Transcript 8_23_cancer

Innate immune effector mechanisms –
Complement
• Complement:
– complex group of plasma proteins that are pre-formed (not
made in response to infection)
– found in serum and body fluids
– produced mainly by liver cells
– can be thought of as a form of innate humoral immunity
• Activation of complement results in a cascade of molecular
events, which results in:
– enhanced phagocytosis of microbes
– recruitment of inflammatory cells
– direct lysis of bacteria
• There are three different activation pathways for
complement:
– alternative pathway (induced by direct interactions with
molecules in the surface of pathogens)
– classical pathway (antibody-mediated)
– lectin pathway (induced by the mannose-binding protein, an
acute-phase reactant)
• The poorly-named alternative pathway is perhaps the most
active and important means of activating complement, in that it
can act early in infection, before the stimulation of other
responses.
• Some complement
components are
activation/proteolytic
enzymes.
• Other complement
components are membranebinding proteins that act as
opsonins.
• Other complement
components are mediators of
inflammation.
• Still others form part of what is
called the membrane-attack
complex, which can lyse
microbes.
• All three complement pathways intersect at the point of
having some enzyme (a C3-convertase) that can cleave a
molecule called C3 into C3b and C3a, as well as an enzyme
that can cleave C5 (C5 convertase).
• C3b is a potent opsonin.
• C3a and C5a are peptide mediators of inflammation.
• C5b forms part of the membrane attack complex
Innate immune effector mechanisms – Macrophagedriven inflammatory responses, Acute Phase Response
Antibody Effector Functions
• Antibodies can exert a wide variety of effector functions,
including helping induce complement activation via the
classical pathway, enhancing phagocytosis, as well as arming
NK cells in ADCC
• In addition to this, antibody molecules can carry out a wide range
of biological functions. Antibodies can directly neutralize
viruses, bacteria, or bacterial toxins
The different
immunoglobulin
isotypes have
different biological
properties, and are
selectively
distributed
throughout the
body:
• IgM is found primarily in blood,
and is very efficient at activating
complement.
• IgE can activate mast cell
degranulation, inducing allergic
responses.
• IgA is readily transported across
epithelial barriers and serves as
the primary immunoglobulin type in
gut and mucosal surfaces. IgA
also is found in colustrum and
breast milk.
• IgG is the only isotype that is
transported across the placenta.
Together, these passively-transferred antibodies provide a
significant level of immune protection in the newborn, as newborn
humans cannot produce their own antibodies for some time after
birth:
Cancer - interactions with the immune system
• Cancer refers to a collection of diseases characterized by:
– abnormal cellular proliferation
– invasion of normal tissues
• Cancers are primarily diseases of older people.
• In developed countries where life expectancy has increased
significantly over the last century, due to control of infectious
disease, cancer is a significant clinical problem.
• Nearly a quarter of deaths in developed countries, such as
the United States, are due to cancer.
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All Cancers, White Males, 1950-1994
from NIH-NCI Atlas of Cancer Mortality
Melanoma, White Males, 1950-1994
Lung, White Males, 1950-1994
• Cancer cells are similar enough to normal cells to make
eliminating cancer quite difficult.
• Commonly used approaches, such as surgery, radiation therapy
and cytotoxic drugs either affect normal, non-cancerous cells, or
cannot eliminate all tumor cells, making treatment difficult.
• Tumors arise from mutations that result in uncontrolled
growth.
• In particular, mutations that subvert mechanisms normally
involved in normal controls on cell division and cellular survival
can result in cancer.
• Examples of this are mutations in which proto-oncogenes are
activated, or tumor suppressor gene function is lost.
• These mutations provide a selective
growth advantage to nascent tumor
cells, and these cells then
accumulate further mutations, which
give them a great growth and
viability advantage.
• The cumulative effect of these
multiple mutations is malignant
transformation .
• Therefore, cancer arises from a
single cell that has accumulated the
most optimal set of mutations.
mutations acquired during the
development of colorectal cancer
• Cancer can arise from exposure to carcinogens:
– mutagenic chemicals
– radiation (ultraviolet light)
• Certain viruses have the potential to transform cells:
oncogenic viruses
• Such viruses account for a significant minority of cancers.
• Oncogenic viruses can promote cancer by a variety of means,
including virus-encoded homologues that mimic or subvert human
genes involved in:
– cellular activation (EBV LMP1 ~ CD40 on B cells)
– cellular growth control (HPV E6 & E7; cytokine homologues)
– induction of resistance to apoptosis (bcl2 homologues)
• Oncogenic DNA viruses usually induce long-term infection in
their host cells, and override normal growth/viability control in
these cells.
• Simpler viruses, such as retroviruses, can induce cancer by
inserting into a host cell chromosome in the wrong place,
resulting in uncontrolled host gene expression, since these
viruses are inserted into the host chromosome as proviral
DNA.
• Finally, some viruses may cause cancer by inducing elevated
levels of cellular proliferation and replacement, enhancing the
chances of a genetic error that could result in cancer.
• Immune surveillance theory: the theory that the immune
system plays a significant role in tumor surveillance.
• Based on increasing knowledge of immune function, and the
understanding that immune responses could distinguish
between self and non-self, and could exert cytotoxic responses
that could kill tumor cells.
• A correlate of this theory is that cancer results from some
failure in immune surveillance.
• Does immune surveillance play a central role in cancer
control?
• People who have immune deficiency syndromes do not show a
significant increase in the most common cancers.
