Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents - Current Issue

Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Type 2 diabetic individuals are also characterized by reduced β-cell mass likely due to increased cellular apoptosis. Traditional strategies to treat diabetes have been developed with the main purpose of reducing hyperglycemia, and include insulin sensitizers, α-glucosidase inhibitors, and β-cell secretagogues. However, available drugs do not fully correct the phenotypic abnormalities in diabetes (e.g., insulin resistance, insulin deficiency) and have limited tolerability. Additionally, several available therapies are associated with weight gain or enhanced risk of hypoglycemia. Thus, newer approaches are urgently required. Particular emphasis should be placed on developing pharmacological interventions that are dependent on physiological responses and adequately target underlying defects, such as obesity, insulin resistance, increased glucose output from the liver, secretory dysfunction, or apoptosis of the β-cell. Individual phenotypic and genetic characterization of the diabetic patients will allow to define more and more personalized and effective algorithms for the treatment of hyperglycemia.

Insulin analogs have largely replaced conventional insulin preparations and extensive clinical studies have confirmed the beneficial action profile of these artificial insulin molecules. Tight blood sugar control is a major goal of intensified insulin therapy and this can be obtained much more efficiently when using insulin analogs. Currently, three rapidacting insulin analogs are in clinical use based on either a change of the amino acid sequence (insulin lispro) or exchanges of one (insulin aspart) or two (insulin glulisine) amino acids. Insulin glargine was the first long-acting insulin analog with a well documented low risk of nocturnal hypoglycemia. Insulin detemir is the most recent insulin analog with a longacting profile based on esterification with a fatty acid. For all insulin analogs safety considerations are mandatory and must take into account both the IGF-I and the insulin receptor. Enhanced mitogenic activity and a tumorigenic potential of an insulin analog may involve increased IGF-I receptor signaling and/or sustained insulin receptor activation. Both insulin and IGF-I receptors are involved in the regulation of tumor cell growth. Further, insulin/IGF-hybrid receptors are abundant in these cells and additional studies will be needed to assess the role of these receptors in the long-term action profile and safety of insulin analogs.

The incretin hormone glucagon-like peptide 1 (GLP-1) is produced by post-translational processing of the proglucagon gene in intestinal L-cells. Owing to its glucose-dependent insulinotropic effect, a potential in the treatment of type 2 diabetes has been suggested already 20 years ago. However, rapid enzymatic inactivation of GLP-1 in vivo and the need for parenteral administration have obviated its earlier therapeutic application. In addition to its effects on insulin secretion, GLP-1 suppresses glucagon secretion, decelerates gastric emptying and increases satiety leading to reduced food intake and weight loss. In the light of these features, GLP-1 appears to be an ideal candidate for the treatment of type 2 diabetes. Today, a number of different GLP-1 analogues or derivatives (the so called "incretin mimetics") with more favourable pharmacokinetic profiles have been generated. Exenatide (Byetta; Eli Lilly & Co), a synthetic GLP-1 receptor agonist suitable for twice daily s.c. injection, has now been approved by the FDA for the add-on therapy of patients with type 2 diabetes with insufficient metabolic control during metformin and/or sulfonylurea treatment. A number of other incretin mimetics are currently being studied in clinical trials. An alternative strategy to enhance the action of endogenous GLP-1 is inhibition of its enzymatic degradation by specific inhibitors of the protease DPP 4 (DPP 4 inhibitors), which are absorbed after oral ingestion. Reductions in HbA1c-levels during treatment with incretin mimetics and DPP 4 inhibitors were in the order of 0.5-1 %. Major advantages of using incretin mimetics compared to other antidiabetic drugs available include the lack of a risk for hypoglycaemia due to the strict glucose-dependence of insulinotropic and glucagonostatic GLP-1 actions as well as weight reduction by several kg despite their insulinotropic mode of action. Therefore, incretin mimetics and DPP 4 inhibitors seem to be useful new tools for the future treatment of type 2 diabetes.

