Download Cancer & Transplantation, Aug 22

Complement
• Complement:
– complex group of plasma proteins that are preformed (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
membrane-binding
proteins that act as
opsonins.
• Other complement
components are mediators
of inflammation.
• Still others form part of what
is called the membraneattack 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
Macrophage-driven 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 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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10
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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, noncancerous 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; other viruses - 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
immune-deficient 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 eliminating virus-infected cells (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 cancer cells, antigenically, from other cells in
the body.
• In spite of this, there has been much research
examining the potential role of immune responses in
fighting cancer.
• 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
chemically-induced 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 reactivated embryonic genes, which are not normally
expressed on mature cells.
• In other cases, tumor-associated antigens represent
over-expression 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.
• Recently, monoclonal antibodies directed to tumor
antigens (i.e., Rituximab® [anti-CD20], Herceptin® [antiHER2]), sometimes conjugated to toxins or radioactive
tags, have been utilized in treatment of cancer, with
significant positive results:
• Other experimental
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:
Table B1. Common NHL subtypes: characteristics and molecular lesions
NHL subtype
~ % NHL hypermutated characteristic
associated
in US Ig V regions molecular lesions immune dysfunction
___________________________________________________________________________
Burkitt’s lymphoma (BL)
1-3%
yes
MYC:IgH
h Ig isotype switching ?
follicular lymphoma
35%
yes
BCL2:IgH
h somatic recombination ?
diffuse large B cell
(DLBCL)
30-40%
yes
h BCL6
h somatic hypermutation ?
mantle cell lymphoma
3-10%
BCL2:IgH
no
CYCLIN D1:IgH
h somatic recombination ?
h somatic recombination ?
___________________________________________________________________________
Table B1. Common NHL subtypes: characteristics and molecular lesions
NHL subtype
~ % NHL hypermutated characteristic
associated
in US Ig V regions molecular lesions immune dysfunction
___________________________________________________________________________
Burkitt’s lymphoma (BL)
1-3%
yes
MYC:IgH
h Ig isotype switching ?
follicular lymphoma
35%
yes
BCL2:IgH
h somatic recombination ?
diffuse large B cell
(DLBCL)
30-40%
yes
h BCL6
h somatic hypermutation ?
mantle cell lymphoma
3-10%
BCL2:IgH
no
CYCLIN D1:IgH
h somatic recombination ?
h somatic recombination ?
___________________________________________________________________________
• Isotype switching - change in the type of H-chain that
is used by a given B cell:
• 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 over-expression 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.
Table B1. Common NHL subtypes: characteristics and molecular lesions
NHL subtype
~ % NHL hypermutated characteristic
associated
in US Ig V regions molecular lesions immune dysfunction
___________________________________________________________________________
Burkitt’s lymphoma (BL)
1-3%
yes
MYC:IgH
h Ig isotype switching ?
follicular lymphoma
35%
yes
BCL2:IgH
h somatic recombination ?
diffuse large B cell
(DLBCL)
30-40%
yes
h BCL6
h somatic hypermutation ?
mantle cell lymphoma
3-10%
BCL2:IgH
no
CYCLIN D1:IgH
h somatic recombination ?
h somatic recombination ?
___________________________________________________________________________
Table B1. Common NHL subtypes: characteristics and molecular lesions
NHL subtype
~ % NHL hypermutated characteristic
associated
in US Ig V regions molecular lesions immune dysfunction
___________________________________________________________________________
Burkitt’s lymphoma (BL)
1-3%
yes
MYC:IgH
h Ig isotype switching ?
follicular lymphoma
35%
yes
BCL2:IgH
h somatic recombination ?
diffuse large B cell
(DLBCL)
30-40%
yes
h BCL6
h somatic hypermutation ?
mantle cell lymphoma
3-10%
BCL2:IgH
no
CYCLIN D1:IgH
h somatic recombination ?
h somatic recombination ?
___________________________________________________________________________
• Somatic hypermutation:
– rapid mutation (hypermutation)
of immunoglobulin genes
– results in antigen-binding
affinity that is higher, or lower,
than its original binding affinity
– selection by antigen results in
the generation of BCR with
increased affinity for antigen
• Only those B cells that have
enhanced their antigen receptor’s
binding affinity survive.
Mutation of protooncogenes occurs
in B cells
undergoing
somatic
hypermutation:
This contributes to
the development
of some
non-Hodgkin’s
lymphomas.
Transplantation and the immune system
• An increasing number of diseases are being treated by
transplantation:
*
* in the US
*
• 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 antirecipient 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
non-identical 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.
• Some graft-reactive T cells are cells that respond to nonself
MHC: 1-10% of all T cells in an individual will respond to
stimulation by cells from another, unrelated, member of the
same species.
• In addition to this, host T cells respond, in a more
conventional manner, to foreign graft antigens presented
by APC.
• This form of T cell-mediated 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: