Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 8, Issue 1, 2008

Reg proteins constitute a conserved family in human and rodents; their production in the pancreas (including the islets of Langerhans) is induced upon β-cell damage. While some members of the family (Reg1 and islet neogenesisassociated protein, i.e. INGAP) have been implicated in β-cell replication and/or neogenesis, including from in vivo studies using transgenic and knockout mice; the roles of the other five members have yet to be characterized. Among them, Reg2 was recently proposed to serve as an autoantigen on β-cells that elicits T-cell attack in type 1 diabetes mellitus. Elucidation of their actions and identification of their molecular targets should provide insight into the biology of these proteins and lead to the design and development of novel strategies aimed at promoting the survival and function of the pancreatic islets. As the current terminology used for mammalian Reg genes/proteins is very confusing, we also proposed a uniformed classification in human and rodents through sequence alignments.

Mycophenolate mofetil (MMF) is an inosine monophosphate dehydrogenase inhibitor, that inhibits the de novo pathway of guanosine nucleotide synthesis, the proliferative responses of T and B lymphocytes as well as antibody production by B-lymphocytes. It is indicated for the prophylaxis of organ rejection after allogeneic cardiac, hepatic and renal transplants . It has recently also been used with good success in patients with lupus nephritis . Based on these actions, MMF appears to be a novel agent for the treatment of systemic sclerosis, especially during early disease where an inflammatory infiltrate preceeds the development of fibrosis. Disease modification early on during the inflammatory stage of systemic sclerosis may lead to an overall decrease in fibrotic complications both in relation to cutaneous and internal organ involvement.

Mycobacterium tuberculosis (M. tuberculosis) is one of the worlds' most successful and sophisticated pathogens. It is estimated that over 2 billion people today harbour latent M. tuberculosis infection without any clinical symptoms. Since most new cases of active tuberculosis (TB) arise from this (growing) number of latently infected individuals, urgent measures to control TB reactivation are required, including more effective drugs and new TB vaccines. The currently widely used BCG vaccines, as well as most new generation TB-vaccines that are being developed are designed as prophylactic or as BCG-booster vaccines. Unfortunately, many of these vaccines are unlikely to be effective in individuals already latently infected with M. tuberculosis. Here we argue that detailed analysis of M. tuberculosis genes that are switched on predominantly during the latent stage of infection may lead to the identification of new M. tuberculosis targets for drug and vaccine development. First, we will describe essential host-pathogen interactions in TB with particular emphasis on TB latency and persistent infection. Subsequently, we will focus on a novel group of late-stage specific genes, encoded by the M. tuberculosis dormancy (dosR) regulon, and summarize recent studies describing human T-cell recognition of these dormancy antigens in relation to (latent) M. tuberculosis infection. We will discuss the possible relevance of these new classes of antigens for new TB intervention strategies.

Various proteins that are required for the building of new complete human immunodeficiency type 1 virions (HIV-1) are coded by unspliced or partly spliced virus-derived mRNAs. HIV-1 has developed special strategies for moving these mRNAs to the cytoplasm to be translated. In the nucleus of the infected cell the virus-derived protein Regulator of expression of viral proteins (Rev) can bind both the viral intron-containing mRNAs and the cellular co-factor HIV-1 Rev binding protein (HRB) and this complex may be shuttled through the nuclear pores. HRB genes have been relatively well conserved during evolution, from Drosophila to humans. However, as a consequence of reading-frame shifts due to nt insertions/deletions, the protein products generated may differ considerably from the prototypal HRB protein, which comprises one Arf-GAP zinc finger domain, several Phenylalanine-Glycine (FG) motifs and four Asparagine-Proline- Phenylalanine (NPF) motifs. This variability is best exemplified by four HRB proteins of the dog, which are discussed here in more detail. The hypothesis is advanced that atypical HRB proteins may not be able to bind Rev and possibly have other, still undetermined, functions. Since the cellular co-factor HRB is essential for viral replication and spread but is not required for cell viability and main bodily functions, it might be an attractive candidate for anti-HIV-1 drug targeting.

