Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 7, Issue 2, 2007

Antimicrobial proteins (AMP) are endogenous, gene-encoded proteins, which are able to kill bacteria, fungi and viruses at micro- and nanomolar concentrations. The constitutive as well as inducible production of AMP provides a rapid first-line of defense against invading microorganisms. The significance of such ancient defense system is reflected by the wide distribution of AMP in the plant and animal kingdom. There is increasing evidence that AMP may play an important role in several infectious and inflammatory diseases such as atopic dermatitis, cystic fibrosis and Crohn's disease. In this review we aim to provide a short overview about the role of antimicrobial proteins in human diseases. In addition, the use and selective induction of AMP for the development of novel potential therapeutic strategies are addressed. The benefits and possible restrictions of AMP utilization as a new class of antibiotic compounds are discussed.

Diabetic nephropathy is a leading cause of end-stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and hemodynamic factors, which activate common pathways that lead to renal damage. Recent large prospective clinical studies have shown that intensive glucose control reduces microvascular complications effectively among patients with diabetes, and the renin-angiotensin system (RAS) is also an important target for both metabolic and hemodynamic derangements in diabetic nephropathy. High glucose, via various mechanisms such as increased production of oxidative stress and advanced glycation end products (AGEs), activation of the RAS and protein kinase C (PKC), and stimulation of the polyol pathway, elicits vascular inflammation and alters gene expression of growth factors and cytokines, thereby it might be involved in the development and progression of diabetic nephropathy. Therefore, to develop novel therapeutic strategies that specifically target these metabolic and hemodynamic derangements is desired for patients with diabetic nephropathy. In this review, we discuss the molecular mechanisms of diabetic nephropathy and review the promising therapeutic targets for this devastating disorder.

Recently, several new classes of agents were developed to treat patients with malignant diseases. This progress has been based on the advances made in our understanding of critical pathways involved in tumor development and growth. Dysregulated processes leading to uncontrolled regulation of proliferation, cell cycle progression, angiogenesis and apoptosis have provided rational targets for novel therapies. Compounds inhibiting protein phosphorylation and signal transduction like tyrosine kinase inhibitors and inhibitors of proteasomal degradation have demonstrated promising results and were approved for the treatment of patients with malignant diseases. However, based on in vitro and in vivo studies, there is now an emerging evidence that these agents can affect the function and differentiation of normal, non-malignant cells like dendritic cells or T lymphocytes, resulting in immunosuppression. In our review we present recent data on the immune regulatory effects of tyrosine kinase inhibitors like imatinib that is approved to treat chronic myeloid leukemias, or inhibitors of FLT3, currently used to treat acute leukemias, as well as proteasome inhibitors and peroxisome proliferator- activated receptor agonists and discuss their possible role and application in the treatment of autoimmune and graft versus host disease.

There is little doubt that cytotoxic T lymphocytes (CTLs) can kill tumor cells in-vivo. However, most CTLinducing immunization protocols examined so far in cancer patients have yielded only limited clinical benefits, underscoring the urge to improve current approaches for the effective induction of tumor-reactive CTLs. The tumor side of the immunological frontline is armed with large masses, high mutability and an arsenal of immune evasion and suppression mechanisms. Accordingly, the confronting CTLs should come in large numbers, recognize an assortment of MHC class I (MHC-I) bound tumor-associated peptides and be brought into action under effective immunostimulatory conditions. Naive CTLs are activated to become effector cells in secondary lymphoid organs, following their productive encounter with MHC-I-bound peptides at the surface of dendritic cells (DCs). Therefore, many cancer vaccines under development focus on the optimization of peptide presentation by DCs at this critical stage. The elucidation of discrete steps and the subsequent identification of inherent bottlenecks in the MHC-I antigen presentation pathway have fueled elaborate efforts to enhance vaccine efficacy by the rational targeting of proteins or peptides, formulated into these vaccines, to this pathway. Protein- and gene-based strategies are accordingly devised to deliver tumor-associated peptides to selected cellular compartments, which are essential for the generation of functional CTL ligands. Many of these strategies target the conventional, endogenous route, while others harness the unique pathways that enable DCs to present exogenous antigens, known as cross-presentation. Here we dissect the intricate machinery that produces CTL ligands and examine how knowledge-based cancer vaccines can target the sequence of workstations, biochemical utensils and molecular intermediates comprising this production line.