• While there is a marked increase in cancer in such immunedeficient people, they tend to develop certain rare cancers
(Kaposi’s sarcoma, lymphoid malignancies), most of which are
virus-associated cancers.
• Therefore, immune responsiveness almost certainly plays a
key role in controlling tumor cell growth and development in
the case of virus-associated cancers, by controlling virusinfection by normal means (CTL, NK cells, etc).
• However, loss of immune surveillance may not be as important
in the genesis of more common forms of cancer.
• Curiously, tumor cells are
easily killed by cytotoxic T
cells that are responding to
allogeneic differences:
tumor cells that are not of
the same MHC type as the
host are readily killed by
normal cellular immune
responses
• Therefore, tumor cells are not inherently resistant to cytotoxic
effector cells.
• Tumor cells are not killed in an animal that shares MHC type
with the tumor cell because the tumor cell is not antigenic.
• Since the genetic changes that occur in tumor cells are slight
(in tumors not associated with virus infection), the host immune
system may not be able to distinguish these cells, antigenically,
from other cells in the body.
• Tumor antigens are molecules expressed on tumors that can
elicit an immune response
• Tumor antigens :
– tumor-specific antigens - antigens that are unique to a
given tumor
– tumor-associated antigens - antigens that are widely
expressed on tumor cells, but which are not unique (these
same antigens may be expressed on normal cells of other
tissue types, or at other stages of development)
• Tumor-specific antigens are often seen in chemicallyinduced tumors, in which a mutagen has induced a change
that is sufficiently large to result in a clear antigenic change.
• Some tumor-associated antigens are products of re-activated
embryonic genes, which are not normally expressed on mature
cells.
• In other cases, tumor-associated antigens represent overexpression of normal molecules that are expressed at much
lower levels in non-malignant cells:
• It is possible that there is some level of immune response
initiated against a nascent tumor clone - as the progeny of the
original tumor cells accumulate further mutations, some rare
cells evolve the ability to evade host immune responses.
• Some tumor cells have been seen to have lost expression of
MHC class I genes, which would allow them to evade CTL
killing.
• However, such cells would be more susceptible to NK cell killing.
• In any case, it is possible that enhancing anti-tumor immune
responses, either humoral (antibody) or cellular (CTL, NK),
might allow control of tumor cell growth.
• Many experimental immune-based therapies are being
examined for their ability to result in anti-cancer effects.
• For instance, monoclonal antibodies directed to tumor
antigens, and conjugated to toxins or radioactive tags, have
been utilized in experimental treatment:
• Other approaches
include attempts to
enhance anti-tumor T cell
responses by enhancing
the effectiveness of
tumor antigen
presentation to
potentially
cytotoxic cells:
There are tumors of
immune system cells,
and these mirror the
various stages of
these cells’
development:
• Chromosomal translocations can result in the uncontrolled
expression of a normal gene that is involved in inducing cellular
proliferation or viability (myc proto-oncogene), inducing the overexpression of that gene, resulting in uncontrolled cellular growth:
c-myc:Ig gene translocation. This chromosomal translocation is
commonly seen in Burkitt’s lymphoma, including AIDSassociated Burkitt’s lymphoma and SNCCL. This genetic
lesion, believed to occur during the process of Ig isotype
switching, results in the transcriptional activation of the
translocated c-myc oncogene, contributing to lymphomagenesis.
• Isotype switching - change in the type of H-chain that is
used by a given B cell:
Transplantation and the immune system
• An increasing number of diseases are being treated by
transplantation:
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* in the US
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• A significant clinical problem
in tissue transplantation has
been the development of
immune responses to the
grafted tissue: transplant
rejection:
• Another potential
transplant-associated
problem are anti-recipient
responses by immune
cells in the grafted tissue
to the host (graft vs host
disease – GVH).
• A lot of research in
immunology was driven
by the need to
understand
transplantation rejection.
• In fact, MHC, or major histocompatibility complex molecules,
were first studied because they were associated with graft
rejection, and only later were seen to play key roles in the
generation of immune responses.
• It was seen that matching MHC type between donor tissues
and the host resulted in decreased rejection, and in significantly
increased graft survival:
• Autograft - tissue
transplanted from one site
to another on the same
person: not rejected.
• Syngeneic transplants transplants between
genetically-identical
animals (twin humans or
inbred mouse strains):
not rejected
• Allograft - transplants
between genetically
different individuals:
rejected
• The exception to this was
pregnancy, in which the fetus,
which is genetically nonidentical to the mother (fetal
allograft) is not rejected (why
this is so is still not
completely clear).
• Graft rejection was seen to involve several immune
mechanisms.
• Subjects who had pre-formed antibodies that reacted with
antigens on the graft often showed a very rapid antibodymediated form of rejection - hyperacute rejection:
• Other forms of graft rejection were mediated by host T cells
that were stimulated by foreign antigens on the graft to become
activated and develop into effector cells.
• This form of rejection, acute rejection, is due to alloreactions
to graft MHC class I and class II molecules that are different
from those of the host.
• The development of effective immunosuppressive drugs has
been of great clinical importance in prolonging graft survival.
• One of the most important immunosuppressive drugs is
cyclosporin, which is a potent T cell-inhibitory drug.
• Cyclosporin inhibits signaling induced following ligation of the
TCR complex, preventing induction of IL-2 and IL-2 receptor
gene expression:
• This cyclosporin-mediated inhibition of IL-2 and IL-2 receptor
gene expression effectively inhibits T cell activation and
proliferation in response to antigen: