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IMMUNOLOGY
7105306
IMMUNE RESPONSES AGAINST TUMORS
AND TRANSPLANTS
(UPDATED)
Part-12
References:
Immunology , David Male et al 8th ed 2013
Basic Immunology , Abul K. Abbas and Andrew H. Lichtman, 3ed, 2011
Instructor: Dr Alaeddin Abuzant, PhD Microbiology and Immunology
Email: [email protected]
Cancer and organ transplantation represent two clinical
situations in which the role of the immune system has
received a great deal of attention.
Enhancing immunity against the tumors holds much promise for treatment.
In organ transplantation, of course, the situation is precisely the reverse,
suppression of immune response to transplanted organs is needed in this case
Immune responses against tumors and transplants share
several characteristics.
The main immune mechanism by which tumor cells are destroyed involves
cytotoxic T cells
Immune mechanisms that mediate attacking tissue transplants involve:
1- CD8 T cells
2- CD4 T cells
3- Antibodies
I- Tumors Immunology
Introduction:
It was mentioned earlier that in addition to combating microbes the immune system
is responsible for detecting and destroying cancer cells . However, the immune system
is not always successful in doing this
Note: The process of detecting and destroying cancer cells is known as immune
surveillance
Initial Evidence That Supported Potential Roles of the
Immune In Defending Against Tumors
(Specially, Cell Mediated Immunity)
You need to know and memorize this table (memorize the concepts of these points)
Most Tumors (Cancers) Trigger Weak Immune Reponses:
The fact that most cancers develop in immunocompetent individuals (individuals with
normal immune system), indicates that the immune response triggered by cancer cells
is either:
1- Inefficient or weak ( in contrast to immune reponses induced by microbe) OR
2- There is a good immune response, however, the immune system is overwhelmed
by the rapidly growing (dividing) cancer cells that spread rabidly though out the body of
the patient at the expense of normal cells
Accordingly, tumor (cancer) immunologists have been interested in:
1- Identifying tumor antigens that can induce an effective immune response against
cancer cells
2 Enhancing and maximizing immune reponses so as to have an effective immune
reponses against cancer cells
TUMOR ANTIGENS:
Malignant tumors express various types of molecules that may be recognized by the
immune system as foreign antigens
I- In Experimental Animals:
In animal studies, tumors can be induced by chemical carcinogens or radiation
In these animals, many tumor antigens (mutated tumor proteins) can be generated
and may be detected as foreign proteins by the immune system of these animals.
These mutant proteins may be mutants of any normal cellular proteins. However,
these mutant proteins may play NO role in tumorigenesis (cancer development).
2- In Spontaneous Human Tumor
Most of proteins in cancer development in spontaneous human tumor (cancers) are
products of mutated or translocated oncogenes OR tumor suppressor genes ( genes
that are presumably involved in the regulation of the cells cycle).
These tumor proteins results in the transformation of normal cells into cancer cells (a
process known as tumorigenesis). Surprisingly, it has been found that in most cases,
immune reponses against tumors are not induced by these proteins
However, it has been found that in spontaneous human tumor , the tumor antigens
(proteins) that induce an immune response against cancer cells appear to be proteins
that are not involved in tumorigenesis ( not proteins that are involved in cell cycle
regulation).
These proteins that induce an immune reponses in spontaneous human cancers are
mostly:
1. Normal proteins that are over-expressed in cancer cells, or
2. Normal proteins that are aberrantly (bizarrely) expressed due to dysregulation of
gene expression in cancer cells such as:
A- Normal proteins that over-expressed in cancer cells, or
B- Normal proteins expresses in a tissue that is not supposed to be expressed in cancer
cells of a particular cancer ( example: lymphocytic cancer cells express protein of
muscle cells )
C- Proteins that are expressed in during in utero ( during fetal development in the
uterus) and are not supposed to be expressed after birth. (expressed in cancer cell
because of the dysregulation in gene expression in cancer cells)
3- In oncogenic viruses-induced tumors, tumor antigens may be viral proteins
IMMUNE MECHANISMS OF TUMOR REJECTION
The principal immune mechanism of tumor eradication is killing of tumor cells by
CTLs ( Effector CD8+ T cells) specific for tumor antigens.
