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White Blood Cell -- Immune System Cell
Function of HLA Antigens
All cells of the body have on their
surfaces proteins or peptides called HLA (human leukocyte antigens). These
are depicted in the figure below. These antigens serve as antennae or "fly
paper" that recognize and capture foreign interlopers--such as germs,
viruses or cancer cells--that get into our bodies. With the new captured
information, these cells signal the immune system to make antibodies (IgM,
IgG and IgA) against the germ, virus or cancer cell.
HLA Antigens:
serve as antennae to recognize foreign germs or viruses entering the body.
Communicate this information to the white blood cells to initiate an
immune response.
A pregnancy must also be recognized as a
foreign being (father puts HLA antigens on the placenta that are different
from those of the mother). When this applies, the mother makes an antibody
called a blocking antibody that attaches to the placenta and makes it look
to her like a "wolf in sheep's clothing." The antibody she makes in this
circumstance does not kill; it protects the baby and makes the placental
cells grow faster.
When the father's HLA antigens placed on
the placenta are too similar to the mother's HLA antigens, she does not
make the antibody. In this circumstance the baby is not protected, the
placental cells are not stimulated to grow and the baby dies. She
interprets the pregnancy as "altered self" (i.e., a cancer cell).
Therefore, when the cells of the baby die, she activates other immune
problems from Category 2, 3, 4 or 5 where the natural killer cells that
she was born with are now misinterpreting the baby as a cancer. This
occurs in couples sharing DQ alpha HLA antigens.
Immune Response to Pregnancy (Alloimmunity)
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Function: to alert the mother to react
to the baby as a baby, not as an infection.
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Consequence: blocking antibody
production (crossmatch positive by flow cytometry).
Immune Response to Infection (Infectious Immunity)
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Separate Reference From Above
Group Leader:
Chris
Parish
Overview:
The major research interest of the Cancer and Vascular
Biology Group is the molecular basis of cell adhesion, cell migration and cell
invasion, with a particular emphasis on the immune system, tumour metastasis and
the growth of new blood vessels (angiogenesis). Of particular focus is the role
of anionic carbohyd actrates, such as heparan sulfate (HS), in these processes.
The Group is led by Professor Chris Parish, and comprises 3 laboratories, the
Cellular Laboratory headed by Chris, the Molecular Mechanisms Laboratory headed
by Dr Mark Hulett, and the Matrix Biology Laboratory headed by Dr Craig Freeman.
Model structure of the human heparanase active site
domain
Research Projects:
Role of heparanase in cell
invasion and angiogenesis
The major barrier for invading tumour cells, migrating
leukocytes, and growing blood vessels (endothelial cells) is the basement
membrane (BM) that surrounds the vessels, and the extracellular matrix (ECM)
which forms a scaffold in tissues to hold cells together.
The BM and ECM are composed of an
interlocking network of proteins and complex carbohydrates, and for cells to
breach this barrier, they deploy a battery of enzymes that break down these
proteins and carbohydrate components.
The major carbohydrate is heparan sulphate
(HS), which acts as the glue to maintain the integrity of the BM and ECM. The
enzyme responsible for cleaving HS, heparanase, has been shown to play a key
role in the degradation of the BM and ECM, and its activity strongly correlates
with the metastatic capacity of tumour cells and the migratory capacity of
leukocytes and endothelial cells.
HS in the ECM also binds a number of
angiogenic growth factors, and the release of these by heparanase promotes
angiogenesis and tumour growth. Following our recent cloning of mammalian
heparanase, we have been able to develop the tools to investigate how heparanase
functions at the molecular level and to directly determine the role of
heparanase in cell invasion, angiogenesis and inflammation.
Role of histidine-rich
glycoprotein (HRG) in regulating immune complex clearance and cell invasion
The group has also been studying the plasma protein, histidine-rich glycoprotein
(HRG), particularly examining the ability of the protein to inhibit cell
adhesion by masking cell surface carbohydrates.
Recently, the group demonstrated that HRG plays an
important role in the immune system by interacting with complement components
and by preventing the insolubilisation of complexes between antibody and antigen
(termed immune complexes). In fact HRG also assists in the uptake of these
complexes by phagocytic cells. Thus HRG is probably a key molecule in regulating
complement activity and in aiding the elimination of immune complexes from the
circulation. In fact, deficiencies in HRG may lead to immune complex-associated
diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosis (SLE).
In a related study we have shown that HRG
can tether plasmin/plasminogen to the surface of cells and potentially aid cell
invasion.
Thus HRG represents a multifunctional protein that appears
to play an important role in the immune system, inflammation and wound healing.
A major focus of the group in the future is to better understand the functional
significance of this intriguing plasma protein.
Development of a novel
tumour vaccine
In collaboration with Dr Paul Foster's group in the Division of Molecular
Biosciences, JCSMR, a new approach to cancer immunotherapy has been developed.
