insights. Substantial literature indicates that diabetes (experimental as well as spontaneous) in pregnant rats and mice is attended by retardation of growth and developmental delay during embryogenesis, and a variable incidence of birth defects. Poor metabolic regulation of the diabetic mother during early organogenesis may also be followed by subsequent resorption of the conceptus at the site of implantation. Vulnerability to diabetes-related resorptions and all other forms of embryopathy appears to begin during the early postimplantation period and is greatest near the onset of neurolation. Overall susceptibility is markedly influenced by genetic factors and may be modified by the antecedent metabolic exposures of the conceptus ("carry-over effects"). Mediation for the anomalous embryo development in pregnancies of diabetic rodents appears to be multifactorial; all the aberrant fuels and fuel-related components of "the diabetic state" (e.g. high glucose; ketones; somatomedin inhibitor(s); osmolality, etc.) which have been tested to date display dysmorphogenic potential ("fuel-mediated organ terato-genesis") in vitro. All tissues in the conceptus appear to be at risk. Dose-response relationships for the individual metabolic teratogens may be influenced by additive and synergistic interactions so that the integrated possibilities cannot be assessed fully by measurements confined to a single fuel or fuel-related component. In the context of the day-to-day variability in diabetes "control" of the poorly regulated mother, and the relatively longer duration of organogenesis, these multifactorial possibilities may account for the multiple birth defects that can occur in individual offspring, and the seemingly non-specific pattern of diabetic embryopathy. Insulin therapy diminishes the dysmorphogenic effects of "the diabetic state" in rodents with experimental or spontaneous diabetes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pregnancy-associated homeostasis and dysregulation: lessons from genetically modified animal models

Unlimitedly proliferating cells need to acquire the telomere DNA maintenance mechanism, to counteract possible shortening through multiple rounds of replication and segregation of linear chromosomes. Most human cancer cells express telomerase whereas the other cells utilize the alternative lengthening of telomeres (ALT) pathway to elongate telomere DNA. It is suggested that ALT depends on the recombination between telomere repetitive DNAs. However, the molecular details remain unknown. Recent studies have provided evidence of special structures of telomere DNA and genes essential for the phenotypes of ALT cells. The molecular models of the ALT pathway should be validated to elucidate recombination-mediated telomere maintenance and promote the applications to anti-cancer therapy.     

Effector T cells in rheumatoid arthritis: lessons from animal models

The development of an immune response to self antigens drives naive T cells to differentiate into subsets of CD8(+) and CD4(+) effector cells including T(H)1, T(H)2, cells and the more recently described T(H)17, and regulatory T cells (T(reg)). Rheumatoid arthritis is an autoimmune disease that engages an uncontrolled influx of inflammatory cells to the joints, eventually leading to joint damage. The role that effector T cells play in the local or systemic maintenance of, or protection against, inflammation and subsequent joint damage is now becoming better understoodthrough the use of animal models. In this review, we will explore the different animal models of RA, and their contribution to elucidating the role that effector T cells play in the regulation, induction, and maintenance of inflammatory joint disease. This understanding will aid in the design of more effective therapeutic strategies for rheumatoid arthritis and other autoimmune disorders.     

VTEC: lessons learned from British outbreaks

Important Escherichia coli O157 outbreaks in England and Scotland since 1982-83 are reviewed. The scientific lessons learned from them are described and their legal consequences outlined. The light shed by them on relationships between law and science is discussed, and questions of blame are analysed in the context of Reason's 'resident pathogen' metaphor and Vaughan's study of the 1986 Challenger Space Shuttle disaster.     

Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models

Systemic lupus erythematosus (SLE) is a complex disease characterized by the appearance of autoantibodies against nuclear antigens and the involvement of multiple organ systems, including the kidneys. The precise immunological events that trigger the onset of clinical manifestations of SLE are not yet well understood. However, research using various mouse strains of spontaneous and inducible lupus in the last two decades has provided insights into the role of the immune system in the pathogenesis of this disease. According to our present understanding, the immunological defects resulting in the development of SLE can be categorized into two phases: (a) systemic autoimmunity resulting in increased serum antinuclear and antiglomerular autoantibodies and (b) immunological events that occur within the target organ and result in end organ damage. Aberrations in the innate as well as adaptive arms of the immune system both play an important role in the genesis and progression of lupus. Here, we will review the present understanding - as garnered from studying mouse models - about the roles of various immune cells in lupus pathogenesis.     

Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models

Normal pregnancy is associated with reductions in total vascular resistance and arterial pressure possibly due to enhanced endothelium-dependent vascular relaxation and decreased vascular reactivity to vasoconstrictor agonists. These beneficial hemodynamic and vascular changes do not occur in women who develop preeclampsia; instead, severe increases in vascular resistance and arterial pressure are observed. Although preeclampsia represents a major cause of maternal and fetal morbidity and mortality, the vascular and cellular mechanisms underlying this disorder have not been clearly identified. Studies in hypertensive pregnant women and experimental animal models suggested that reduction in uteroplacental perfusion pressure and the ensuing placental ischemia/hypoxia during late pregnancy may trigger the release of placental factors that initiate a cascade of cellular and molecular events leading to endothelial and vascular smooth muscle cell dysfunction and thereby increased vascular resistance and arterial pressure. The reduction in uterine perfusion pressure and the ensuing placental ischemia are possibly caused by inadequate cytotrophoblast invasion of the uterine spiral arteries. Placental ischemia may promote the release of a variety of biologically active factors, including cytokines such as tumor necrosis factor-alpha and reactive oxygen species. Threshold increases in the plasma levels of placental factors may lead to endothelial cell dysfunction, alterations in the release of vasodilator substances such as nitric oxide (NO), prostacyclin (PGI(2)), and endothelium-derived hyperpolarizing factor, and thereby reductions of the NO-cGMP, PGI(2)-cAMP, and hyperpolarizing factor vascular relaxation pathways. The placental factors may also increase the release of or the vascular reactivity to endothelium-derived contracting factors such as endothelin, thromboxane, and ANG II. These contracting factors could increase intracellular Ca(2+) concentrations ([Ca(2+)](i)) and stimulate Ca(2+)-dependent contraction pathways in vascular smooth muscle. The contracting factors could also increase the activity of vascular protein kinases such as protein kinase C, leading to increased myofilament force sensitivity to [Ca(2+)](i) and enhancement of smooth muscle contraction. The decreased endothelium-dependent mechanisms of vascular relaxation and the enhanced mechanisms of vascular smooth muscle contraction represent plausible causes of the increased vascular resistance and arterial pressure associated with preeclampsia.     

Mitochondrial efficiency: lessons learned from transgenic mice

Metabolic research has, like most areas of research in the life sciences, been affected dramatically by the application of transgenic technologies. Within the specific area of bioenergetics it has been thought that transgenic approaches in mice would provide definitive proof for some longstanding metabolic theories and assumptions. Here we review a number of transgenic approaches that have been used in mice to address theories of mitochondrial efficiency. The focus is largely on genes that affect the coupling of energy substrate oxidation to ATP synthesis, and thus, mice in which the uncoupling protein (Ucp) genes are modified are discussed extensively. Transgenic approaches have indeed provided proof-of-concept in some instances, but in many other instances they have yielded results that are in contrast to initial hypotheses. Many studies have also shown that genetic background can affect phenotypic outcomes, and that the upregulated expression of genes that are related to the modified gene often complicates the interpretation of findings.     

Dissecting phosphorylation networks: lessons learned from yeast

Protein phosphorylation continues to be regarded as one of the most important post-translational modifications found in eukaryotes and has been implicated in key roles in the development of a number of human diseases. In order to elucidate roles for the 518 human kinases, phosphorylation has routinely been studied using the budding yeast Saccharomyces cerevisiae as a model system. In recent years, a number of technologies have emerged to globally map phosphorylation in yeast. In this article, we review these technologies and discuss how these phosphorylation mapping efforts have shed light on our understanding of kinase signaling pathways and eukaryotic proteomic networks in general.     