Most tumor antigens that induce immune responses in tumor-bearing individuals (
persons that have cancers) are endogenously synthesized cytosolic proteins that are
displayed by MHC-I. ( some of these tumor proteins are ubiquitinated , degraded by
the proteosome, generated peptides are transported into ER by TAP to be loaded
on MHC-I of tumor cells )
Therefore, these tumor cells are recognized by CD8+ T cells that attacks and kill
tumor cells displaying tumor peptides on MHC-I on their surface
The role of CTLs in tumor rejection has been established in animal models that have
inoculated by tumor cells. Transplanted tumors in these animals have been shown
to be destroyed when tumor transplanted animals receive tumor-reactive CD8+ T
cells specific to tumor peptides displayed on MHC-I on the cells of the transplanted
tumor cells.
CTL responses against tumors often are induced by
recognition of tumor antigens on host antigen presenting
cells (DCs), which ingest tumor cells or their antigens and
present these antigens to CD8+ T cells
Tumors may arise from virtually any nucleated cell type.
 As all normal nucleated cells, tumor cells are able present peptide antigens
on MHC-I ( but some of these peptide antigens are of certain proteins
expressed by tumor cells (tumor proteins)
Tumor cells do not express co-stimulators or class II MHC molecules.
Note: Recall that MHC-II are expressed by antigen presenting cells)
How can tumors of different cell types stimulate CTL responses?
Tumors cells stimulate CTL activation by cross-presentation.
The process of cross-presentation involves that tumor cells are ingested by dendritic
cells. Then the protein antigens of the tumor cells are processed and displayed by the
class I and class II MHC molecules on the surface of these dendritic cells.
At the same time, these dendritic cells express co-stimulators (B-7) that provide
“second signals” for the activation of both CD4 and CD8 T cells that have receptors
specific for tumor peptide antigens.
Thus, tumor antigens may result in the activation of both CD8+ T cells and by CD4+ T
Once naive CD8+ T cells have differentiated into effector CTLs, they are able to
kill tumor cells expressing tumor peptide antigens on MHC-I
What about the role of activated CD4 T cells that have
receptors specific for tumor peptide antigens ?
Anti-tumor CD4+ T cell may help in the activation of B cells that have
receptors specific for tumor proteins to produce anti-tumor antibodies
Antibodies against tumor proteins have been detected in patients, but
there is little convincing evidence that these antibodies actually
protect individuals against tumor growth.
What about the role of NK cells and macrophages in
defending against tumor cells?
Experimental studies have shown that cytokines from effector anti-cancer CD4+
helper T cells may activate both macrophages and NK cells
These studies have shown that both activated macrophages and NK cells can
attack and kill tumor cells
However, the protective role of macrophages and NK cells in attacking and killing
tumor cells in cancer patients is unclear.
So, It seems that activated anti-tumor CD8+ T cells
play the major role in attacking and killing if cancer
cells
EVASION OF IMMUNE RESPONSES BY TUMORS
Immune responses often fail to inhibit tumor growth, because:
1- The immune response is ineffective (Immune responses against tumors may
be weak because many tumor antigens are weakly immunogenic, perhaps
because they differ only slightly from self antigens)
2- The growing tumor suppresses immune reponses ((Some tumors may
secrete cytokines, such as transforming growth factor-β, that suppress immune
responses))
3- Tumors evolve to evade immune attack (down regulate MHC-I so that CLT
can not recognize cancer cells ).
