Project Details
Description
Abstract
There are numerous examples of a vaccine that results in neutralizing antibodies in one population, but not
others. Rotavirus, polio, cholera, and tuberculosis (TB) are examples. BCG vaccination for TB has significantly
higher rates of protection the further north the vaccine is used. Reasons for differences in vaccine efficacy are
unknown with genetic or environmental factors thought to be important factors. An interesting parallel
observation is that population based measures of CD4 T cells also vary geographically, with people living in
northern latitudes having significantly greater numbers of CD4 T cells than people living close to the equator. In
our studies of mechanisms of loss of CD4 T cells in HIV infection, we showed that HIV replication in lymphoid
tissues caused inflammatory damage to the Fibroblastic Reticular Cell network (FRCn) in the form of collagen
deposition into the network. The FRCn is the primary source of IL-7 outside of the thymus and loss of the
network results in decreased production of IL-7 and the net result is increased T cell apoptosis. Our data
suggest this is a significant mechanism of CD4 loss in HIV infection. We speculated that infections other than
HIV might cause inflammatory damage to the FRCn and might be a reason CD4 T cells are depleted in
populations of people living in tropical climates, especially developing economies. This may be a factor in
limiting vaccine responses in these populations. We studied lymph nodes in HIV negative people living in
Uganda and show in our preliminary data that the FRCn and CD4 T cell populations are depleted and that
levels of inflammatory cytokines and tissue markers of immune activation are elevated. We vaccinated them
with yellow fever vaccine (YFV) and found the peak neutralizing antibody titer correlated to our quantitative
analyses of the FRCn and measures of inflammatory cytokines and immune activation. These data support our
model of inflammatory damage to the architecture of lymph nodes as a contributing factor to failure of vaccine
efficacy in the developing world. We now propose to build on these preliminary studies by giving YFV to a
larger cohort of Ugandans but also to add a cohort in Minnesota where we have shown limited inflammatory
damage to the FRCn. We will conduct extensive immunologic and microbial investigations of factors that limit
durable immune responses. Our hypothesis is that endemic infections other than HIV can cause LN
inflammation and collagen damage to the FRCn which will lead to CD4 T cell depletion and impaired vaccine
responses.
Status | Finished |
---|---|
Effective start/end date | 2/25/19 → 1/31/24 |
Funding
- National Institute of Allergy and Infectious Diseases: $601,902.00
- National Institute of Allergy and Infectious Diseases: $604,933.00
- National Institute of Allergy and Infectious Diseases: $653,365.00
- National Institute of Allergy and Infectious Diseases: $616,774.00
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