Researchers resolve controversy over how COX inhibitors cause heart hazards, and offer alternative treatment strategy
Inhibitors of cyclooxygenase-2 (COX-2) were developed to relieve inflammatory pain as effectively as nonsteroidal anti-inflammatory drugs (NSAIDS), but without one of their major side effects, gastrointestinal bleeding. However, an unexpected adverse cardiovascular effect – a higher incidence of myocardial infarction – was subsequently detected, causing the highly publicized withdrawal of COX-2 inhibitors from the market in late 2004. A number of large, randomized, controlled trials designed to test the efficacy of different COX-2 inhibitors for a variety of indications have confirmed the cardiovascular toxicity, suggesting that this is an effect of all drugs in this class. However, just how this class of drug causes this heart hazard has remained controversial. Now, in a study appearing online on April 13 in advance of print publication in the May issue of the Journal of Clinical Investigation, Garret FitzGerald and colleagues from the University of Pennsylvania School of Medicine report how COX-2 inhibitors increase the incidence of myocardial infarction and stroke. In addition, they propose a new therapeutic approach that retains the beneficial anti-inflammatory effects of NSAIDS and COX-2 inhibitors, while avoiding their adverse cardiovascular consequences.
COX-2 inhibitors are believed to exert both their beneficial and their adverse effects by suppression of COX-2–derived prostacyclin (PGI2) and prostaglandin E2 (PGE2). These substances help prevent platelet clumping in blood vessels and vessel relaxation and/or constriction, respectively. Therefore, the challenge has been to identify a mechanism whereby PGI2 and PGE2 expression can be suppressed while avoiding adverse cardiovascular events. FitzGerald and colleagues now show that selective inhibition, knockout, or mutation of COX-2, or deletion of the receptor for COX-2–derived PGI2, accelerates the formation of blood clots and elevates blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin.
PGE2 biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). In the effort to propose an alternative therapeutic option to COX-2 inhibitors, FitzGerald et al. showed that deletion of mPGES-1 suppressed PGE2 expression, augmented PGI2 expression, but most importantly, affected neither blood clotting nor blood pressure. These results suggest that inhibitors of mPGES-1 may offer anti-inflammatory efficacy by depressing PGE2, while avoiding the adverse cardiovascular consequences associated with COX-2–mediated PGI2 suppression.
TITLE: Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function
AUTHOR CONTACT:
Garret A. FitzGerald
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Phone: (215) 898-1184; Fax: (215) 573-9135; E-mail: garret@spirit.gcrc.upenn.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=27540
PHYSIOLOGY
When sticks and stones break your bones, PlGF repairs them
Each year, some 6.2 million Americans will suffer a broken bone, and while the repair of a fracture is generally a rapid and efficient process, for 10% of patients the fracture takes longer than expected to heal or fails to heal in a reasonable amount of time. In a study appearing online on April 13 in advance of print publication in the May issue of the Journal of Clinical Investigation, Geert Carmeliet and colleagues from the Catholic University in Leuven, Belgium, show that placental growth factor (PlGF) is required for normal fracture repair and consequently may possess therapeutic potential for the repair of broken bones.
PlGF has previously been shown to play an important role in the growth of small blood vessels in order to deliver nutrients and oxygen, as well as the recruitment of cells of the immune system and stem cells into injured tissue to promote healing. Given the importance of blood vessel growth and the inflammatory response in fracture repair, Carmeliet and colleagues hypothesized that PlGF may also help mend broken bones.
The authors examined the process of bone repair following fracture in normal and PlGF-deficient mice. They found that lack of PlGF impairs the repair of broken bone, causing delayed or incomplete healing. Remarkably, PlGF was found to be required for multiple crucial stages of bone repair: (i) initiation of the inflammatory response and new vessel growth; (ii) activation of bone stem cells to form new bone; (iii) stimulation of cartilage turnover; and (iv) optimal remodeling of the fracture site to correct any deformities that may remain as the result of the injury. PlGF was expressed at increased levels throughout the bone repair process, and several cell types involved in the repair process expressed the PlGF receptor on their surface. In sum, the study demonstrates that PlGF is required for coordinating key and successive stages of fracture repair.