4- Rabidly growing cancer cells that overwhelm the immune response
Continue…… in the next slide
5- Some tumors stop expressing the peptide antigens on MHC-I that are the
targets of immune attack by CD8+ T cells. These tumors are called “antigen loss
variants.” (provided that the lost tumor protein antigen is not involved in
maintaining the malignant properties of the tumor)
6- Some tumors engage normal T cell inhibitory pathways, such as those
mediated by CTLA-4 or PD-1, and thus suppress anti-tumor immune responses
(such tumors may release certain cytokines that increase the expression of
these molecules on T cells)
IMMUNOLOGICAL APPROACHES FOR CANCER THERAPY
At present, the treatment of disseminated cancers (which cannot be treated
surgically ) relies on chemotherapy and irradiation that have devastating effects
on normal non-tumor tissues.
Importance of Immunological Approaches
Because the immune response is highly specific, it has long been hoped that
tumor-specific immunity may be used to selectively eradicate tumors without
injuring the patient
.
The main strategies for cancer immunotherapy aim to provide
anti-tumor effectors (antibodies and T cells) to patients by:
1- Passive Immunization
2- Actively immunize patients against their tumors (vaccines)
3- Stimulate the patients’ own anti-tumor immune responses
Tumor immunologists have been suing several approaches of tumor immunotherapy in
experimental animals and in humans. Clinical trials of these approaches are currently
underway.
I- Passive immunization by monoclonal antibodies
against various tumor antigens:
A- Anti-tumor antibodies directed against tumor antigens. Binding of these antibodies
to tumor antigens can consequently activates host effector mechanisms, such as
phagocytes ADCC or the complement system
B- Anti-tumor antibodies coupled to potent toxins: these antibodies have been used to
deliver toxins to the tumor cells.
Example: Antibodies specific for CD20 coupled to potent toxins:
CD20 is expressed on tumor B cells have been used to kill B cell tumor cells.
Antibodies specific for CD20 coupled to potent toxins kill both normal and cancer B
cells. However, because CD20 is not expressed by hematopoietic stem cells, normal B
cells can be replenished after the antibody treatment (coupled to potent toxins) is
stopped.
C- Monoclonal antibodies directed against/ or activate certain signaling pathways
Example: Anti-Her2/Neu antibodies.
These antibodies are used to treat certain types of breast cancer.
Anti-Her2/Neu antibodies inducing apoptosis in breast cancer cells that overexpress
HER-2/neu (by unknown mechanism)
D- Antibodies directed against the vascular endothelial growth factor.
Endothelial growth factor is important for angiogenesis, which is the process of the
development of blood vessels
The endothelial growth factor is important for the development of blood vessels that
supply tumors with nutrients needed for their growth
Anti-endothelial growth factor antibodies have been used to treat colon cancer and
other tumors
II- Adoptive Cellular Immunotherapy
In this approach, T lymphocytes may be isolated from the blood or tumor infiltrates of
cancer patients
The isolated T cells presumably contain tumor-specific CTLs ( but may be in low
numbers)
The isolated T cells are then expanded in vitro by cell culture (using certain growth
factors).
This will results in increasing the number tumor-specific CTLs ( in vitro/ by cell culture)
which then injected back into the same patient (this approach is used to increase the
number tumor-specific CTLs in vitro)
Adoptive cellular immunotherapy has has been tried as a therapy for several types of
metastatic (spreading) cancers, but the results have been variable among different
patients and tumors.
II- Vaccination Strategies
1- Stimulating immune responses against tumors by vaccinating cancer patients with
their own tumor cells or tumor antigens. (the most important point is to identify
immunogenic tumor antigens that will induce a strong immune response agaisnt tumor
cells)
Tumor vaccines may be administered as recombinant proteins ( tumor proteins produced
in the lab) with an adjuvant
Recall that adjuvant activate antigen presenting cells to express the co-stimulators B-7
important for T cell activation ( in this case activation of T cells having receptors for
peptide tumor antigens)
.