Currently most attempts at cancer immunotherapy involve the generation of CD8+
cytotoxic T lymphocytes (CTLs) against tumour-specific antigens. Recently we
demonstrated that tumour-specific CD4+ T cells, that exhibit a cytokine
secretion profile characteristic of Th2 cells, are capable of clearing
established lung and visceral metastases of a B16 melanoma that is resistant to
CTL lysis. Clearance of the lung metastases by Th2 cells was found to be
dependent on degranulating eosinophils, with the eosinophil chemokine, eotaxin,
playing an essential role. In contrast, tumour-specific CD4+ Th1 cells, that
recruited macrophages into the tumour, had no effect on tumour growth. This work
provides the basis for a new approach to cancer vaccination that is effective
against CTL-resistant tumours and is, potentially, less susceptible to immune
evasion.
Th2 inhibition of tumour metastasis. The effect of
adoptive transfer of ovalbumin-specific Th2 cells on the growth of established
lung metastasis from a highly metastatic mouse B16-F1 melanoma secreting
ovalbumin in a mouse model is shown.
Group Members:
Key Publications:
Hulett, M.D., Freeman, C., Hamdorf, B.J., Baker, R.T.,
Harris, M.J. and Parish, C.R. (1999).
Cloning of mammalian heparanase, an important enzyme in tumour invasion and
metastasis. Nature Med. 5, 803-809.
Parish CR, Freeman C and Hulett MD (2001)
Heparanase: a key enzyme involved in cell invasion.
Biochem. Biophys. Acta 1471, M99-M108.
Freeman, C., Browne, A.M. and Parish, C.R. (1999)
Evidence that platelet and tumour heparanases are similar enzymes.
Biochem. J., 342, 361-368.
Parish, C.R., Freeman, C., Brown, K.J., Francis, D. and
Cowden, W.B. (1999).
Identification of sulfated oligosaccharide-based inhibitors of tumor growth and
metastasis using novel in vitro assays for angiogenesis and heparanase activity.
Cancer Res. 59, 3433-3441.
Gorgani, N.N., Parish, C.R., and Altin, J.G. (1999).
Differential binding of histidine-rich glycoprotein (HRG) to human IgG
subclasses and IgG molecules containing kappa and lambda light chains.
J. Biol. Chem., 274, 29633-29640.
Gorgani, N.N., Altin, J.G. and Parish, C.R. (1999).
Histidine-rich glycoprotein regulates the binding of IgG and immune complexes to
monocytes. Int. Immunol., 11, 1275-1282.
van Broekhoven, C.L., Parish, C.R., Vassiliou, G. and
Altin, J. (2000).
Engrafting costimulator molecules onto tumor cell surfaces with chelator lipids:
a potentially convenient approach in cancer vaccine development.
J. Immunol. 164, 2433-2443.
Hulett MD, Hornby JR, Ohms J, Zeugg J, Freeman C, Gready JE
and Parish CR (2000)
Identification of active site residues of the pro-metastatic endoglycosidase
heparanase. Biochemistry 39, 15659-15667.
Manderson AP, Pickering MC, Botto M, Walport MJ and Parish
CR (2001)
Continual low-level activation of the classical complement pathway.
J. Exp. Med. 194, 745-756.
Hindmarsh, E.J., Staykova, M.A, Willenborg, D.O. and
Parish, C.R. (2001)
Cell surface expression of the 300 kDa mannose-6-phosphate receptor by activated
T lymphocytes. Immunol. Cell Biol, 79, 436-443.
Armitt, D.J., Banwell, M.G., Freeman, C. and Parish, C.R.
(2002)
C-glycoside formation via Lewis-acid promoted reaction of O-glycosylimidates
with pyrroles. J. Chem. Soc., Perkin Trans. 1, 1743-1745.
Francis, D.J., Parish, C.R., McGarry,Y. M., Santiago, F.S.,
Brown, K.J., Bingley, J.A., Hayward, I.P., Cowden, W.B., Campbell, J.H.,
Campbell, G.R., Chesterman, C.N. and Khachigian, L.M. (2003)
Blockade of vascular smooth muscle cell proliferation and intimal thickening
after balloon injury by the sulfated oligosaccharide PI-88: phosphomannopentaose
sulfate directly binds FGF-2, blocks cellular signaling and inhibits
proliferation. Circ Res 92, E70-E77.
Mattes, J., Hulett, M., Xie, W., Hogan, S., Rothenberg,
M.E., Foster, P. and Parish, C.R. (2003)
Immunotherapy of cytotoxic T cell resistant tumors by T helper 2 cells: an
eotaxin-1 and STAT-6-dependent process. J.Exp.Med. 197, 387-393.
Parish, C.R. (2003)
Cancer immunotherapy: The past, the present and the future.
Immunol. Cell Biol. - 81, 106-113.
Wall D, Douglas S, Ferro V, Cowden W and Parish C (2001)
Characterisation of the anticoagulant properties of a range of structurally
diverse sulfated oligosaccharides. Thromb. Res. 103,
325-335.
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