During the past 10 years a multitude of clinical and observational studies have confirmed the efficacy of the antidiabetic drug, glimepiride, in lowering fasting and postprandial blood glucose in lean and obese type 2 diabetic patients even after a single administration per day, only, as well as its high safety and patient's compliance. Additional findings obtained in these studies suggested a number of clinical advantages compared to other sulfonylurea drugs on the market (e.g. glibenclamide), in particular, the lower risk for hypoglycemia, weight gain and atherosclerotic vascular disease as well as the less pronounced hyperinsulinemia. Studies investigating the molecular basis underlying the clinical profile of glimepiride provide strong evidence for multiple molecular targets/mechanisms for the blood glucose-lowering effect of glimepiride operating at both pancreatic ß-cells and extrapancreatic cells. (i) Interaction with the sulfonylurea receptor, SUR, at the ß-cell plasma membrane triggers insulin release. (ii) Interaction with lipid rafts, DIGs, at the plasma membrane of adipose and muscle cells induces the insulin-mimetic activity via the activation of a glycosylphosphatidylinositol- specific phospholipase, redistribution of signaling components and positive cross-talk downstream to the insulin signaling cascade. (iii) Interference with additional molecular mechanisms in extrapancreatic cells (e.g. regulation of adipocytokine release from and differentiation of adipocytes), relying on or independent of SUR and DIGs, contributes to the insulin-sensitizing activity of glimepiride. Differences in the engagement of these targets/mechanisms between glimepiride and glibenclamide are compatible with the more favorable blood glucose-lowering profile and the lower risk for weight gain, hypoglycemic incidences and cardiovascular side effects. The molecular and clinical findings with glimepiride raise doubts that the potential of sulfonylureas for the therapy of type 2 diabetic patients has already been fully explored and feeds the hope for more efficient and nevertheless safe antidiabetic drugs derived from this "old" pharmacophore class in the future.

The prevalence of Type 2 diabetes (Non-Insulin-Dependent Diabetes Mellitus) increases at an alarming rate in the world's population, reaching an epidemic proportion. Moreover, impaired glucose tolerance and insulin resistance are being diagnosed nowadays in a growing subpopulation of obese children and adolescents, mostly in Western societies. This adds to the concern that not only the number of NIDDM patients will increase dramatically to over 300 millions within 20 years, but also that overt diabetes and diabetes-related complications will develop earlier in life. The main goal of pharmacological therapy of diabetic patients is to reduce blood glucose levels to the normal range. Indeed, most diabetic patients require oral antihyperglycemic drug therapy; yet, the relatively high rate of failure of these drugs and the chronic nature of the disease, which is associated with progressive dysfunction and exhaustion of pancreatic insulinproducing β-cells, lead in many cases to insulin therapy. Most available antihyperglycemic drugs sensitize β-cells to secrete insulin or overcome peripheral insulin resistance by sensitizing insulin-responsive tissues towards insulin. Nevertheless, genuine insulin mimetic drugs or drugs aimed at directly augmenting the glucose transport system in insulinsensitive tissues are still being sought. This review describes briefly current molecular targets for antihyperglycemic drugs and discusses potential compounds that may act as insulin-mimetics or enhancers. In addition, a novel concept is introduced for the development of carbohydrate derivatives that may augment glucose transport in insulin-sensitive tissues in an insulin-independent manner.

Protein phosphorylation is the most common mechanism of protein function regulation. Protein kinases are key signaling enzymes that participate in the regulation of multiple cellular responses. Insulin regulates whole-body glucose homeostasis by modulating the activities of protein kinases in its target tissues: muscle, liver and fat. Defects in insulin's ability to modulate protein kinase activity lead to 'insulin resistance' or impaired insulin action. Recently, many serine kinases have been involved in the pathogenesis of obesity, metabolic syndrome and diabetes. These include the discovery of c-Jun N-terminal kinase (JNK), I kappa beta kinase (IKK), protein kinase C (PKC) theta, glycogen synthase kinase 3 (GSK3), S6 kinase-1 (S6K1) and 5'AMP-activated protein kinase (AMPK) as critical regulators of insulin action and glucose homeostasis. In this review, the mechanisms underlying kinases-induced insulin resistance, the impact of blocking this pathway in obesity and diabetes and the status of small molecule inhibitors will be discussed. It is expected that elucidation of the molecular mechanisms underlying regulation and specificity may prompt novel approaches for the pharmacological modulation of protein kinase activities involved in metabolic diseases. This review will give detail on recent discoveries and highlight emerging kinase targets that hold potential to reduce insulin resistance and normalize blood glucose.

Graft-versus-host disease (GVHD) is a devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). Although significant progress in the treatment of GVHD has been made, several obstacles remain in overcoming this complication. Animal models have been critical to our understanding of the pathophysiology of GVHD, and multiple clinical approaches have been taken, based on experimental animal models. This volume brings together contributions from experts in the fields of HSCT and GVHD research, reviewing GVHD pathophysiology and GVHD therapy. Ferrara et al. review the pathophysiology of acute GVHD, considering this disorder as a three-step process in which the innate and adaptive immune systems interact. Ikehara reviews a new HSCT method, intra-bone marrow transplantation, by which GVHD is prevented even when donor lymphocyte infusion is carried out. Fowler and Gress review the role of sirolimus in allogeneic HSCT, and they describe a new adoptive Th2 cell therapy using sirolimus. Iwasaki reviews novel therapies aimed at protecting against GVHD by using protective growth factors, focusing on hepatocyte growth factor and sphingosine-1-phosphate. Via et al. review the parent-into-F1 model of GVHD that is useful for studying immune responses in non-myeloablative conditioning regimens, chronic GVHD, and autoimmunity. Finally, Levy reviews approaches to regulate experimental as well as clinical GVHD during three different stages, including the use of CD4+CD25+ regulatory T cells. We gratefully acknowledge the generous efforts of all of these contributors. I hope this book will prove valuable to those who are working in the fields of hematology and oncology.

The pathophysiology of acute graft versus host disease (GVHD) can be considered as a three-step process where the innate and adaptive immune systems interact (Fig. 1). The three steps are: 1) tissue damage to the recipient by the radiation/chemotherapy pre-transplant conditioning regimen, 2) donor T cell activation and clonal expansion, and 3) cellular and inflammatory factors. This schema underscores the importance of mononuclear phagocytes and other accessory cells to the development of GVHD after complex interactions with cytokines secreted by activated donor T cells. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to damage and activation of host tissues throughout the body and the secretion of inflammatory cytokines Tumor Necrosis Factor (TNFα) and Interleukin (IL-1). These cytokines may enhance donor T cell recognition of host alloantigens by increasing expression of major histocompatibility complex (MHC) antigens and other molecules on host antigen presenting cells (APCs). Inflammatory cytokines may also stimulate chemokine release, recruiting donor T cells into host target organs. In step 2, host APCs present alloantigen (an HLApeptide complex) to the donor T cells. Co-stimulatory signals are required for T cell activation and these signals further activate APCs which in turn enhance T cell stimulation, characterized by cellular proliferation and the secretion of cytokines. IL-2 expands the T cell clones and induces cytotoxic T cell (CTL) responses; whereas, IFNγ has multiple effects, including the priming of mononuclear phagocytes to produce TNFα and IL-1. In step 3, effector functions of mononuclear phagocytes and neutrophils are triggered through a secondary signal provided by mediators such as lipopolysaccharides (LPS) that leak through the intestinal mucosa damaged during step 1. This inflammation, along with direct lysis of target cells by CTL, causes pathologic changes in target organs. Risk factors, as well as strategies to prevent GVHD, can be conceptualized according to this three-step model and will be reviewed in this article.

A new bone marrow transplantation (BMT) method, "intra-bone marrow (IBM)-BMT" has recently been developed. This method was found to prevent not only graft-versus-host (GvH) reaction but also host-versus-graft (HvG) reaction, since IBM-BMT can efficiently recruit donor-derived stromal cells (including mesenchymal stem cells: MSCs), which produce immunosuppressive cytokines. This paper shows that IBM-BMT prevents GvHD even when donor lymphocyte infusion (DLI) is carried out, and that the combination of IBM-BMT + DLI not only prevents GvHD but also inhibits the growth of solid tumors in mice. In addition, it has been shown that IBM-BMT will be applicable to the treatment of various intractable diseases.

An ability to modulate three distinct yet inter-related immune processes is required for successful allogeneic hematopoietic stem cell transplantation (HSCT): reduction in graft-versus-host reactivity that initiates graft-versus-hostdisease (GVHD), inhibition of host-versus-graft reactivity that causes allograft rejection, and enhancement of graftversus- leukemia (GVL) and graft-versus-tumor (GVT) effects that primarily account for the curative capacity of allogeneic HSCT. Each of these inter-related processes is susceptible to modulation by sirolimus, which restricts receptor and nutrient mediated signaling in multiple cell types through inhibition of the central regulatory molecule, mammalian target of rapamycin (mTOR). In experimental models, sirolimus beneficially: (1) prevents GVHD; (2) prevents graft rejection; and (3) directly mediates anti-tumor responses in tumors with constitutive activation of the phosphoinositide-3 kinase (PI3K) pathway that lies upstream to mTOR. However, sirolimus detrimentally may: (1) abrogate GVL and GVT effects; (2) reduce function of APC populations; and (3) inhibit hematopoiesis. As such, utility of interventions that inhibit mTOR will depend upon the balance of beneficial vs. detrimental effects generated. Recent clinical trials indicate that sirolimus can indeed yield a favorable balance to this equation, as the drug appears to prevent GVHD without marked impairment of alloengraftment or anti-tumor effects. However, sirolimus therapy is limited by drug toxicity and a relatively narrow therapeutic window. This limitation may be overcome in part through in vitro usage of sirolimus for allograft T cell engineering in clinical trials now in progress.

Graft-versus-host disease (GVHD) has been the primary limitation to the wide application of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is initiated by activation of donor T cells recognizing host tissue antigens, with subsequent dysregulated inflammatory cytokine production by monocytes and macrophages. These inflammatory cytokines are crucial for the pathogenesis of acute GVHD and these inflammatory manifestations are recognized as clinical acute GVHD. This paper presents a brief review of the mechanisms underlying inflammatory cytokine responses during acute GVHD and various strategies aimed at the prevention of acute GVHD. As cytokines and growth factors that are protective against GVHD are also produced during inflammatory cytokine responses, the factors contributing to the protection against GVHD are also reviewed. Attention has focused on the mechanisms responsible for the protection against GVHD conferred by hepatocyte growth factor and sphingosin-1-phosphate, which are abundantly stored in platelets. These factors are produced during inflammation and tissue injury and regulate immune, hematopoietic and regenerative responses. Novel therapies aimed at protection against GVHD using protective growth factors are discussed, although in most cases, their clinical relevance has not been established. Carefully designed clinical trials are awaited to evaluate their usefulness in the prevention and management of GVHD.

Since its description roughly 30 years ago, the parent-into-F1 model of graft-vs.-host disease has provided insights into the mechanisms of in vivo T cell activation and the pathogenesis of autoimmune conditions. A new and emerging role for the P→F1 model is one of identifying agents with immunomodulatory activity and defining in vivo mechanisms that promote cell mediated or antibody mediated immune responses. Because F1 mice are not irradiated prior to donor cell transfer, the P→F1 model has in the past not been strictly analogous to human hematopoetic stem cell transplantation. However with the advent of newer non-myeloablative conditioning regimens, the model may assume more relevance. In this article, we first provide a review of relevant earlier fundamental observations followed by a summary of recent work from our laboratory in which acute and chronic GVHD in this model have been used not only to study normal T cell responses in vivo but also to define mechanisms important in the pathogenesis of autoimmunity and immunomodulation.

Graft vs. host disease (GVHD) represents the major obstacle to more widespread clinical application of allogeneic hematopoietic cell transplants and experimentally provides perhaps the most important model for immunologists to study the significance and regulation of allogeneic T cell responses in situ. The sensitivity of induction to donor T cell numbers, the target tissues 'attacked' in the host and the clinical sequelae associated with the pathogenesis of GVHD in the mouse remarkably parallel that which occurs in humans and thus has provided an extremely useful tool to dissect the underlying cells and mechanisms involved in this complex disorder. This review describes the general features of GVHD followed by a description of the three stages which define this response. Approaches being developed to regulate experimental as well as clinical GVHD during these different stages are then discussed. We conclude that advances towards the targeting of each stage of the process are raising hope that clinicians will one day be able to control both the 'light' and 'dark' sides of GVHD. The challenge to refine and implement such approaches at the bedside necessitates continued interactions and collaborative efforts between laboratories dedicated to applying the underlying cellular and molecular biology of hematolymphoid cells to transplantation together with clinician scientists motivated by the goal to perform hematopoietic cell transplants without fear of complications.