The Immune System and Our Bodys Defenses Against Cancer

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The Immune System and Our Bodys Defenses Against
Cancer

• A quick overview of the immune system and the
  ways it helps to fight cancer, both on its own
  and with help from modern medicine

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The organs of the bodys immune system marrow
for cell formation, lymph nodes and thymus for
cell maturation, and spleen for cell recycling.
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Birth and maturation pathways for different
lymphocytes. Peripheral lymphoid organs include
adenoids, tonsils, and Peyers patches
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The morphology of lymphocyte differentiation
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T cell morphology, even with the resolution of
the electron microscope tells us little. These
cells come in several varieties, including
helpers, suppressors, and killers. We will see
how they get that way.
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Start with B Cells, which are easier to
understand.

• B cell differentiation provides diversity. The
  cells that will proliferate and differentiate to
  maturity are selected by the presence of an
  antigen, meaning a molecule that the antibody
  they make will bind to.

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This differentiation takes time, so the formation
of antibodies is not immediate (days). A 2nd
exposure works faster. The system can remember
antigens.
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Memory is accomplished by special lymphocytes
(memory cells) that get set aside early in the
differentiation and proliferation processes, so
they are there to respond quickly upon future
stimulation by the same or a similar antigen.
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Lymphocytes proliferate then go through any of
several changes to establish their final
fate.Final differentiation occurs in the
peripheral lymphatics.
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In a peripheral lymphoid organ, like a lymph
node, partially mature lymphocytes encounter
foreign antigens, which can stimulate them, or
self antigens that lead to their death or
inactivation clonal selection.
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Much lymphocyte differentiation takes place in
lymph nodes
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When a partially differentiated B cell encounters
an antigen that binds to the one antibody that it
can make (which is presented on the cells
surface) the B cell is stimulated to grow and
divide, then to make and secrete lots of antibody
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Structure of an antibody molecule (IgG) presented
in diagrammatic form. The C-terminal part of the
light and heavy chains have the same sequence
from one IgG to another. These are called the
constant regions.
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Antibodies made by and secreted from B-cells can
bind to their antigen(s) in solution or on the
surface of an invading or malignant cell. The
constant fragment of the immunoglobulin molecule
(Fc), is recognized by receptors on phagocytic
cells.
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An electron micrograph of a phagocyte engulfing
an infecting bacterium, thanks to a coating by
immunoglobulins, which leave their Fc portions
exposed.
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The polypeptide chains that make up
immunoglobulins come in several kinds two for
the light chains and 5 for the heavy. The
relative positions of the variable and constant
regions on the two Ig chains are shown.
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Diagrams showing how the light and heavy chains
map onto the immunoglobulin fold so as to put
all the variable regions in two places, where
they can participate in making the antigen
binding sites.
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The antigen binding sites can have many different
geometries 3 are diagrammed here. Within each
shape class, there are many exact binding sites,
based on the positions of positive and negative
charges, of hydrogen bonding groups and
hydrophobic residues.
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The diversity of antibody structure is generated
by DNA rearrangements at the immunoglobulin loci
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While B-cells can make diverse antibodies,
T-cells generate a different kind of molecular
variety

• T-cells dont make antibodies, they make proteins
  called the T-cell receptors
• T-cell receptors (TCRs) are membrane- bound
  proteins that have constant and variable regions
  like antibodies, but their sequences and
  functions are different from those of the
  immunoglobulins (Igs).

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Two diagrams of a TCR
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A TCR is part of the molecular machinery that
carries on a conversation between a T-cell and a
cell, like a macrophage, contains a foreign
antigen and has chewed it into small pieces, so
it can present this antigen to the immune system.
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Antigens are presented on the surface of an
antigen-presenting cell by membrane proteins that
are products of the genetic locus called the
Major Histocompatability Complex (MHC).
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There are two kinds of MHC proteins Class I and
class II. Each of these is a dimer that spans
the plasma membrane and includes an extracellular
site designed to bind a polypeptide that has been
cut from a foreign antigen.
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A closer view of the peptide binding cleft on an
MHC class II. Each MHC has the ability to bind a
variety of peptides in its antigen-presenting
groove.
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MHCs do not have variable portions, like Abs, and
TCRs, but there are many alleles at this locus,
so the MHCs of one individual are characteristic.

• In mice, where they were discovered, MHCs are
  called H-2 antigens
• In people they are called HLA (human
  leucocyte-associated antigens)
• There are gt200 alleles of the MHCs in most
  species, and each individual expresses about 12,
  so it is rare for unrelated people to have the
  very same MHC antigens.
• Each MHC contains a groove for peptide binding,
  and with a foreign peptide in place, the MHC is
  unique.

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The MHCs on an antigen-presenting cell display
foreign peptides to the TCRs
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A T Cell will be activated only if its TCR fits
well with the MHC and the peptide it is presenting

• While MHCs do not show great structural
  variation, when there is a foreign peptide in
  their binding site, they make a unique complex.
• It is the specificity of this structure and its
  ability to bind a particular TCR that defines
  WHICH T- cell will become activated by a given
  antigen.
• So how does the antigenic peptide get into the
  groove on the MHC protein and then onto the
  surface of the presenting cell?

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Initial steps in the preparation of an antigenic
peptide for presentation by and MHC protein
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Final steps in antigen presentation by MHC
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Once a foreign peptide is presented by an MHC
protein on that cells surface, it is accessible
to TCRs. When a T cell that makes a compatible
TCR happens along, the two cells will bind.
Other cell surface molecules then participate,
and signals stimulate the T cell to secrete a
lymphcyte growth factor, or Interleukin, e.g.,
IL2, which stimulates the growth and division of
that T cell.
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Some partially differentiated T cells express a
surface protein called CD8. These will interact
with class I MHCs and become activated
cytotoxic or killer T cells. Other T cells
make CD4. These interact with class II MHCs and
become activated helper T cells, which will go on
to stimulate B cells that recognize the same
antigen.
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The pathway by which a helper T cell activates an
appropriate B cell is complex. The result is
that this B cell is strongly stimulated, both to
grow and divide and to make and secrete its
antibody.
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Cytotoxic T cells will bind to a cell that
presents antigens they recognize on class I MHCs.
They then secrete proteins that kill the target
cell.

• Many cell types can use the antigen presentation
  pathway to show the molecules they contain on
  their surface. This can reveal a virus infection
  or a mutation that leads to the expression of an
  abnormal protein that is not recognized as
  self.
• The result is the death of the unusual cell.

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There are two pathways for T cell-mediated
killing. One makes pores in the target cell to
let in secreted proteases.
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The second pathway uses an indirect route to
activate apoptosis in the target cell.
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Antigen presentation allows T-cells to recognize
and destroy a wide range of cells that are
disadvantageous to the host organism

• A virus-infected cell will present virus-specific
  proteins that are non-self, leading cytotoxic
  T-cells (CTCs) to kill them, even before they
  have released any virus.
• A cancer cell that expresses a mutant protein can
  be recognized as foreign and killed before it can
  proliferate.
• Some scientists think that cancers arise in our
  body all the time and are killed by our CTCs

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Cancer probably results in part from a failure of
the immune system to do its normal job.

• Some oncogenes represent mutations in structural
  genes, so their protein products should be
  recognizable as non-self, leading to CTC
  killing
• Other oncogenes may be over-expression alleles
  and therefore be immunologically silent.
• Still others may result in expression of proteins
  that are normally made in fetal life, before the
  immune system develops, and these should be seen
  as non-self, leading to cellular death.

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It follows that stimulating the immune system
sounds like a good bet to kill off cancer cells

• If a melanoma is growing, it is evading the
  immune system, so how can you fix things?
• Isolate the melanoma cells, grow them up in
  culture, irradiate them to block their future
  cell division, and re-inject them into the
  patient
• This should work, but doesnt, so we need
  another trick.
• Use our knowledge of T-cell activation to make
  the injected cells better CTC stimulators.

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Engineer isolated tumor cells to express GMCSF, a
growth factor for T-cells

• Isolate melanoma cells and transform with the
  gene for GMCSF under a strong promoter
• Grow up lots of the cells, then irradiate them,
  so they wont divide again (prevent them from
  increasing the patients tumor burden)
• Inject, and they then stimulate the CTCs that
  recognize the injected melanoma cells. These
  CTCs can also kill real tumor cells. Recovery!