Current Pharmaceutical Design - Volume 15, Issue 17, 2009

This issue summarizes the pharmaceutical and cellular strategies of recent advances in immunotherapy. The articles in this issue cover a broad range of topics including treatments of cancer and graft versus host disease, and HIV as well as immune modulators that can be developed for therapeutic vaccines. The article written by Gaurnier-Hausser and Tuszynski [1] describes an immunomodulatory role for angiocidin, a novel angiogenesis inhibitor. The authors describe how angiocidin can stimulate immune cells to present antigen. Experiments are shown that demonstrate the ability of angiocidin to differentiate peripheral blood monocytes into macrophage like cells that can function to present antigen and posses properties important in immune modulation. The authors further described novel pathways activated by angiocidin that stimulate production of molecules important in immune modulation. There data suggest that angiocidin could be used as an adjuvant for production of vaccines for diseases such as cancer, viral diseases, and arthritis. The article written by Keibel et al. [2] reviews advancements in clinical and epidemiological studies that have demonstrated a strong association between chronic inflammation and cancer. The authors show that proinflammatory cytokines, chemokines as well as adhesion molecules regulate the sequential recruitment of leukocytes frequently observed in the tumor microenvironment. These early desmoplastic changes could stimulate fibroblast and endothelial cells to produce molecular components for tissue remodeling and neovascularization which ultimately could promote the neoplastic process. In this review the current understanding of the role of chronic inflammation in neoangiogenesis, tumor initiation and promotion are presented. The article by Actor et al. [3] describes the natural immune modulation of lactoferrin, an iron binding glycoprotein. This molecule bridges innate and adaptive immune functions by regulating leukocyte response. It is a pleotropic molecule that directly assists antigen presenting cells and the development of T-helper cells. The review provides a comprehensive understanding of research regarding the role of lactoferrin in immune modulation as it relates to infectious disease, trauma and injury. The information presented in this review is highly relevant to the development of therapeutic interventions and vaccines.

The observation that many tumors exist in a microenvironment comprised of immune cells has led to the hypothesis that the immune system may play a significant role in the suppression of tumor growth. It is now clear that immune effector cells are capable of recognizing and destroying some cancer cells. However, tumors have developed numerous mechanisms by which they avoid immune recognition and death. Cancer immunotherapy attempts to harness the power of the immune system and direct it against tumor growth, while circumventing the immune-evasion strategies utilized by tumors. Many approaches are currently being investigated, including the re-infusion of autologous immune effector cells (i.e. cytotoxic T lymphocytes and macrophages) back into hosts after ex vivo expansion and activation. The therapeutic effects of specific cytokines are also being evaluated for their impact on tumor growth. Our lab has discovered a novel thrombospondin-1 (TSP-1) binding protein, termed “angiocidin”, with potent anti-tumor and anti-angiogenic capabilities. To further investigate the anti-tumor activity of angiocidin, we examined whether angiocidin could play a role in immune system modulation. We have found that the monocytic leukemia cell line THP-1, as well as freshly isolated human peripheral blood monocytes, differentiate into macrophage-like cells when treated with angiocidin. These cells underwent dramatic morphological changes and became more phagocytic. Angiocidin-treated monocytes also activated T lymphocytes in co-culture conditions. Angiocidin-treated THP-1 cells upregulated cytokine mRNA expression and secretion via NF-κB, MAPK, and PI3-K. Based on these data, we hypothesize that angiocidin's ability to elicit tumor cell death may be mediated in part by it's pro-inflammatory effects on immune cells in the tumor microenvironment.

Since Virchow first proposed in 1863 that tumors could originate from sites of chronic inflammation, it has been well established that chronic inflammation both contributes to cancer progression and predisposes tissue to various types of cancer. Experimental, clinical, and epidemiological studies have all demonstrated the strong association between chronic inflammation and cancer, and many studies have correlated the prolonged presence of the inflammatory milieu with an increased risk for developing cancer. Proinflammatory cytokines, chemokines and adhesion molecules, which regulate the sequential recruitment of leukocytes, are frequently observed in tumor microenvironment. These early desmoplastic changes could stimulate fibroblasts and endothelial cell division and produce components for tissue remodeling and neovascularization, ultimately promoting neoplastic processes. In this review article we overview the current understanding of the role of chronic inflammation in neoangiogenesis, tumor initiation, promotion, and progression.

