New Possibilities for Control of Chronic Inflammation
Pilar Alcaide, PhD, joined the Molecular Cardiology Research Institute (MCRI) at Tufts Medical Center in 2011. She is also a faculty member of the Immunology Program in the Sackler School of Graduate Biomedical Sciences at Tufts University. Alcaide works on the causes, prevention, and suppression of chronic inflammation, particularly focusing on vascular immunology. In addition to its well-known association with the autoimmune diseases arthritis and psoriasis, inflammation is now known to be associated with hypertension, diabetes, heart failure, and cancer—all strong candidates for new mechanisms of suppression. Alcaide’s research focuses on the recruitment of circulating T lymphocytes, or T cells, into vascular endothelial cells that have been activated by injury, infection, or disease. T cells are white blood cells (leukocytes) that play an active role in cell-mediated immunity, and blood vessels are lined with a thin layer of endothelial cells.
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Alcaide earned her PhD in molecular biology/immunology from the Universidad Autonoma de Madrid. She did postdoctoral research as a Fulbright scholar in pathology at Harvard Medical School and in vascular biology at Brigham and Women's Hospital. Prior to joining Tufts she was an instructor in pathology at Harvard Medical School and a research associate at Brigham and Women’s Hospital.
“We study how the immune cells that are generally circulating in the blood stream get to the places where they’re needed in response to injury,” says Alcaide. “We’re trying to understand how those cells traffic in the blood vessels, and how they decide where to exit the vascular system and migrate into the tissues.” Immune cells are recruited to injured tissues as a self-limiting protective response to remove injurious agents and initiate the process of tissue repair. However, if this immune response to injury is extended over time, active inflammation occurs with subsequent recruitment of more immune cells, which is often detrimental and causes chronic inflammation.
Alcaide’s idea is that an understanding of the basic mechanisms of how immune cells migrate into tissues, and how that process might vary for different immune cells and in different tissues, could lead to new medications that suppress inflammation in specific diseases or at specific sites. Medications exist that suppress inflammation systemically, but long-term use can increase the risk of infection because these medications basically suppress the immune system. A medication targeted to a specific disease or tissue—say, psoriasis, or the skin—could be a much better option for those suffering from chronic inflammation.
“One of our projects is trying to identify differences between different types of inflammatory cells, so if one type is creating most of the damage in one disease, you could inhibit that one but not the other ones,” says Alcaide. Her research group uses a tissue culture flow model for direct microscopic examination of interactions between T cells and activated vascular endothelial cells under physiological flow conditions, i.e., slow flow for small capillaries and fast flow for large arteries. "If you are interested in a particular molecule, you can label it in one color and then see what that molecule does during the process of extravasation [the movement of cells through the endothelium]," she says. "You add equal numbers of cells labeled in different colors and you can quantify if one type is more prone to extravasate the endothelium than the other one." Live cells are imaged using combined differential interference contrast (DIC) and fluorescence microscopy. A video example of this type of imaging can be seen on Alcaide's research website (link provided at end of article).
A 2012 paper by Alcaide's research group suggests how circulating T cells might cross the activated vascular endothelium. The group hypothesizes that when the vascular endothelium gets activated, the endothelial adhesion molecule selectin gets upregulated and binds to the selectin ligands on circulating T cells. “This causes the T cells to begin to roll," Alcaide explains. "Once they roll, they slow down and then other activated molecules—chemokines, integrins—cause the cells to arrest and then transmigrate [through the endothelium]." Alcaide's group has identified some selectin ligands and other signaling molecules that are different on two types of T cells—Th1 cells and Th17 cells—a step toward the goal of discovering differences in how various T cells transmigrate. Alcaide is especially interested in Th17 cells because they were described recently and little is known about their trafficking or migration properties.
To figure out the spatial and temporal recruitment of T cells in different diseases, the Alcaide group is conducting a major study of the endothelial cells through which T cells transmigrate. “We’re looking at the endothelium because we know the endothelial cells in the small capillaries are different from the endothelial cells in the bigger vessels, and the endothelial cells in the heart are different from the endothelial cells in the lung or the skin,” says Alcaide. “We’re particularly interested in the vascular endothelium in the heart.” Alcaide’s research group is characterizing the regulation of different inflammatory cell types during the progress of heart disease in a mouse model of heart failure. “We’re isolating T cells from those mice and we’re putting them in contact with the heart endothelium in our flow chambers with the imaging system. We can use endothelium from both sick mice and healthy mice, and we can take immune cells from both sick mice and healthy mice, so we can look at it from both ways. And the nice thing is that you make the videos and you see it—you see the cells are more proactive right in the video.”
The Alcaide lab is also working on T regulatory cells, which seem to play a role in regulating T effector cells (those that cause inflammation) and may suppress endothelial cell activation. “We published in 2011 that if you pretreat the vascular endothelium with these T regulatory cells, and then you perfuse effector T cells, they don’t transmigrate,” says Alcaide. “I think that’s progress on T reg-based therapies.” Continuing work on these “good” T reg cells includes characterizing what normal and activated endothelium looks like before and after pretreatment with T regs. Alcaide’s group is currently working with mouse cells but expects to be working with human cells soon.
“The MCRI environment is very collaborative,” says Alcaide. “Tufts in general is collaborative.” Alcaide looks forward to future collaborative research at Tufts. She can offer collaboration in live cell imaging and leukocyte trafficking, and would like to find a collaborator with expertise in glycobiology.
For more information, please see http://sackler.tufts.edu/Faculty-and-Research/Faculty-Research-Pages/Pilar-Alcaide.