Overcoming immune evasion in T cell therapy of cancer: lessons from animal models

Cancer antigen-specific cytotoxic T lymphocytes (CTL) are the major effectors against cancer cells. However, large established tumors are usually not fully controlled by CTL for at least two reasons. First, large established tumors have immune suppressive networks that not only suppress CTL effector function but also permit tumor progression. Second, the genetic instability of cancer cells often results in the selection of antigenic variants by CTL, which allow cancer cells to escape destruction. Simply enhancing T cell capacity may not fully control large established tumors. Other measures, such as enhancing local costimulation, inhibiting angiogenesis and down-regulating functions of tumor associated myeloid cells should also be considered. In this paper we will review some of the progress from animal studies.     

Congenital viral infections of the brain: lessons learned from lymphocytic choriomeningitis virus in the neonatal rat

The fetal brain is highly vulnerable to teratogens, including many infectious agents. As a consequence of prenatal infection, many children suffer severe and permanent brain injury and dysfunction. Because most animal models of congenital brain infection do not strongly mirror human disease, the models are highly limited in their abilities to shed light on the pathogenesis of these diseases. The animal model for congenital lymphocytic choriomeningitis virus (LCMV) infection, however, does not suffer from this limitation. LCMV is a well-known human pathogen. When the infection occurs during pregnancy, the virus can infect the fetus, and the developing brain is particularly vulnerable. Children with congenital LCMV infection often have substantial neurological deficits. The neonatal rat inoculated with LCMV is a superb model system of human congenital LCMV infection. Virtually all of the neuropathologic changes observed in humans congenitally infected with LCMV, including microencephaly, encephalomalacia, chorioretinitis, porencephalic cysts, neuronal migration disturbances, periventricular infection, and cerebellar hypoplasia, are reproduced in the rat model. Within the developing rat brain, LCMV selectively targets mitotically active neuronal precursors. Thus, the targets of infection and sites of pathology depend on host age at the time of infection. The rat model has further shown that the pathogenic changes induced by LCMV infection are both virus-mediated and immune-mediated. Furthermore, different brain regions simultaneously infected with LCMV can undergo widely different pathologic changes, reflecting different brain region-virus-immune system interactions. Because the neonatal rat inoculated with LCMV so faithfully reproduces the diverse neuropathology observed in the human counterpart, the rat model system is a highly valuable tool for the study of congenital LCMV infection and of all prenatal brain infections In addition, because LCMV induces delayed-onset neuronal loss after the virus has been cleared, the neonatal rat infected with LCMV may be an excellent model system to study neurodegenerative or psychiatric diseases whose etiologies are hypothesized to be virus-induced, such as autism, schizophrenia, and temporal lobe epilepsy.     

How our view of animal phylogeny was reshaped by molecular approaches: lessons learned

In the late 1980s, researchers began applying molecular sequencing tools to questions of deep animal phylogeny. These advances in sequencing were accompanied with improvements in computation and phylogenetic methods, and served to significantly reshape our understanding of metazoan evolution. Prior to this time, researchers asserted phylogenetic hypotheses based on their experience with taxa and to some degree, their authority. Molecular phylogenetic tools provided discrete methods and objective characters for reconstructing phylogeny. Nonetheless, major changes to widely accepted views, such as animal phylogeny, take time to be accepted. Development and acceptance of our current understanding of animal evolution occurred in three main phases: initial hypotheses based on 18S data, confirmation with additional molecular markers, and continued refinement with phylogenomics. With the advent of ideas such as Lophotrochozoa and Ecdysozoa, flaws in the traditional view became apparent. We now understand that complex morphological and embryological features (e.g., segmentation, coelom formation, development of body cavities) are much more evolutionarily plastic than previously recognized. Here, I explore how the transition from the traditional to the modern phylogenetic understanding of animal phylogeny occurred and examine some implications of this change in understanding. As the field moves forward, the utility of morphological and embryological characters for reconstruction of deep animal phylogeny should be discouraged. Instead, these characters should be interpreted in the light of independent phylogeny.