Researchers at the Gladstone Institute of Virology and Immunology have learned how T-cell levels may be maintained in people. The study has important implications for developing treatment strategies for patients who have diseases like HIV and cancer where the immune system is destroyed and for patients whose immune system is suppressed by chemotherapy or who are undergoing a bone marrow transplant, the researchers said.
The Gladstone researchers were looking for factors that regulated the levels of T-cells. T-cells are disease fighting white blood cells derived from the thymus that are essential for a healthy immune system. Infection with HIV destroys T-cells and decreases T-cell production resulting in immunodeficiency. The researchers found that the level of interleukin (IL)-7, a cytokine that stimulates production and expansion of T-cells, increases when the level of CD4+ cells (the T-cells targeted and killed by HIV) falls in HIV-infected patients. The researchers hypothesized a "compensatory feedback loop:" HIV reduces the number of T-cells; dendritic-like cells in peripheral lymph nodes sense the loss and cause the production of IL-7; IL-7 then stimulates the thymus and other immune tissues to produce T-cells in an attempt to restore T-cells to their proper level.
The lead author on the study, which is published in the January issue of Nature Medicine, Laura Napolitano, MD, is a staff scientist in the lab of co-author Joseph M. McCune, MD, PhD, a professor of medicine and senior investigator at the UCSF-affiliated Gladstone Institute for Virology and Immunology.
"Our first step was to identify the cytokine or hormone which might stimulate the production and expansion of T-cells in response to T-cell loss. We found that IL-7 increases as CD4+ cells declined. The next step was to identify the cells that could sense the depletion of T-cells and produced IL-7 in response," said Napolitano.
"We looked in lymph nodes, the home for many of the body's T-cells, knowing that HIV disease emptied these reservoirs. If there was a mechanism that sensed the absence of T-cells, we figured that it should be located within them," said McCune.
The researchers examined the lymph nodes of healthy people and people with advanced HIV disease, finding increased IL-7 in the T-cell depleted lymph nodes of people with advanced HIV, Napolitano said. "We hypothesized that support cells, called "stromal" cells, in peripheral lymph nodes might sense the loss of T-cells due to HIV. They could respond by increasing production of IL-7 that then stimulates the thymus and other immune tissues to produce more T-cells. This study supports our theory and has identified IL-7 as an important factor in T-cell homeostasis," she concluded.
Unlike some immune restoration therapies currently being investigated which only stimulate the production of existing T-cells, IL-7 can expand the entire repertoire of T-cells. For instance, if HIV has destroyed all of the T-cells that target a specific disease, the patient will lack the proper T-cells to fight that disease. Even though an immune restoration therapy might succeed in restoring the total number of T-cells to the proper level, a patient may still have "holes" in his immune system unless new T-cells are produced. By stimulating T-cell production in the thymus in addition to stimulating the expansion of existing T-cells, IL-7 has the potential to rebuild the entire T-cell compartment and to fully restore its ability to fight disease.
However, the authors of the study believe that IL-7 may pose problems if administered as a therapy for HIV patients. IL-7 can also increase the replication of the HIV virus and, by stimulating the usually dormant thymus, may open it up to infection. In the setting of HIV disease, IL-7 might be safely given to rebuild damaged immune systems if the side effect of viral replication is controlled by antiviral therapies. In addition, IL-7 could be useful without the side effect of viral replication in settings where the immune system has been destroyed by other means such as through chemotherapy or due to bone marrow transplantation.
The study initially looked at small cohort of 19 HIV-infected individuals. A strong inverse correlation was found between IL-7 levels and CD4+ counts. Similar correlations were not found with 9 other cytokines and hormones that were studied.
The investigation was then extended to a larger "cross-sectional" cohort of 168 HIV-infected individuals. This study also found that as CD4+ cells fell, IL-7 levels rose. The finding was further confirmed by an analysis of 11 HIV-infected patients who were followed "longitudinally" over 6 to 25 months. As CD4+ cells decreased in these individuals, their IL-7 levels rose correspondingly. This indicated that IL-7 levels might be rising in response to T-cell loss.
Researchers next investigated whether IL-7 was being produced in peripheral lymph nodes. By analyzing IL-7 production at the single-cell level within peripheral nodes from patients with advanced HIV disease, IL-7 producing, ' dendritic-like' cells were identified.
The study then compared lymph nodes depleted of T-cells with normal ones full of T-cells to determine if the T-cell depleted lymph nodes produce more IL-7. Researchers looked at 12 lymph specimens: 6 depleted lymph nodes from patients with advanced HIV disease and 6 lymph nodes from HIV-infected patients that were still full with T-cells. They found a marked increase in IL-7 production within the lymph nodes that were depleted of T-cells. They concluded that increased IL-7 production was designed to increase the production and expansion of T-cells in response to T-cell depletion.
The Gladstone Institute of Virology and Immunology, founded in 1991, focuses its research on HIV and AIDS. The Institute is one of three that make up the J. David Gladstone Institutes, a private biomedical research institute affiliated with UCSF and named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing interest in medical education and research.
Study co-investigators in addition to McCune are Robert M. Grant, MD, UCSF assistant professor of medicine and assistant investigator at the UCSF-affiliated Gladstone Institute of Virology and Immunology; Steven G. Deeks, MD, assistant clinical professor of medicine at UCSF's Positive Health Program at SFGHMC; Diane Schmidt, BS, senior research associate at the UCSF-affiliated Gladstone Institute of Virology and Immunology; Stephen C. De Rosa, MD, postdoctoral fellow at Stanford University's Genetics Department; Leonore A. Herzenberg, DSc, professor of genetics at Stanford University's Genetics Department; Brian G. Herndier, MD, PhD, UCSF associate professor, pathology and laboratory medicine; Jan Andersson, Department of Infectious Diseases, Karolinska Institute, Huddinge University Hospital, Stockholm,Sweden.
The research was supported by grants from the National Institutes for Health, the Medical Research Council, and the Elizabeth Glaser Pediatric AIDS Foundation.
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