2- Vaccinating cancer patients with plasmids containing a complementary DNA
(cDNA) (genes) encoding a tumor protein antigen. ( this cDNA is obtained from
the tumor cells of the cancer patient)
When such plasmids are injected into cancer patients, they can be taken by several
types of cells including dendritic cells
Within dendritic cells (and other cells that took up the plasmid), the gene on the
plasmid encoding the tumor protein antigen will expressed to produce the tumor
protein antigen
Peptide antigens from the expressed tumor protein will be displayed on MHC
molecules of the surface of dendritic cells ( that took up the plasmid)
So, these dendritic cells will display tumor peptides on MHC molecules to activate
T cells that have receptors specific for these peptide antigens of the tumor protein
generating CLT cells that will attack and kill cancer cells
3- Tumors caused by oncogenic viruses can be prevented by vaccinating against these
viruses ( vial vaccines of oncogenic viruses).
Such vaccines will produce antibodies that will protect against infection with these
viruses( that may cause transformation of the cells they infect in human body)
Two such vaccines that are proving to be remarkably effective are against hepatitis B
virus (the cause of many liver cancers) and certain types of human papillomavirus (the
cause of cervical cancer)
Hepatitis B virus cause hepatitis B
Certain Human papillomavirus causes (genital warts)
Since these two viruses may transform the cells they infect ( causing the transformation
of infected cells into cancer cells), these two viruses are called oncogenic viruses (
these are many other oncogenic viruses )
III- Strategies used to Boost the host’s Own Immune Responses
Against Tumors
A-Tumor-Pulsed” Dendritic Cells
Precursors of dendritic cells are isolated from the blood of cancer patients and expanding them by
culture with growth factors in the lab
After that, these dendritic cells are exposed to tumor cells or tumor antigens ( obtained from the
cancer patient) in vitro (cross presentation)
These dendritic cells will uptake tumor cells (cross- presentation) or tumor antigens, process them
and display tumor specific peptides on MHC molecules ( the used tumor cells are taken from the
cancer patient and the used tumor antigens is either taken from the cancer patient or the cancer
cells of the patient express the same antigen)
These dendritic cells can be also stimulated to express co-stimulators by certain cytokines (so these
dendritic cells will display tumor peptides on MHC molecules as well as express B-7)
Then, these activated dendritic cells ( called tumor-pulsed” dendritic cells) are used as vaccines ( by
injecting them into cancer patients)
It is hoped that these dendritic cells will mimic the normal pathway of and will generate CTLs that
will attack and kill the tumor cells in the body of
B- By vaccinating with host dendritic cells transfected with plasmids containing
complementary DNAs encoding tumor antigens that are injected directly into patients
or used to transfect dendritic cells
C- By vaccinating with tumor cells transfected with genes encoding B7 costimulators or the T cell growth factor interleukin-2 (IL-2) (such tumor cells will
function as DCs in activating naïve CD8 T cells that have receptors specific for tumor
peptide antigens found on MHC I on tumor cells (provided that tumor cells still
express MHC-I) cells
Strategies for enhancing anti-tumor immune
responses.
A-By enhancing tumor-specific immune responses by
using patient's dendritic cells that have been pulsed
(incubated) with tumor antigens
B- By vaccinating with host dendritic cells transfected
with plasmids containing complementary DNAs
encoding tumor antigens that are injected directly
into patients or used to transfect dendritic cells
C- By vaccinating with tumor cells transfected with
genes encoding B7 co-stimulators or the T cell growth
factor interleukin-2 (IL-2) (such tumor cells will
function as DCs in activating naïve CD8 T cells that
have receptors specific for tumor peptide antigens
found on MHC I on tumor cells (provided that tumor
cells still express MHC-I) cells
APC, antigen-presenting cell; cDNA, complementary
DNA.
D- Treat patients with cytokines that stimulate immune responses (systemic
therapy or local administration at sites of tumors)
A- The first cytokine to be used in this way was interleukin-2 (IL-2), but its applications
are limited by serious toxic effects at the high doses that are needed to stimulate
anti-tumor T cell responses.
