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Human Immunology: vaccine
development, cancer and autoimmunity
Bacterial minicells:
a novel approach to vaccine delivery. Baceterial
minicells provide an unique opportunity for the delivery
of antigens for the purpose of eliciting protective
immune responses. Minicells are achromosomal and,
therefore, have no ability to replicate or to cause
infection. They carry, however, a normal component
of bacterial proteins and membrane components, which
allows them to elicit inflammation and act as an adjuvant
to promote the immune response. Minicells can also
be designed to contain any protein and/or plasmid
DNA found in the parent strain of E. coli used
to produce them. We are working in conjunction with
MPEX Pharmaceuticals, a biotech company that has developed
an E. coli strain that produces minicells upon
command, to demonstrate that these minicells are an
efficient delivery mechanism for vaccines. Current
studies are utilizing antigens from LCMV, a virus
that causes encephalitis, and studies will begin soon
on the development of vaccines to diarrhea caused
by enteric bacteria. Several projects ongoing in the
lab are designed to test the efficacy of the vaccine
at protecting animals from infection, safety of the
vaccine, the most efficient routes of administration
of the vaccine, and the storage requirements of the
vaccine.
Salmonella host-specificity:
studies on the involvement of the host immune response.
Closely related to the vaccine project are studies
on the involvement of the host immune response in
determining the specificity of Salmonella infections
in different hosts. While different Salmonella strains
can infect humans, only S. typhi causes a systemic
disease. In other animals, other strains of Salmonella
cause systemic disease but S. typhi can not.
We think understanding these differences, and knowing
how the host immune response contributes to these
differences, will be important in the development
of vaccines to Salmonella strains that cause
intestinal disorders. We are working in collaboration
with Dr. Stan Maloy, also of the Department of Biology
at SDSU, to answer this question.
Colorectal cancer:
immune responses to tumors that do or do not express
genetic instability. Microsatellite instability
in colorectal cancer is associated with greater survival
in patients and yet black patients appear to exhibit
less instability and more aggressive tumors than whites.
A study is underway to determine if this is indeed
the case. We are involved in trying to determine if
immune responses to the tumors differs with respect
to genetic instability, contributing to the control
of the tumor. These studies are being done in conjunction
with Dr. John Carethers at the UCSD Cancer Center.
Antisense transcription
and complementary proteins: Do they play a role in
autoimmunity? In a recent sabbatical in Chile,
I started working with Dr. David Holmes, a bioinformaticist
at Universidad Andres Bello in Santiago, Chile. Dr.
Holmes works on the potential of genomes to express
antisense products. Antisense is defined as the strand
of DNA opposite to that encoding a known gene. In
a recent report in Nature the gene that encodes the
known autoantigen in a form of autoimmune vasculitis
was found to encode on the antisense strand not only
a mRNA but also a protein product. Like many “antisense
proteins” (called a complementary protein), this one
induced Abs that induced anti-idiotype Abs that cross-react
with the sense strand protein, leading to the autoimmunity.
A careful examination of the literature suggested
that this might be much more common that previously
thought and we have begun a collaboration to find
out if this is the case.
Representative Recent
Publications:
M. Iacobelli, F. Rohwer, P. A. Shanahan, J. A. Quiroz and K. L. McGuire.
1999. IL-2-mediated cell cycle progression and inhibition
of apoptosis does not require NF-kB or AP-1 activation in primary human T cells. J. Immunol. 162:3308-3315.
McGuire, K. L., F. Rohwer, H. Sebsavari, A. Theophilopoulous, M. Fung,
and K. Bower. 1999. Signal transduction, cell cycle
progression and gene expression in primary human T
cells stimulated with IL-2. Recent Res. Devel. Immunology
1:149-163.
Iacobelli, M., W. A. Wachsman and K. L. McGuire. 2000. Repression of
IL-2 promoter activity by the novel basic leucine
zipper p21SNFT protein. J. Immunol. 165:860-868.
McGuire, K. L. 2001. Genetics of the Human Immune System; a Bioinformatics
Tutorial for the Biology Student Workbench. http://peptide.ncsa.uiuc.edu/tutorials/.
Bower, K. E., R. Zeller, T. Martinez , W. A. Wachsman and K. L. McGuire.
2002. Correlation of transcription repression by
p21SNFT with changes in DNA/NFAT complex
interactions. J. Biol. Chem. 277: 34967-34977.
Fung, M., F. Rohwer and K. L. McGuire. 2003. IL-2 activation of a PI3K-dependent
STAT3 serine phosphorylation pathway in primary human
T-cells. Cell. Signal. 15:625-636.
Beshgetoor, D., S. Arrues and K. L. McGuire. 2004. Lack of immune suppression observed in female master
athletes. Intl. J. Sports Med. 25:553-558.
Bower, K. E., J. M. Fritz, and K. L. McGuire. 2004. Transcriptional
repression of MMP-1 by p21SNFT and reduced
in vitro invasiveness of hepatocarcinoma cells.
Oncogene 23:8805-8814.
Fung, M. M., Y.-L. Chu, J. L. Fink, A. Wallace, and K.
L. McGuire. 2005. IL-2- and STAT5-regulated cytokine
gene expression in cells expressing the Tax protein
of HTLV-1. (Oncogene, in press)
Ph. D. students:
Michelle Fung
Tong Xu
Matthew Giacolone
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