|
|
|
|
|
|
|
|
|
| |
|
| |
| |  People infected with many serious illnesses, including tuberculosis and hepatitis C, may show no symptoms of disease for long periods of time. These inactive, or "latent," infections, however, can develop into active disease without warning, and also can be passed on to others. New approaches that focus on controlling or stimulating the immune system to cure latent infections or prevent them from causing disease have the potential to significantly reduce illness, death, and disease transmission.
Dr. Ahmed and his team are working to create safe and effective immunological therapies for chronic hepatitis C infection and other viral infections such as HIV by developing methods to reactivate “exhausted” immune cells that are thought be unable to clear the infection.
Scientists have discovered that viruses causing chronic infections such as hepatitis C and HIV can result in a reduction of natural immune defenses, allowing the infections to spread throughout the body. Dr. Ahmed and his colleagues are exploring the mechanisms that cause immune system T cells, which usually fight off chronic viral infection, to stop working, a condition called T cell “exhaustion”. The project team is working on the development of therapies capable of reversing immune exhaustion and switch on the body's natural defenses again.
Investigators are working to decipher the inhibitory pathways that play critical roles in T cell exhaustion during chronic infections. Their work using experimental model systems has proven to be applicable to human infections including hepatitis C and HIV, and has provided new insight into therapies capable of reversing immune exhaustion and restoring anti-viral immunity in chronic infections. |
| | |
| | | Optimize strategies for enhancing immunity during chronic infections by utilizing monoclonal antibody therapy against receptors on T cells, using the lymphocytic choriomeningitis virus (LCMV) model in mice | | | | | Evaluate monoclonal antibody therapy in monkeys against SIV (a HIV-like viral infection) and in chimpanzees chronically infected with hepatitis C | | |
| |
| | BACK TO THE TOP |
| | |
| | | Blocking PD-1/PD-L1 inhibitory signals on exhausted CD8+ T cells in combination with therapeutic vaccination enhances functional CD8+ T cell responses and improves viral control in LCMV-infected mice. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. | | | | | Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of programmed death (PD-1) molecules and low levels of CD127 expression. Hepatitis C virus-specific peripheral T cells from infected patients express significantly higher levels of the PD-1 molecule compared to uninfected controls. Intra-hepatic T cells from patients with hepatitis C virus are phenotypically exhausted, with high expression of PD-1 and low expression of the IL-7 receptor (CD127). This phenotypic exhaustion correlates with reduced function specifically, decreased ability to proliferate, which can be reversed by blocking the interaction of PD-1 with its ligand. | | | | | Expression levels of inhibitory receptor PD-1on simian immunodeficiency virus (SIV)-specific CD8+ T cells are elevated during chronic infection, but not after vaccination. Investigators have found evidence that CD+8 T cells specific to SIV express PD-1 after exposure to antigen, but down-regulate expression under conditions of antigen clearance. Also, the vitro blockade of PD-1/PD-L1 interactions enhanced the proliferation of SIV-specific T cells, similar to HIV infection. | | |
| |
| | BACK TO THE TOP |
| | | |
| | | Dr. Gordon J. Freeman, Dana Farber Cancer Institute, Massachusetts, United States - US | | | | | Children’s Research Institute, Washington, D.C., United States - US | | | | | Harvard University, Massachusetts, United States - US | | | | | Rockefeller University, New York, United States - US | | | | | National Institute of Health, Maryland, United States - US | | | | | Leiden University Medical Center (LUMC), Leiden, Netherlands - NL | | |
| |
| | BACK TO THE TOP |
|
|
|
|
|
|
|
|
|
|
|