B- To avoid serious toxic effects of systemic administration of cytokines, Tumor
immunologists have tried to use particular cytokine genes in plasmid DNA-based
vaccine to immunize cancer patients. By using this strategy, the cytokine gene will
be expressed in certain immune cells ((say dendritic cells)) that will enhance the
patient’s anti-tumor immune response
E- Increase the expression of the co-stimulator B7 in cancer patients dendritic cells to
enhance immune responses against tumors in cancer patients
F- Eliminate normal inhibitory signals for lymphocytes. In some animal models,
blocking the inhibitory receptor of B7 (the CTLA-4) has led to strong immune responses
against transplanted tumors.
II- Immune Responses Against Transplants
Immune Responses against Transplants:
1-Since the beginning of tissue transplantation trials, it was realized that
individuals reject grafts from other individuals in a normal, out-bred
population.
2- It has been noticed that tissue transplantation rejection is caused by
inflammatory reactions that damage the transplanted tissues.
Transplants Rejection is Mediated by Adaptive Immune System:
It was noticed that graft rejection of transplanted tissue is mediated by the adaptive
immune system based on that facts that tissue rejection was:
Dependent on lymphocytes
It shows specificity and Memory
Initial knowledge about the immunology of transplantation:
Initial knowledge regarding the immunology of transplantation came from
studies with inbred strains of rodents, particularly mice.
Inbred Strain (clone) : An inbred strain of an animal ( such as mice) is
defined as a group of animals that are identical genetically to each other (
known also as a clone)
However, they are different ( genetically) from the members of another
inbred strains (a group of animals that belong to a different inbred strain)
Inbred Strain A
Clone A
All members
are genetically
Identical
Inbred Strain B
Clone B
All members
are genetically
Identical
Transplants exchanged between animals of the same inbred strain were accepted
However:
Transplants exchanged between animals of the different inbred strains were rejected
Based on these observations, it was concluded that that graft rejection is determined by
inherited genes whose products are expressed in all tissues.
The individual that provides the graft is called the donor
The individual that receives the graft is called the recipient or
host
In animals that are identical to one another ( same inbred strain ), grafts exchanged among
these animals are accepted. The animals are said to be Syngeneic animals //Syngeneic
grafts
Animals (and grafts) of an inbred strain of a particular animal species transplanted into
animals of a different inbred strain of the same species are said to be Allogeneic animals
/ Allogenic grafts
Animals (and grafts) of a particular animal species transplanted into a different animal
species are said to be Xenogeneic animals/ Xenogeneic grafts.
 Syngeneic grafts are always accepted
 Allogeneic and Xenogeneic grafts (also called Allografts and Xenografts) are
always rejected.
In Allogeneic Grafts
The antigens that serve as the targets of rejection are called alloantigens
The antibodies and T cells that react against these alloantigens antigens are said
to be alloreactive
Allogeneic Grafts
In Xenogeneic Grafts
The antigens that serve as the targets of rejection are called xenoantigens
The antibodies and T cells that react against xenoantigens are said to be
xenoreactive
Xenogeneic Grafts
In the clinical situation, transplants usually are exchanged between allogeneic
individuals, who are members of an out-bred species who differ from one another
Human population is composed ( mostly) of allogeneic individuals
(Allogenic grafts)
(In most the clinical situations)
Human to Human transplantation
In this case, the donor and the recipient belong to same species (humans) but not
genetically identical (except, of course, for identical twins)
Same species but genetically not identical
same species but genetically not identical
Syngeneic Grafts
Mice belong to the same inbred
Identical Twins
(Genitally Identical)
( Inbred(Genetically Identical)
What about human cloning? Watch the
movie: THE ISLAND
Xenogeneic Grafts.
((In most clinical situations))
TRANSPLANTATION
Antigens of allografts that serve as the principal targets of rejection are human leukocyte
antigen (HLA) proteins.