TITLE: Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair
AUTHOR CONTACT:
Geert Carmeliet
Katholieke Universiteit Leuven, Leuven, Belgium
Phone: 32-16-345974; Fax: 32-16-345934; E-mail: geert.carmeliet@med.kuleuven.be
View the PDF of this article at: https://www.the-jci.org/article.php?id=26772
ONCOLOGY
Enhancing the immune response to cancer
Most antigens expressed on the surface of cancer cells are also expressed by non-cancerous cells, and as the immune system is designed to avoid launching an immune response against oneself, researchers have struggled to design treatment protocols to kill cancer cells without harming normal cells. In a study appearing online on April 13 in advance of print publication in the May issue of the Journal of Clinical Investigation, José Guevara-Patiño and colleagues from the University of Chicago have found a way to trigger a robust T cell response to skin cancer cells in mice.
Tyrosinase-related protein 1 (Tryp1) is expressed by skin cancer cells but does not trigger an immune response. The researchers show that the introduction of specific mutations in Tryp1, followed by immunization of mice with mutated Tryp1 DNA, triggers T cells to recognize multiple epitopes in the non-mutated Tryp1 protein and in doing so mount an immune response against the tumor, prolonging survival in these animals. The mutated protein was processed differently within the cells, leading to the generation of altered peptide ligands, which increased the ability of immune cells to recognize and destroy the tumor.
The study demonstrates how the rational design of a DNA vaccine directed against a self antigen can generate multispecific T cell responses to otherwise non-immunogenic antigens, thereby enhancing the immune response against cancer self antigens.
TITLE: Optimization of a self antigen for presentation of multiple epitopes in cancer immunity
AUTHOR CONTACT:
José A. Guevara-Patiño
University of Chicago, Chicago, Illinois, USA
Phone: (773) 702-5438; Fax: (773) 834-8140; E-mail: jguevara@surgery.bsd.uchicago.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25591
IMMUNOLOGY
T cell cross-reactivity may surprisingly lessen efficacy of the T cell response
The immune system possesses a diverse repertoire of T cells, whose receptors (T cell receptors; TCRs) are capable of recognizing and reacting to many different antigen epitopes. However, in the case of some viral infections, like HIV, Epstein-Barr virus, and Hepatitis C virus infections, the T cells generated in response to infection are reactive against only a small number of antigen epitopes, which may allow the virus to escape detection and killing. The reasons underlying the diverse versus restricted nature of the TCR repertoire have remained elusive.
So called "memory T cells" are created in reaction to viral infection and these cells can subsequently influence the immune response to, and any adverse immune reactions associated with, infection by a second, unrelated virus. This "cross-reactive" nature of memory T cells is referred to as heterologous immunity. In a study appearing online on April 13 in advance of print publication in the May issue of the Journal of Clinical Investigation, Raymond Welsh and colleagues from University of Massachusetts Medical School show that the narrowed TCR repertoire and viral "escape" can be a consequence of T cell cross-reactivity.
The authors examined the changes in TCR repertoire in mice after exposure to LCMV virus versus exposure to infection with both LCMV and Pichinde virus (PV). Surprisingly, concurrent infection with the 2 different viruses led to the development of a narrowed TCR repertoire, which allowed the generation of an LCMV "escape" variant.
The results of this study have implications for the design of peptide-based vaccines. The data suggest that researchers should avoid the use of cross-reactive epitopes in their vaccine design protocols that may unintentionally narrow or skew the TCR response.
TITLE: Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity
AUTHOR CONTACT:
Raymond M. Welsh
University of Massachusetts Medical School, Worcester, Massachusetts, USA
Phone: (508) 856-5819; Fax: (508) 856-0019; E-mail: raymond.welsh@umassmed.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=27804
Journal
Journal of Clinical Investigation