Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 7, Issue 1, 2007

Calprotectin, a protein composed by two subunits of 8 and 14 kD respectively, is released by neutrophils in the biological fluids under inflammatory states. For instance, detection of calprotectin in faeces represents a diagnostic tool in the case of inflammatory bowel disease. Quite interestingly, calprotectin is increased in the stool of healthy newborns from day three up to day thirty and, physiologically, this increase may be interpreted as a defense mechanism against yeast and fungi. Therapeutic attempts at inhibiting the deleterious effect of calprotectin have been experimentally made by using lycoricinidol. This natural compound is able to hamper the calprotectin-induced apoptosis on the one hand. On the other hand, the same compound plays a prophylactic role in the course of experimental arthritis in rats.

Acute or chronic inflammation is thought to play a major role in the etiology and/or pathogenesis of autoimmune disease. Often viral infections are the initial cause for a local inflammatory reaction resulting in tissue infiltration by activated leukocytes. The activation and trafficking of these leukocytes to the site of inflammation is conducted by chemoattractant cytokines, termed chemokines. Depending on the genetic background and the history of previous infections, such infiltrating leukocytes can potentially include autoaggressive lymphocytes with specificity to tissue antigens. The number of specific precursor lymphocytes, strength of activation and degree of counteracting immunoregulatory measures determine whether such an autoimmune incident ultimately results in autoimmune disease. Thus, by blocking the initial inflammatory insult one could in theory prevent the excessive attraction of autoaggressive lymphocytes to the inflammation site and the subsequent formation of a pattern that leads to autoimmune disease. This review focuses on blocking of chemokines in animal models of type 1 diabetes and discusses the possible applications of such treatments in human autoimmune disease.

The Wnt/β-catenin pathway plays critical roles in cell physiology, including determination, proliferation, migration and differentiation in embryonic development and adult homeostasis. Several components of the Wnt/β-catenin pathway, such as SFRPs, WIF-1, DKK-1, APC, AXIN2, ICAT, LEF1 and β-catenin, are the target of mutations or epigenetic inactivation leading to the deregulation or constitutive activation of the Wnt/β-catenin pathway. Aberrant activation of the Wnt signalling pathway abrogates controlled growth and impairs cell differentiation. Alterations of the Wnt signalling pathway have been found in cancer, osteoporosis, ischemic neuronal death and other human diseases. Here we review the alterations of the Wnt/β-catenin signalling cascade and discuss the biological significance and relationship between mutation and/or epigenetic silencing within the same pathway.

CD40L-based therapy is currently under intensive investigation for its potent anti-tumor effects in experimental animal models of cancer as well as in Phase I clinical trials. CD40L is one of the strongest inducers of Th1 responses although it stimulates both innate and adaptive immunity. The molecule is normally expressed by activated immune cells such as T helper cells that act on dendritic cells to induce their maturation and capability of activating tumor-reactive T cells. Moreover, recent findings implicate that CD40L stimulation abrogates the suppressive effect of T regulatory cells. Interestingly, while being an activator of immune cells, CD40L has been shown to directly induce apoptosis in tumor cells by mechanisms only beginning to emerge. These two major effector mechanisms synergize to combat tumor growth. Optimal use of this multipotent molecule might therefore result in effective immunotherapy of cancer. CD40L can be administered to patients as soluble protein trimers. To achieve membrane-bound expression, viral vectors can be used to transfer CD40L cDNA into 1) tumor cells ex vivo for creating CD40L-expressing tumor vaccines, 2) ex vivo cultured dendritic cells for cell therapy, and 3) tumor nodules in situ. CD40L substitutes such as CD40-directed agonistic antibodies have been evaluated with interesting results in experimental models. In this survey, different types and mechanisms of CD40Lbased therapy will be discussed from bench to bedside.

Bortezomib is the first proteasome inhibitor to be used clinically for the treatment of multiple myeloma and has been suggested as a possible treatment for a wide variety of hematologic and solid malignancies. Recent data suggests that potent immunomodulatory effects can also occur with systemic proteasome inhibition. This has been recently shown to occur in a graft-versus host disease model following bone marrow transplantation in mice. The suggested direct immunological effects of bortezomib treatment to include a decrease in anti-apoptotic protein levels, an increase in expression of TNF-family receptors (specifically Apo2L/TRAIL), induction of apoptosis, and inhibition of the transcription factor NF- κB. The NF- κB pathway has been associated with the regulation of numerous immune and inflammatory response mediators. In this review, we will present recent information concerning the potential therapeutic implications of bortezomib for a range of immune disorders. These findings would suggest that bortezomib treatment may be of clinical significance to suppress solid organ transplant rejection, autoreactive T cell responses, pro-inflammatory cytokine production, and consequently disease progression and pathology in autoimmunity.

Multiple sclerosis (MS) is a chronic disabling disease with significant implications for patients and society. The individual disease course is difficult to predict due to the heterogeneity of clinical presentation as well as radiological and pathological findings. Although its etiology still remains unknown, the last decade has generated considerable success in understanding the underlying pathophysiology of MS. In addition to its view as a prototypic inflammatory autoimmune disorder, recent data support the importance of primary and secondary neurodegenerative mechanisms such as oligodendrocyte death, axonal loss and ion channel dysfunction. The deepened understanding of the immunopathogenesis as well as the limited effectiveness of the currently approved disease modifying therapies have led to a tremendous number of trials investigating potentially new drug targets. Emerging treatments take into account the different immunopathological mechanisms as well as strategies to protect against axonal damage or to promote remyelination. This review provides a compilation of novel immunotherapeutic strategies or new aspects of known immunotherapeutic agents which have evolved recently. The pathogenetic rationale of these novel drug targets for the treatment of MS as well as accompanying preclinical and clinical data are highlighted.

Insulin resistance is a pathophysiological link of obesity to type 2 diabetes. The initial cause of insulin resistance is critical for prevention and treatment of type 2 diabetes. Lipotoxicity is a well-known concept in the explanation of initiation of insulin resistance. Although there are several prevailing hypotheses about the cellular/molecular mechanisms of lipotoxicity, such as inflammation, oxidative stress, hyperinsulinemia, and ER stress, the relative importance of these hypothesized events remains to be determined. The role of hyperinsulinemia is relatively under documented in the literature for the initiation of insulin resistance. In this review, an interaction of fatty acid and beta-cells, and a synergy between free fatty acids (FFAs) and insulin are emphasized for the role of hyperinsulinemia. This article presents the evidence about FFA-induced insulin secretion in vitro and in vivo, recent advances in the molecular mechanism of FFA action in beta-cells, a role of GPR40 in the development of insulin resistance, and the negative feedback loop of the insulin receptor signal pathway. The negative feedback loop is discussed in detail with a focus on IRS-1 serine kinases. This article provides a substantial support for the role of insulin in the early stages of FFA-associated insulin resistance. The hypothesis of insulin's role in lipotoxicity is referred to as the “insulin hypothesis” in this review. According to this hypothesis, prevention of increased beta-cell response to glucose may be a potential approach for early intervention of metabolic syndrome.