Transgenic expression of GM-CSF in T cells causes disseminated histiocytosis.

Recent studies highlight surprising roles for granulocyte-macrophage colony-stimulating factor (GM-CSF) production by T cells. T-cell-derived GM-CSF is required for the differentiation of monocyte-derived inflammatory dendritic cells during inflammation and for the pathogenicity of IL-17 producing T helper cells in autoimmunity. To gain further insight into these findings, we engineered in vivo overexpression of GM-CSF specifically in T cells, under the control of the Lck promoter.

Purification and characterization of a high specificity polyclonal antibody to the adenomatous polyposis coli tumour suppressor protein.

Recombinant proteins, commonly expressed in fusion with an affinity tag to facilitate purification, are often used as immunogens for polyclonal antibody production. Careful immunopurification of the antibody product is often the key to obtaining a high-specificity polyclonal antibody against the protein domain of interest. This study describes the purification and characterization of such an antibody directed against the adenomatous polyposis coli (APC) tumour suppressor.

Targeting lymphocyte Peyer's patch adhesion molecule-1: a relay approach to gut immunization.

Targeting vaccines to dendritic cells (DCs) can enhance responses to weak vaccine antigens. Although there are molecules that are relatively specific for the various DC subsets, there are none that are both region-specific and DC-specific. This has provided some limitation to targeting regional DC populations.

CR1/CR2 interactions modulate the functions of the cell surface epidermal growth factor receptor.

Recent crystallographic data on the isolated extracellular domain of the epidermal growth factor receptor (EGFR) have suggested a model for its activation by ligand. We have tested this model in the context of the full-length EGFR displayed at the cell surface, by introducing mutations in two regions (CR1 and CR2) of the extracellular domain thought to be critical for regulation of receptor activation. Mutations in the CR1 and CR2 domains have opposing effects on ligand binding affinity, receptor dimerization, tyrosine kinase activation, and signaling competence.

Identification of a T1D susceptibility gene.

It is not known what causes type 1 diabetes (T1D) which affects over 1 million people in the U.S. alone.

The control of apoptosis in lymphocyte selection.

The stochastic nature of rearrangement and diversification of the gene segments encoding immunoglobulins (Igs) and T cell receptors (TCRs) inevitably gives rise to immature B and T lymphocytes that lack antigen receptors or express useless or dangerous (self-antigen-specific) ones. Signaling through antigen receptors promotes survival, proliferative expansion and further differentiation of useful cells and deletion of the useless and dangerous ones. During immune responses, pathogen-specific B and T lymphocytes, as well as cells of the innate immune system, undergo extensive proliferation and develop effector functions, such as antibody secretion, cytotoxicity or cytokine production.

Analysis of pfcrt, pfmdr1, dhfr, and dhps mutations and drug sensitivities in Plasmodium falciparum isolates from patients in Vietnam before and after treatment with artemisinin.

We have analyzed artemisinin sensitivity in Plasmodium falciparum isolates obtained from patients in South Vietnam and show that artemisinin sensitivity does not differ before and after drug treatment. There was an increase in the level of mefloquine resistance in the isolates after drug treatment that was concomitant with a decrease in chloroquine resistance, suggesting that treatment with artemisinin has selected for increased mefloquine resistance. Mutations in the pfmdr1 gene, previously shown to be associated with sensitivity to mefloquine, were selected against.

Transmembrane TNF and IFNgamma induce caspase-independent death of primary mouse pancreatic beta cells.

Tumor necrosis factor (TNF) is important in the pathogenesis of autoimmune diabetes. It has an important role in immunological and inflammatory processes, and has also been shown to induce apoptotic cell death. We have shown that TNF + IFNgamma induce islet cell death in vitro.

Genetics of autoimmune diseases in humans and in animal models.

Recent applications of the genetic characterisation of autoimmunity in humans and in animal models have allowed the further mapping of many disease loci and, in some cases, the identification of disease genes. New approaches to the analysis of mapping, characterisation and identification of susceptibility genes have also been developed.

Leukemia inhibitory factor and interleukin-11: cytokines with key roles in implantation.

Members of the interleukin-6 family of cytokines include leukaemia inhibitory factor (LIF), interleukin-6, interleukin-11, cardiotrophin, ciliary neurotropic growth factor, oncostatin M and the recently discovered cardiotropin-like cytokine (NNT-1). These ligands signal via heterodimeric receptors composed of ligand-specific alpha chains and the common signal-transducing subunit gp130. Gene targeting in mice provided the first indication of a role for interleukin 6 family cytokines in implantation with the generation of mice with a null mutation of the gene encoding LIF.

The Plasmodium falciparum genome--a blueprint for erythrocyte invasion.