There is a great need for new intervention and prevention strategies against Crohn's disease (CD), a chronic, relapsing tissue-destructive inflammatory bowel disease (IBD). Estimates indicate more than 1 million cases of IBD in the United States occur annually, with 50% involving CD. The clinical features of CD correlate with certain mouse models of colitis, including the spontaneous colitis observed in interleukin-10 deficient (IL-10-/-), senescence accelerated mice (SAMP1/Yit) and trinitrobenzene sulfonic acid (TNBS)-treated mice. Chemokines undoubtedly play a pivotal role in the regulation (i.e., initiation, maintenance, and suppression) of mucosal inflammation and tissue destruction. A number of key advances have led to greater understanding of the steps responsible for colitis and the roles played by chemokines. In fact, CXCR3 and the ligands for this chemokine receptor, monokine-induced by interferon-γ (IFN-γ) (MIG/CXCL9), IFN- γ-inducible 10 kDa protein (IP-10/CXCL10), and IFN-γ-inducible T cell α-chemoattractant (I-TAC/CXCL11) are differentially expressed at sites of colitis in IL-10-/- mice and in clinical cases of CD. While we have demonstrated that antibodies directed against CXCL10 could both prevent the onset and cure of pre-existing colitis in IL-10-/- mice, studies by other investigators have shown the efficacy of CXCR3 blockade to mitigate colitis and other inflammatory diseases. This review describes the hallmarks of IBD, CXCL9-11, and CXCR3 expression during murine colitis and IBD, gives an overview of the antagonist therapies targeting the CXCR3 axis, details current and pending bio-therapies for IBD, and discusses what is known about the cellular and CXCR3-mediated mechanisms of colitis.

Glucocorticoids play a pivotal role in the regulation of most essential physiological processes, including energy metabolism, maintenance of electrolyte balance and blood pressure, immune-modulation and stress responses, cell proliferation and differentiation, as well as regulation of memory and cognitive functions. There are several levels at which glucocorticoid action can be modulated. On a tissue-specific level, glucocorticoid action is tightly controlled by 11β- hydroxysteroid dehydrogenase (11β-HSD) enzymes. The conversion of inactive 11-ketoglucocorticoids (cortisone and 11- dehydrocorticosterone) into active 11β-hydroxyglucocorticoids (cortisol and corticosterone) is catalyzed by 11β-HSD1, which is expressed in many tissues and plays an important role in metabolically relevant tissues such as the liver, adipose tissue and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11β-HSD1 activity rather than elevated systemic glucocorticoid levels has been associated with metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that compounds inhibiting 11β-HSD1 activity ameliorate the adverse effects of excessive glucocorticoid concentrations on metabolic processes, providing promising opportunities for the development of therapeutic interventions. This review addresses recent findings relevant for the development and application of therapeutically useful compounds that modulate 11β-HSD1 function.

Human immunodeficiency virus type 1 (HIV-1) requires a chemokine receptor (CCR5 or CXCR4) as a coreceptor not only for initiate viral entry but also protecting highly conserved neutralization epitopes from the attack of neutralizing antibodies. Over the past decade, many studies have provided new insights into the HIV entry mechanism and have focused on developing an effective vaccine strategy. However, to date, no vaccine that can provide protection from HIV-1 infection has been developed. One reason for the disappointing results has been the inability of current vaccine candidates to elicit a broadly reactive immunity to viral proteins such as the envelope (env) protein. Here, we propose that chemokine receptors are attractive targets of vaccine development because their structures are highly conserved and that our synthetic cycloimmunogens can mimic conformational-specific epitopes of undecapeptidyl arches (UPAs: R168-C178 in CCR5, N176-C186 in CXCR4) and be useful for HIV-1 novel vaccine development.