Adjuvanting and delineating the mechanisms of induction of gut homing CD8 T cells elicited Público
Ganguly, Sumita (2010)
Abstract
An efficacious HIV (Human immunodeficiency Virus) vaccine is
crucial to curb
the global pandemic of the disease, AIDS. Gene-based (DNA) and
viral-vector based
vaccines are two vaccine design strategies that are in advanced
stages of development.
Here, we investigate the potential of co-stimulation through 4-1BB
as an adjuvant for a
HIV-1 DNA vaccine in mice. We designed plasmid DNAs expressing
either the
membrane bound or soluble form of 4-1BBL, and compared with the
agonistic anti-4-
1BB Ab for their ability to adjuvant the Gag DNA vaccine. Both,
anti-4-1BB agonistic
Ab as well as 4-1BBL DNA enhanced the Gag-specific cellular immune
responses.
However, in complete contrast to the agonistic Ab that suppressed
humoral immunity to
Gag, 4-1BBL DNA adjuvanted vaccines enhanced Gag-specific IgG
responses.
Importantly, the expression of Gag and 4-1BBL from the same plasmid
was critical for
the adjuvant activity. Collectively, our data suggest that for a
HIV-1 vaccine, 4-1BBL
expressed by a DNA vaccine is a superior adjuvant than anti-4-1BB
agonistic Ab.
An effective HIV vaccine must also be able to confer protective
immunity at the
gut-associated mucosal tissue. Recent studies have shown that
intramuscular
immunization with some live viral vectors can prime
antigen-specific CD8 T cells with
gut homing potential. However, the mechanisms by which parenteral
immunizations
elicit antigen-specific CD8 T cells in the gut are not understood.
Here we show that an
adenovirus type 5 (Ad5) based HIV-1 vaccine primes a strong and
durable antigen-
specific CD8 T cell response in the gut following intramuscular
immunization in mice.
We also show that Ad5 rapidly induces expression of retinal
dehydrogenase enzymes in
splenic conventional DC (cDC) and enhances their ability to prime
antigen-specific CD8
T cells with gut homing specificity in vitro. This effect of
Ad5 did not require signaling
through toll-like receptors, DNA-dependent activator of IRFs and
several MAP kinases,
or replication capacity of the virus, but was dependant on
NF-ï«B. These results provide
an innate mechanism through which Ad5 primes antigen-specific CD8 T
cells with gut
homing potential and have implications for the development of novel
mucosal adjuvants
for subunit vaccines administered via the intramuscular
route.
Table of Contents
Table of Contents
Distribution Agreement
Approval Sheet
Dissertation Abstract Cover Page
Abstract
Dissertation Cover Page
Acknowledgements
Table of Contents
List of Figures
Chapter 1: Introduction
A. Pathogenesis of the Human immunodeficiency
virus-1(HIV-1)
A.1. Basic Virology of HIV-1
1
A.2. Immunology of HIV-1 infection
3
B. HIV Vaccines
B.1. Correlates of immune protection
6
B.2. Challenges in designing a HIV vaccine
7
B.3. HIV Vaccine strategies
8
B.3.i. Strategies to adjuvant DNA vaccines
13
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