25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production.

25-Hydroxycholesterol is produced in mammalian tissues. The function of this oxysterol is unknown. Here we describe a central role for 25-hydroxycholesterol in regulating the immune system.

Targeting mammalian target of rapamycin to both downregulate and disable the P-glycoprotein pump in multidrug-resistant B-cell lymphoma cell lines.

Previous studies have shown that rapamycin can inhibit the growth of several different types of human tumor cells in vitro. In certain cases, it can reverse the phenotype of multidrug resistant (MDR) cells. However, there is limited information concerning its effect on P-glycoprotein (P-gp), a pump that is responsible for chemoresistance in many MDR cells.

Specific thermal ablation of tumor cells using single-walled carbon nanotubes targeted by covalently-coupled monoclonal antibodies.

CD22 is broadly expressed on human B cell lymphomas. Monoclonal anti-CD22 antibodies alone, or coupled to toxins, have been used to selectively target these tumors both in SCID mice with xenografted human lymphoma cell lines and in patients with B cell lymphomas. Single-walled carbon nanotubes (CNTs) attached to antibodies or peptides represent another approach to targeting cancer cells.

Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy.

Pro-inflammatory CD4(+) T-cell-mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes, are hypothesized to be initiated and maintained by activated antigen-presenting cells presenting self antigen to self-reactive interferon-gamma and interleukin-17-producing CD4(+) T-helper (Th) type 1/Th17 cells. To date, the majority of Food and Drug Administration-approved therapies for autoimmune disease primarily focus on the global inhibition of immune inflammatory activity. The goal of ongoing research in this field is to develop both therapies that inhibit/eliminate activated autoreactive cells as well as antigen-specific treatments, which allow for the directed blockade of the deleterious effects of self-reactive immune cell function.

The contribution of gammadelta T cells to the pathogenesis of EAE and MS.

Gammadelta T cells are a multifaceted group of cells which have both innate and adaptive characteristics and functions. Although they are most commonly known for their response to mycobacterium and their locations at mucosal sites, their roles in autoimmunity are still unclear. gammadelta T cells have been seen in the CSF and lesions of Multiple Sclerosis patients and although their function is not entirely understood, it is clear these cells may have roles in regulating autoimmune inflammation in the CNS.

Prospects for antigen-specific tolerance based therapies for the treatment of multiple sclerosis.

A primary focus in autoimmunity is the breakdown of central and peripheral tolerance resulting in the survival and eventual activation of autoreactive T cells. As CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for onset and progression of most autoimmune diseases, they are a logical target for therapeutic strategies. One method for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T cell activation.

Mitochondria influence Fas expression in gp120-induced apoptosis of neuronal cells.

The human immunodeficiency virus-1 (HIV-1) destroys the immune system and also induces neurological disease culminating into dementia (HIV-associated dementia). Though the HIV viral protein gp120 induces apoptosis in neuronal cells, the mechanism of action is still poorly defined. Recent studies show that cells die during apoptosis by Fas aggregation aided by the mitochondrial proapoptotic proteins.

Cross-linking of CD80 on CD4+ T cells activates a calcium-dependent signaling pathway.

CD80 expressed on the surface of APCs provides a positive costimulatory signal to naive CD4+ T cells via CD28 during activation. However, CD80 is also expressed on the surface of activated CD4+ T cells, and cross-linking CD80 on the surface of CD4+ T cells activated in the presence of Th1-promoting cytokines induces a direct up-regulation of T-bet, IFN-gamma, and Bcl(XL) expression in primary CD4+ T cells. The present data show that naive CD4+ T cells activated in Th1-promoting conditions in the presence of anti-CD80 mAb increase the level of IFN-gamma produced by increasing the rate of IFN-gamma mRNA transcription, which is supported by an increase in the level of T-bet phosphorylation and T-bet binding to the third intronic enhancer in the IFN-gamma locus.

The role of infections in autoimmune disease.

Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.

Differential induction of experimental autoimmune encephalomyelitis by myelin basic protein molecular mimics in mice humanized for HLA-DR2 and an MBP(85-99)-specific T cell receptor.

Multiple sclerosis (MS) is a chronic autoimmune neurological disease characterized by infiltration of peripheral inflammatory cells to the central nervous system (CNS) and demyelination of CNS white matter. Epidemiological evidence suggests a possible infectious trigger. One potential mechanism by which an infectious agent may trigger MS is via molecular mimicry wherein T cells generated against foreign epitopes cross-react with self-myelin epitopes, such as myelin basic protein (MBP), with sufficient sequence similarity.

PD-1 ligands expressed on myeloid-derived APC in the CNS regulate T-cell responses in EAE.

Disease progression in experimental autoimmune encephalomyelitis (EAE) is regulated by programmed death receptor 1 (PD-1) and its ligands, B7-H1 (programmed death ligand 1 (PD-L1)) and B7-DC (PD-L2). B7-H1 and B7-DC have negative regulatory effects upon binding PD-1 on activated T cells and B7-H1 deficiency increases severity of both diabetes and EAE. However, the role of PD-L expression on different APC in the CNS in regulating local T-cell function during relapsing EAE has not been examined.

Intrinsic and induced regulation of the age-associated onset of spontaneous experimental autoimmune encephalomyelitis.

Multiple sclerosis is characterized by perivascular CNS infiltration of myelin-specific CD4(+) T cells and activated mononuclear cells. TCR transgenic mice on the SJL background specific for proteolipid protein (PLP)(139-151) develop a high incidence of spontaneous experimental autoimmune encephalomyelitis (sEAE). We examined the intrinsic mechanisms regulating onset and severity of sEAE.

The antitumor activity of an anti-CD54 antibody in SCID mice xenografted with human breast, prostate, non-small cell lung, and pancreatic tumor cell lines.

We have previously described the development and testing of a monoclonal anti-human CD54 antibody (UV3) in SCID mice xenografted with human multiple myeloma, lymphoma, and melanoma cell lines. In all 3 cases, UV3 was highly effective at slowing the growth of tumors and/or prolonging survival. Since CD54 (ICAM-1) is up-regulated on many different types of cancer cells, we have now investigated the anti-tumor activity of UV3 in several other CD54(+) epithelial tumors.

Memory B cells in common variable immunodeficiency: clinical associations and sex differences.

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired antibody responses, recurrent infections, inflammatory, autoimmune and malignancy-related conditions. We evaluated the relationship between memory B cell phenotype, sex, age at diagnosis, immunologic and clinical conditions in 105 CVID subjects from one medical center. Reduced numbers of switched memory B cells (cutoff View Article and Find Full Text PDF

Astrocytes in multiple sclerosis: a product of their environment.

It has long been thought that astrocytes, like other glial cells, simply provide a support mechanism for neuronal function in the healthy and inflamed central nervous system (CNS). However, recent evidence suggests that astrocytes play an active and dual role in CNS inflammatory diseases such as multiple sclerosis (MS). Astrocytes not only have the ability to enhance immune responses and inhibit myelin repair, but they can also be protective and limit CNS inflammation while supporting oligodendrocyte and axonal regeneration.

Production of CCL2 by central nervous system cells regulates development of murine experimental autoimmune encephalomyelitis through the recruitment of TNF- and iNOS-expressing macrophages and myeloid dendritic cells.

Experimental autoimmune encephalomyelitis is a T cell-mediated demyelinating disease of the CNS that serves as a model for the human disease multiple sclerosis. Increased expression of the chemokine CCL2 in the CNS has been demonstrated to be important in the development of demyelinating disease presumably by attracting inflammatory cells. However, the mechanism of how CCL2 regulates disease pathogenesis has not been fully elucidated.

Cutting edge: central nervous system plasmacytoid dendritic cells regulate the severity of relapsing experimental autoimmune encephalomyelitis.

Plasmacytoid dendritic cells (pDCs) have both stimulatory and regulatory effects on T cells. pDCs are a major CNS-infiltrating dendritic cell population during experimental autoimmune encephalomyelitis but, unlike myeloid dendritic cells, have a minor role in T cell activation and epitope spreading. We show that depletion of pDCs during either the acute or relapse phases of experimental autoimmune encephalomyelitis resulted in exacerbation of disease severity.

Engineering therapeutic monoclonal antibodies.

During last two decades, the chimerization and humanization of monoclonal antibodies (mAbs) have led to the approval of several for the treatment of cancer, autoimmune diseases, and transplant rejection. Additional approaches have been used to further improve their in vivo activity. These include combining them with other modalities such as chemotherapy and redesigning them for improved pharmacokinetics, effector function, and signaling activity.

Generation of multidrug resistant lymphoma cell lines stably expressing P-glycoprotein.

The objective of this study was to generate new P-glycoprotein (P-gp)-expressing multidrug resistant (MDR) cell lines by drug selection. Since our previous studies have been carried out with cells infected with a P-gp-containing vector, it was important to confirm our findings in cells generated by drug selection. In this report, we describe three B-lymphoma cell lines which became drug-resistant by stepwise exposure to vincristine (VCR): Raji cells resistant to 18 nM VCR (R18V), Namalwa cells resistant to 21 nM VCR (N21V) and DHL-4 cells resistant to 12 nM VCR (DHL-4/12V).

Pro-inflammatory functions of astrocytes correlate with viral clearance and strain-dependent protection from TMEV-induced demyelinating disease.

Intracerebral infection of susceptible strains of mice, e.g. SJL/J, with Theiler's murine encephalomyelitis virus (TMEV) leads to a persistent CNS infection accompanied by development of a chronic-progressive inflammatory CNS autoimmune demyelinating disease which is clinically and pathologically similar to human multiple sclerosis.

Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes.

Background: Mutations in the gene coding for transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) have been identified in common variable immunodeficiency (CVID). Mutations coincided with immunodeficiency in families, suggesting dominant inheritance.

Objective: Because most subjects with CVID have no immunodeficient family members and heterozygous mutations predominate, the role of TACI mutations in sporadic CVID is unclear.

Molecular mimics can induce novel self peptide-reactive CD4+ T cell clonotypes in autoimmune disease.

It has been postulated that infectious agents may precipitate autoimmune disease when T cell responses raised against the pathogen cross-react with self-peptides, a phenomenon known as molecular mimicry. However, there are very little data available characterizing the similarity between the repertoire of the cross-reactive self-specific T cell population compared with the pathogen-specific T cell repertoire. In this study, we use immunoscope analysis to identify the T cell populations induced upon priming SJL/J mice with a pathogen-derived mimic of the immunodominant encephalitogenic myelin peptide PLP(139-151), which is contained within the protease IV protein of Haemophilus influenzae (HAE(574-586)).

Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion.

Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model suggest that adherent white blood cells (WBCs) play a key role in vaso-occlusion by capturing circulating red blood cells (RBCs) in venules. Commercial intravenous immunoglobulin (IVIG) given before the inflammatory stimuli increased microcirculatory blood flow and survival. To mimic the clinical situation in which SCD patients seek medical attention after the onset of symptoms, we developed an in vivo model in which the therapeutic intervention (eg, IVIG) was administered after in the inflammatory challenge.