Vitamin A is essential for development and differentiation of multiple tissues. Its derivatives, the retinoids, are potent drugs used to treat and prevent a variety of diseases. Retinoid effects are mediated by retinoic acid receptors (RARs) and retinoid X receptors (RXRs). There are three known RARs (α, β, and γ), and multiple isoforms of each receptor exist. Many of the therapeutic effects of retinoids including cancer chemoprevention and treatment of dermatologic disorders are mediated through RARβ. In humans, five isoforms of this gene have been described. Specific isoforms of RARβ exert distinct and sometimes opposing functions by altering patterns of target gene induction. Functional isoforms that activate distinct cassettes of target genes with differing biologic consequences include RARβ1' and RARβ2. Dominant negative isoforms of this gene that inhibit target gene activation include RARβ4 and RARβ5. RARβ1 is poorly understood although this may function as an oncogene in certain cancers. Chromatin modifying drugs have been shown to trigger isoform-specific changes in the RARβ gene. This review focuses on the structure and function of RARβ isoforms as well as recent work in the epigenetic targeting of specific RARβ isoforms. Discerning isoform-specific functions will be critical for exploiting the full potential of retinoid-based therapy including rational approaches to combining retinoids with chromatin modifying drugs.

G protein coupled receptors (GPCRs) are extremely important drug targets and the β-arrestin intracellular scaffolding and adaptor proteins regulate major aspects of their pharmacology. β-arrestin binding to activated, GPCR kinase (GRK)-phosphorylated receptors has the capacity to terminate G protein coupling, internalize the receptors into clathrincoated vesicles and establish a secondary signaling complex independent of G protein signaling. These events appear to be differentially regulated by GRK phosphorylation, ubiquitination and potentially β-arrestin oligomerization, which are likely to be highly receptor and cell-type dependent. The role of β-arrestins in switching from G-protein dependent to independent signaling places them in a pivotal position to dictate the downstream effects of ligand binding. Consequently, we must appreciate the functioning of these molecules as we strive to discover and optimize new GPCR drug therapies for endocrine, metabolic and immune disorders.

Conventional treatment of autoimmune hemolytic anemia (AIHA) comprises corticosteroids and splenectomy and/or other immunosuppressive drugs for refractory/relapsed patients. Monoclonal antibodies (MoAbs) rituximab and alemtuzumab have gained widespread acceptance in the management of B-cell malignancies. More recently, they have been used to treat a number of autoantibody-mediated diseases, such as both idiopathic and secondary AIHA, with encouraging results. Herein we report an overview of the medical literature on the use of MoAbs to treat AIHA. The therapeutic mechanism of action of rituximab in the treatment of autoimmune diseases such as rheumatoid arthritis and lupus is currently a subject of considerable investigation. We have proposed that cell-associated IgG immune complexes, generated by the binding of rituximab to CD20 on B cells, may serve as decoys that attract FcγR-expressing effector cells and downregulate effector cell pathogenic action, thus reducing inflammation and tissue destruction in these diseases. We briefly review evidence that suggests that this immune complex decoy hypothesis plays a role in the therapeutic action of rituximab in AIHA, and we propose new measurements that should allow for a more complete evaluation of the importance of this mechanism in AIHA.

Fibrotic diseases are characterized by the appearance of myofibroblasts, the key cell type involved in the fibrogenic reaction, and by excess accumulation of extracellular matrix with resultant tissue contraction and impaired function. Myofiborblasts are generated by fibroblast-myofibrobalst conversion, and in certain tissues through epithelialmesenchymal transition (EMT), a process through which an epithelial cell changes its phenotype to become more like a mesenchymal cell. Although inflammatory/fibrogenic growth factors/cytokines produced by injured tissues orchestrate the process of EMT, transforming growth factor β (TGFβ) is believed to play a central role in the process. Unlike fibrotic lesions in kidney or other tissues where myofibroblasts are generated from both fibroblasts and epithelial cells, fibrotic lesions in the eye crystalline lens are derived only from lens epithelial cells without contamination of fibroblast-derived myofibroblasts. Thus, this tissue is suitable to investigate detailed mechanisms of EMT and subsequent tissue fibrosis. EMT in retinal pigment epithelium is involved in the development of another ocular fibrotic disease, proliferative vitreoretinopathy, a fibrosis in the retina. EMT-related signal transduction cascades, i. e., TGFβ/Smad, are a target to prevent or treat unfavorable ocular tissue fibrosis, e. g., fibrotic diseases in the crystalline lens or retina, as well as possibly in other organs.