Erythrocyte invasion by Plasmodium falciparum involves multiple ligand-receptor interactions and numerous apparent redundancies. The genome sequence of this parasite reveals new gene families encoding proteins that appear to mediate erythrocyte invasion.

Differential regulation of CD36 expression in antigen-presenting cells: Oct-2 dependence in B lymphocytes but not dendritic cells or macrophages.

In mice, three antigen-presenting cell types [B lymphocytes, macrophages and dendritic cells (DC)] express the scavenger receptor CD36. This molecule has been implicated in many important functions, including DC maturation and antigen presentation. In murine B cells, the CD36 gene requires the Oct-2 transcription factor for its expression.

Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children.

Background: Severe asthma is a frequent cause of hospital admission, especially among children. The main environmental triggers of airway inflammation in asthma are viruses and aeroallergens. These agents elicit reciprocal immune responses, characterised by production of T helper 1 and T helper 2 cytokines, respectively.

Transfection technology and the study of drug resistance in the malaria parasite Plasmodium falciparum.

Numerous approaches have been employed to identify the molecules responsible for drug resistance in the human malaria parasite Plasmodium falciparum. However, it was not until the recent development of stable transfection in this parasite that it became possible to prove the role of particular genes in drug resistance and, perhaps more importantly, to characterise the nature of the specific mutations that contribute the resistance phenotype. In this review, the contribution of various molecular genetic approaches to the dissection of drug resistance in P.

Negative regulation of interleukin-12 signaling by suppressor of cytokine signaling-1.

Suppressor of cytokine signaling-1 (SOCS-1) is an inhibitory protein that regulates responses to cytokines. Previously, we have shown SOCS-1 to be a key inhibitor of interferon gamma (IFNgamma). Recent data suggest that SOCS-1 may regulate other cytokines in vivo, in addition to IFNgamma.

Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling.

Suppressor of cytokine signaling (SOCS)-2 is a member of a family of intracellular proteins implicated in the negative regulation of cytokine signaling. The generation of SOCS-2-deficient mice, which grow to one and a half times the size of their wild-type littermates, suggests that SOCS-2 may attenuate growth hormone (GH) signaling. In vitro studies indicate that, while SOCS-2 can inhibit GH action at low concentrations, at higher concentrations it may potentiate signaling.

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains.

Interleukin (Il)-12 is a heterodimeric cytokine composed of 35 and 40 kD chains that plays a key role in the induction of Th1 cells, a T cell subset involved in many autoimmune diseases. We report here the cDNA sequence encoding the IL-12 p40 subunit from the autoimmune-prone non-obese diabetic (NOD) mouse, which spontaneously develops type 1 diabetes. Compared with the C57BL/6 sequence, there are two base changes that lead to amino acid replacements.

A somatic cell genetic system for dissecting hemopoietic cytokine signal transduction.

Somatic cell genetics has proven to be a powerful tool for the dissection of cytokine signal transduction pathways. Here we describe a system in which interleukin-6 (IL-6) signaling may be dissected using myeloid leukemic M1 cells. We utilized two properties of M1 cell differentiation to isolate IL-6-unresponsive mutants.

The non-immune RIP-Kb mouse is a useful host for islet transplantation, as the diabetes is spontaneous, mild and predictable.

Chemically-induced diabetic mice and spontaneously diabetic NOD mice have been valuable as recipients for experimental islet transplantation. However, their maintenance often requires parenteral insulin. Diabetogenic chemicals can be cytotoxic to the host's immune system and to other organs some of which are often used as the transplant site.

Immune self-tolerance mechanisms.

Tolerance of both T and B cells to self-antigens can be achieved through a great variety of different routes, at the level of the primary lymphoid organs (thymus and bone marrow) and throughout the secondary lymphoid tissues. Whether self-reactive lymphocytes ignore their target autoantigen, or are tolerized by the various mechanisms discussed, depends on the circumstances.

An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells.

Oncostatin M (OSM), an interleukin-6 type cytokine, acts via the gp130 signaling receptor to inhibit proliferation and induce differentiation of breast cancer cells. EGF, a mitogen for breast cells, signals via EGFR/ErbB tyrosine kinase receptors which are implicated in breast cancer pathogenesis. Here we show paradoxically that EGF enhanced the OSM-induced inhibition of proliferation and induction of cellular differentiation in both estrogen receptor positive and negative breast cancer cells.

TNF cytokine family: more BAFF-ling complexities.

Recent studies on BAFF, a member of the tumor necrosis factor family, and the discovery of a new BAFF receptor have revealed that this ligand-receptor pair is essential for B-cell survival and differentiation, holding promise for a better understanding and treatment of some autoimmune diseases and lymphomas.