News
Johns Hopkins immunologists awarded $10 million NIH grant
January 5, 2009 - from The JHU Gazette
Researchers at the Johns Hopkins School of Medicine have been awarded a $10.3 million grant — the largest basic immunology grant ever received by the university — from the National Institutes of Health to dissect the human immune system.
Specifically, they aim to learn more about what happens when the immune system goes wrong, and how to suppress undesired immune responses in the cases of rejected tissue or organ transplants or in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis or lupus.
"The current approach to immune responses gone awry is to hit the TV set with a hammer and use drugs that globally suppress all immune activity," said project leader Jonathan Schneck, a professor of pathology. "We know these approaches are limited in their effectiveness; it would be great to develop targeted therapies, and in order to do that, we need to know more about how the immune system works."
The comprehensive research brings together experts from across Johns Hopkins to "build a better overview" of the immune response. The team will take on five different projects, led by five researchers in addition to Schneck: From the School of Medicine, Stephen Desiderio, director of the Institute for Basic Biomedical Sciences, head of the ImmunoICE program within the Institute for Cell Engineering, and professor of molecular biology and genetics; Abraham Kupfer, professor of cell biology; Joel Pomerantz, assistant professor of biological chemistry; and Jonathan Powell, associate professor of oncology; and from the School of Arts and Sciences, Michael Edidin, professor of biology.
The team will study how protein receptors on the surface of immune cells are organized in order to understand how they respond to foreign cells and particles in the body, as well as how they recognize the body's own cells. The researchers also will study how to use the immune system to fight cancer, and how immune cells communicate with themselves and with other cells.
"We're really excited about this opportunity because it breaks down traditional boundaries found at many research institutions and allows us to cross-fertilize ideas and projects across many disciplines," Desiderio said. "It's a huge investment to basic immunology research, and we are eager to get started on the work."
Names in the News
December 22, 2008 - from The Baltimore Sun
Dr. Jonathan Schneck, a professor of pathology at the Johns Hopkins University School of Medicine, is leading a team of researchers who have been awarded a $10.3 million grant - the largest basic immunology grant ever received by Hopkins - from the National Institute of Health to dissect the human immune system.
The researchers aim to learn more about what happens when the immune system goes wrong, and how to suppress undesired immune responses in the cases of rejected tissue or organ transplants or in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis or lupus.
The team will take on five projects, led by five researchers in addition to Schneck: Dr. Stephen Desiderio, Director of Hopkins' Institute of Basic Biomedical Sciences, Head of the ImmunoICE Program within the Institute of Cell Engineering and Professor of Molecular Biology and Genetics; Dr. Michael Edidin, Professor of Biology at Hopkins' Homewood campus; Dr. Joel Pomerantz, Assistant Professor of Biological Chemistry; Dr. Abraham Kupfer, Professor of Cell Biology; and Dr. Jonathan Powell, Associate Professor of Oncology.
The team will study how protein receptors on the surface of immune cells are organized to understand how they respond to foreign cells and particles in the body, as well as how they recognize the body's own cells. The researchers also will study how to use the immune system to fight cancer, and how immune cells communicate with themselves and with other cells.
Immune System 'Escape Hatch' Gives Cancer Cells Traction
Discovery explains why anti-cancer vaccines mostly fail
August 6, 2007 - from The JHU Gazette by David March
Scientists at Johns Hopkins and elsewhere say they have mapped out an escape route that cancers use to evade the body's immune system, allowing the disease to spread unchecked.
In a report published in the July 1 issue of the journal Nature Medicine, the Johns Hopkins team, along with researchers from Florida and Nebraska, describe how myeloid-derived suppressor cells, which normally keep the immune system in check and prevent it from attacking otherwise healthy tissue, can suppress the anti-tumor response to cancer.
These suppressor cells block other immune system cells, CD8 "killer" T cells, from binding with proteins that identify the foreign antigens on the surface of unhealthy cancer cells, marking them for destruction, the team reports.
The good news, the scientists say, is that their experiments also suggest that the chain reactions in T-cell tolerance are reversible, raising the possibility of vaccine and drug therapies that break through the blocked immune system.
Previous research had confirmed that myeloid-derived suppressor cells, produced in the bone marrow, were attracted to tumors, but until now, scientists had not identified exactly how the cells inhibit the immune system's ability to mount an attack.
By explaining some of the precise biological workings of myeloid-derived suppressor cells in cancer, the team's findings suggest why experimental cancer vaccines have to date been plagued by T-cell tolerance, a weakened rather than strengthened immune response, says Jonathan Schneck, one of the study's authors.
"Our findings also open up a new door in drug and vaccine development that we never knew existed and provide another opportunity for drug development into autoimmune diseases, where the immune system is in overdrive and needs to be slowed down," said Schneck, a professor of medicine, pathology and oncology at the Johns Hopkins School of Medicine and its Kimmel Cancer Center.
The team's latest report built on research initially conducted at the University of South Florida, where researchers analyzed blood samples and lymph tissue from healthy mice injected with myeloid-derived suppressor cells and found that T-cell levels remained the same, indicating that MDSCs did not destroy the immune response but apparently altered how the T cells behaved.
Using chemical tests in which individual tumor cells can be tagged with a fluorescent dye that allows them to glow when they are not bound to T cells, Florida researchers measured the immune response in mice to various foreign proteins, with and without injections of myeloid-derived suppressor cells. They found an 80 percent suppression of the immune response in the presence of MDSCs, confirming that the suppressor cells were inactivating the T cells.
The Florida team then turned to Schneck, who in 1993 developed several novel proteins to test how various antigens, such as those on cancer cells, specifically latch on to T cells.
Researchers then began experiments to determine if the myeloid-derived suppressor cells' T- cell interference was simply genetic or had some biochemical explanation, testing a half-dozen major reactions known to occur during infection to see if any set path was particularly active during interference.
In tissue tests from tumor-filled mice bred to lack a biochemical reaction, the scientists found that one specific pathway, the reactive-oxygen species, or ROS pathway, stood out, because when inactivated, T-cell tolerance did not develop. Researchers were surprised when subsequent tests showed that ROS actually modified the T cells, altering their structure so they could no longer bind to tumor-cell antigens.
When a known byproduct of ROS, the chemical peroxynitriate, was neutralized, T-cell tolerance failed to develop in test tube studies, pinning down peroxynitrate as the culprit prohibiting immune cell binding to and marking of "foreign" tumor cells.
"Peroxynitrate activity is the escape hatch, and now that we have identified it, we can try to cut it off before T-cell tolerance develops, or you can reverse it," Schneck said.,/
Plans are under way to investigate the binding receptors of MDSCs and different anti-cancer drugs for their ability to lower levels of MDSCs and to explore the role of MDSCs in suppressing the immune response to stress, bacterial and viral infections, organ transplantation and autoimmune diseases. The researchers' goal, they say, is to find some means of accelerating or slowing down T-cell activity gone awry.
Study support was provided with funding from the National Institute of Allergy and Infectious Diseases, and the National Cancer Institute, both members of the National Institutes of Health.
Study co-authors are Kapil Gupta, of Johns Hopkins; Srinavas Nagaraj, Loveleen Kang, Donna Herber and Dimitry I. Gabrilovich, of the H. Lee Moffitt Cancer Center at the University of South Florida; and Vladimir Pisarev, Leo Kinarsky and Simon Sherman, of the University of Nebraska Medical Center and Eppley Cancer Center. Gabrilovich was the study senior author.