Initially, HLA antigens was discovered and named as Major Histocompatibility Complex
(MHC) on the basis of its role in the rejection of grafts exchanged between mice of
different inbred strains.
Histocompatibility: means compatibility between tissues of donor and recipient
NOTE: Histology is the science of an organism’s tissue
Homologous HLA (MHC) genes and molecules are
present in all mammals
It took more than 20 years after the discovery HLA antigens to
show that the physiologic function of HLA MHC molecules is to
display peptide antigens for recognition by T lymphocytes
Recall that every human expresses:
Six class I MHC alleles (one allele of HLA-A, -B, and -C from each parent) and
At least 8 class II MHC alleles (one allele of HLA-DQ and -DP and one or two of
-DR from each parent, and some combinations of these).
MHC genes are highly polymorphic: It is estimated that in the population there
are at least:
Alleles of MCH-I genes in the population:
350 alleles of HLA-A genes
620 alleles of HLA-B genes
HLA-C (have limited polymorphism)
Alleles of MHC-II genes in the population
400 alleles of DR genes
90 alleles of DQ genes.
HLA-DP (have limited polymorphism)
Because these alleles can be inherited and expressed in many
different combinations, every individual is likely to express some
MHC proteins that appear foreign to another individual’s immune
system (except in the case of identical Twins)
All of the MHC molecules may be targets of rejection ( HLA-C and
HLA-DP have limited polymorphism and probably are of minor
significance)
The recognition of the MHC antigens on another individual’s
cells is one of the strongest immune responses known
The reason why individuals react against MHC molecules of other individuals is now
understood quite well.
T cell antigen receptors (TCRs) have evolved to recognize peptide antigens displayed
on MHC molecules. During their maturation we have both positive and negative
selection processes (central tolerance)
1- T cells with receptors that DO NOT recognize self MHC molecules will be
eliminated ( negative selection)
2- T cells with receptors that recognize self MHC molecules weakly ( with low
affinity) , survive (positive selection)
3- T cells with receptors that recognize self peptides displayed on self MHC
molecules strongly ( with high affinity) OR recognize MHC strongly (with high
affinity) will be eliminated ( negative selection)
4- T cells with receptors that recognize self peptides displayed on self MHC
molecules weakly ( with low affinity), survive (positive selection)
All CD4+ T cells and CD8+ T cells that have receptors that recognize self peptides (with
low affinity) displayed by that individual’s (self) MHC molecules will survive ( positive
selection).
All CD4+ T cells and CD8+ T cells that have receptors that recognize self MHC (with low
affinity) will survive (positive selection).
All CD4+ T cells and CD8+ T cells with receptors that recognized self peptides displayed on
MHC molecules (with high affinity) will be eliminated (negative selection).
All CD4+ T cells and CD8+ T cells with receptors that either do not recognize self MHC or
recognize self MHC with high affinity ( strongly) will be eliminated (negative selection).
So, in conclusion positive selection of T cells includes ( survival conditions
during maturation of T cells)
 T cells with receptors that recognize self MHC molecules weakly, survive (
positive selection)
 T cells with receptors that recognize self peptides displayed on self MHC
molecules weakly ( with low affinity), survive ( positive selection)
So, positive selection includes weak recognition of both self MHC and self
peptides
Positive Selection
During T cell Maturation
Negative Selection
During T cell Maturation
Negative Selection
During T cell Maturation
Negative Selection
During T cell Maturation
Allograft Rejected
Allograft Accepted
Note:
The cells of an allograft may express thousands of MHC molecules (specially-MHC-I), every
one of which may be recognized as foreign by recipient’s T cells.
By contrast, in the case of an infected cell, only a small fraction of the self MHC molecules
on the cell surface will carry a foreign microbial peptide recognized by
the host’s T cells.