Lactoferrin, an iron-binding glycoprotein, is a cell-secreted mediator that bridges innate and adaptive immune function in mammals. It is a pleiotropic molecule that directly assists in the influence of presenting cells for the development of T-helper cell polarization. The aim of this review is to provide an overview of research regarding the role of lactoferrin in maintaining immune homeostasis, in particular as a mediator of immune responses to infectious assault, trauma and injury. These findings are critically relevant in the development of both prophylactic and therapeutic interventions in humans. Understanding these particular effects of lactoferrin will provide a logical framework for determining its role in health and disease.

Acute and chronic GVHD after allogeneic hematopoetic stem cell transplantation are still associated with significant morbidity and mortality. For prophylaxis of acute GVHD calcineurin inhibitors in combination with an antimetabolite (MTX or MMF) are administered, and these therapies are based on controlled studies. New prophylaxis strategies include mTOR-inhibitors in combination with tacrolimus but require confirmation by controlled trials. First-line treatment of acute GVHD consists mainly of steroids with doses ranging from 1 mg/kg/day prednisone to 3 mg/kg/day methylprednisolone. Second-line treatment of acute GVHD after failure of steroids is less well defined due to the lack of controlled studies. Treatment options are the use of cytotoxic antibodies (ATG, campath), cytokine blocking agents (etanercept, daclizumab), immunomodulating modalities (photopheresis), and antimetabolites (pentostatin, MMF). Recently, cellular approaches were developed, such as the adoptive transfer of mesenchymal stem cells. Nevertheless steroid-resistant acute GVHD is still a main challenge in alloHSCT and associated with high mortality. First-line treatment of chronic GVHD is also based on steroids with 1 mg/kg/day prednisolone or prednisone, which are often combined with calcineurin inhibitors. There is no consensus on second-line treatment of chronic GVHD and most therapies are solely based on phase II trials. Treatment options are the use of immunomodulating modalities (photopheresis, mTOR-inhibitors) and antimetabolites (MMF, MTX, pentostatin). Recent reports showed an efficacy of rituximab in selected patients. Other treatment options are low dose total nodal irradiation or the use of antibodies like ATG. Moreover, successful topical treatment of manifestations of chronic GVHD manifestations has been reported consisting of topical steroids like budesonide, topical calcineurin inhibitors, or PUVA.

Anti-cytokine therapy has promoted a revolution in the treatment of several inflammatory disorders during the past 10 years. Despite their medical and commercial success, they exhibit several drawbacks: difficulties of production, excessive costs, and a few side-effects. A promising alternative to the passive infusion of monoclonal antibodies or soluble cytokine receptors is the use of the active anti-cytokine immune therapy (ACIT). Surprisingly, clinical studies suggested the interest of this approach during the late 1980's, even before the advent of anti-cytokine passive immunotherapy. In this review, we first explain the involvement of several cytokines in many common diseases involving cytokine overproduction, and identify key targets for anti-cytokine treatments. We then present an update on current advances in preclinical and clinical development of passive anti-cytokine therapeutic approaches. We further discuss progresses in the promising field of active anti-cytokine immunotherapy. Cytokine receptors biologics and small molecules developed using structure/function information, which also constitute important options for treating the cytokine-mediated diseases, are not discussed in this review.

Regenerative Medicine, a recent new medical domain, aims to develop new therapies through the stimulation of natural regenerative processes also in human beings. In this field, Erythropoietin (EPO) represents a significant subject of research. Several studies allow the assertion that EPO, in different concentrations, has protective effects mainly on the central nervous system, cardiovascular system and renal tissue. This action is carried out through one of few regenerative activities of human beings: angiogenesis. This mechanism, which involves endothelial stem cells and VEGF (Vascular Endothelial Growth Factor), has been experimentally demonstrated with Recombinant human erythropoietin (rHuEPO) and Darbepoetin, a long-acting EPO derivate. Furthermore, the demonstration of a cardiac production of EPO in Fugu rubripes and in Zebrafish has led cardiologists to “discover” Erythropoietin, postulating a hypothetical role in treatment of cardiovascular disease for this hormone. This is some of the experimental evidence which demonstrates that EPO can be in reason considered an important element of research of Regenerative Medicine and put in the network of drugs able to regenerate tissues and organs.

Patients with diabetes mellitus (DM) type 2 have a high prevalence of coronary artery disease (CAD), as diabetes is implicated in the formation of atherosclerotic plaque. Hyperglycemia, elevated free fatty acid, increased amount of circulating end-glucosylated serum products and insulin resistance are the main mechanisms involved in the accelerated atherosclerotic process observed in type 2 DM patients. Novel treatments have been proposed to prevent and treat CAD in patients with diabetes, mainly in those with diabetes type 2. Several clinical trials have been designed in order to examine the effectiveness of these agents, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, glitazones, statins and antioxidants, but the results are still controversial.