Current Pharmaceutical Design - Volume 7, Issue 11, 2001

Over the last several years, it has become increasingly clear that dendritic cells (DC) are not only critical for the initiation of T cell immunity, but these cells also determine the course of the subsequent immune response (i.e. tolerance vs. immunity, Th1 vs Th2). However, the mechanisms by which DC can influence the final outcome of a given immune response remain to be understood. Currently, the ability of DC to direct immunity has been linked to: (1) hematopoeitic lineage, (2) maturation stage, and (3) environmental stimuli. While the literature supports each possibility, one common feature of all three hypotheses is that immunological outcome is directly correlated to the profile of DC-derived cytokines. A review of the existing scientific literature strongly suggests that the capacity of DC to orchestrate the immune responses is not an intrinsic quality of the cell, but rather it is the result of environmental stimulation which is reflected in their cytokine and chemokine production.

HIV infects and propagates into CD4+T lymphocytes and macrophages, although many other cell types play an important role in virus spreading and pathogenesis. In addition to regulatory viral proteins, the cytokine network has early been implicated as a major controller of the plastic capacity of HIV to spread productively or rather remain silently integrated in the chromosomes of infected cells. The recent discovery of CCR5 and CXCR4 as essential entry co-receptors together with CD4 has highlighted a novel and potentially important step in the pharmacological hunt for more effective antiviral agents. In addition to regulate HIV expression and replication, several cytokines have demonstrated the capacity of up- or down-modulating chemokine receptors including CCR5 and CXCR4 with the consequence of influencing the susceptibility of T cells and macrophages to HIV infection. Pharmacological agents such as pertussis toxin B-oligomer have demonstrated HIV suppressive effects via non competitive binding of CCR5, whereas interferons or interleukin-16 (IL-16) can prevent post-entry steps in HIV expression. At the clinical level, several cytokines or their receptors are useful markers for monitoring disease progression and its consequence on the immune system. Cytokine-based therapy represents a realistic complementary approach to traditional antiretroviral therapy potentially capable of restoring important adaptive or innate immune functions ultimately curtailing HIV spreading and its consequences on the immune system, as exemplified by the experimental clinical use of IL-2.

Tuberculosis (TB) remains to be a leading infectious cause of death Worldwide. Apparently, the current BCG vaccine that has been used for 80 years, has failed to control the TB epidemic. Hunting for improved TB vaccine formulations represents a daunting task to TB research community. Anti-TB host Defense requires T cell-mediated immunity and we are in desperate need of enhanced understanding of how to develop a new generation of TB vaccines that are able to provoke potent and long-lasting protective cell-mediated immunity, different from almost all of the vaccines currently in use. It is of importance to successful TB vaccine development to identify the key cellular and molecular events governing the generation of anti-TB immunity, but unfortunately little has been understood as to why 90percent of infected humans never develop active TB. However, waiting would not help us to win the battle and an ever-intensifying effort is being made to develop various new formulations according to the immunology that we have been learning, in large part, from experimental models.This review article attempts to unite the current understanding of anti-TB immunity with the rational design of anti-TB vaccines. It examines what may have confounded the immunogenicity of current BCG vaccine and the major obstacles to successful development of TB vaccines. It also discusses about antigen presentation, activation of Th1 and Tc1 cells, anti-TB immune effectors and the generation of memory T cells. The vaccine section describes four types of major TB vaccines under development: mycobacterial-, subunit-, plasmid DNA- and viral-based vaccines. A special section is dedicated to the rationale and current design of cytokine-based adjuvant formulations for TB vaccines. We also take this opportunity to introduce our recent development in cytokine transgene adjuvanted BCG vaccination and recombinant Adenoviral-based TB vaccines.

This review examines the evidence, both from experimental models and Numerous clinical settings, that has suggested that suppression of acute allograft Rejection correlates with a relative decrease in type-1 cytokine production and an increase in type-2 cytokine production. This correlation has spurred studies on cytokine gene polymorphisms, to assess evidence that certain cytokine-producing genotypes are associated with increased incidence of transplant rejection, and also an interest in the value of monitoring cytokine profiles post-transplantation in long-term follow-up of transplant patients. An appraisal is given of the potential for cytokine gene therapy in transplantation, using both dendritic cells (DC) and graft tissue itself as target cells. Along the same lines, gene-targeting of DCs to increase or decrease expression of molecules (CD40/CD80/CD86/CD200) believed to control the polarization of T cell development (and cytokine production) is discussed. The review concludes with consideration of the possibility that one future goal of the pharmaceutical industry will be to develop novel immunosuppressants with selective inhibitory action on the production of distinct cytokines.

Although current pharmacopoeia is effective in alleviating asthma symptomatology, it is equally unable to modify the fundamental immunological basis of the allergic diathesis. The explosion in knowledge of the immunobiology of cytokines that has occurred in the last decade has remarkably clarified our understanding of the pathogenesis of allergic asthma, and has unleashed a plethora of compelling opportunities. In the first part of this review, we will summarize current knowledge on the pathogenesis of allergic asthma, with particular emphasis on relevant cytokine networks. This will position us to appraise critically initiatives in the search to modulate cytokine targets that are key to the expression of the allergic asthma phenotype. We will review the use of recombinant cytokines, soluble cytokine receptors, cytokine receptor antagonists and cytokine inhibitors, in pre-clinical and clinical development. Finally, we will assess the applicability of transgene-based modalities, including anti-sense oligonucleotide technology and gene therapy, as novel therapeutic strategies in the treatment of allergic Asthma.

Cytokines are critical to a myriad of fundamental homeostatic and pathophysiological processes such as fever, wound healing, inflammation, tissue repair and fibrosis. They play important roles in regulating cell function such as proliferation, migration, and matrix synthesis. It is the balance or the net effect of the complex interplay between these mediators, which appears to play a major role in regulating the initiation, progression and resolution of wounds. Wound healing involves a complex process including induction of acute inflammation by the initial injury, followed by parenchymal and mesenchymal cell proliferation, migration, and activation with production and deposition of extracellular matrix. Failure to resolve or abnormal wound healing results in fibrosis. The latter process involves similar cellular interactions via complex cytokine networks, which result in extensive remodeling with heightened extracellular matrix production and their abnormal deposition in the tissue. Various cytokines, both promoting and inhibiting fibrogenesis, have been implicated in the pathogenesis of fibrosis and wound healing. Recent progress in understanding the mechanisms underlying the pathogenesis of fibrosis leads us to expect that inhibitors of pro-fibrogenic cytokines and growth factors may be useful as novel therapeutic agents in controlling undesirable fibrosis. In this review, the role of cytokines in wound healing and fibrosis will be summarized and highlighted with more detailed discussion reserved for the possible points of therapeutic attack in pulmonary fibrosis. In this review, the major cytokines that are in current clinical use will be also discussed. In addition, advances in the application of novel cytokines and anti-cytokines for accelerating wound healing and attenuating fibrosis both at the experimental and the clinical trial levels will be discussed.