The main reasons why allogenic cells of an allograft may evoke very strong immune
response by T cell of the recipient ( the more the difference between the recipient MHC
and the donor MHC (allo-MHC) the stronger the immune response ( REJECTION) and VISEVERSA
Minor Histocompatibility Antigens
Although MHC proteins are the major antigens that stimulate graft rejection,
other polymorphic proteins also may play a role in rejection
Non-MHC antigens that induce graft rejection are called minor histocompatibility
antigens.
The most important minor histocompatibility antigens allelic forms of normal cellular
proteins that MAY happen to differ between donor and recipient.
The rejection reactions that minor histocompatibility antigens elicit usually are not as
strong as reactions against foreign/Allo MHC molecules
Two clinical situations in which minor antigens are important targets of rejection are
blood transfusion and bone marrow transplantation
INDUCTION OF IMMUNE RESPONSES AGAINST
TRANSPLANTS
Because a graft ( transplanted tissue or organ) may contain many cell types, often
including epithelial and connective tissue cells, how can the immune system recognize
and react against all these cells?
During an immune response against an allograft, host (recipient)
T cells may:
1- Recognize allogenic MHC molecules (donor MHC) that are expressed on the surface
allo dendritic cells of the allograft…..this is called direct recognition….this causes
nonspecific host T cell activation
OR
2- Recognize allo-antigens that are may be processed and presented as allo-peptides
by the host’s MHC on hot dendritic cells ………this is called indirect recognition…..this
causes…. this causes specific host T cell activation
1- Direct Recognition of DONOR’s MHC ( Allo-MHC) by Host T
cells
(Roles of host allo-reactive T cells generated by the direct recognition pathway
in allograft rejection)
Transplanted tissues and organs (allografts) contain allo-dendritic cells ( OF THE
DONOR/allo-dendritic cells). When T cells of the recipient (HOST/PATIENT) recognize
donor’s allogeneic MHC molecules on allo-dendritic cells of the donor with high affinity.
Hosts T cells are activated (non specific activation) and differentiate into effector T cells.
Host allo- reactive CTL cells generated by direct recognition start attacking and killing
the cells of the allograft by binding strongly to all MHC-I expressed on nucleated cells of
the allograft resulting in acute ejection of the allograft
Recall that host T cells that recognize self MHC strongly have been eliminated during T
cell maturation…( Negative selection as a part of central tolerance)……BUT, for sure,
that the host contains T cells that will recognize donor MHC expressed on the surface of
the cells (including allo-dendritic cells) of the allografts with high affinity……this will
cause non-specific activation of host T cells……( the more the difference between
recipient MHC and donor MHC ( mainly MHC-I), the stronger the activation of recipient
CD8+ T cells . In this case, finding a donor with MHC as much similar to those of the host
will the best choice in minimizing allograft rejection…..HISTOCOMPATABILITY
Regarding host allo- reactive helper T cells generated by direct recognition , it seems
that these cells do not play a major ole in allograft rejection.
Host allo- reactive helper T cells can activate allo-macrophages found in the allograft, but
the number of these allo-macrophages is large ( no more all- macrophages of the donor
are generated since the transplanted organ or the tissue is now in host (recipient)
body..and no more donor Monocytes come to generate more donor macrophages)
Accordingly, alloreactive CTL of the host ( BUT NOT Helper T cells ) generated by direct
recognition pathways plays a major role in acute allograft rejection
2- Indirect recognition:
Alloreactive helper T cells of the recipient may enter the allograft together with recipient
DCs into the allograft. These recipient DCs will engulf donor cells and present allopeptides on self MHC-I and MHC-II.
In addition, the allograft contains host macrophages that have been derived from host
Monocytes that have migrated into the allograft. So, in the allograft tissue…. We have
both recipient DCs and recipient macrophages that have migrated into the allograft.
These host macrophages are also to engulf cells of the allograft as well as allo-antigens
and present allopeptides on self MHC-II and MHC-I
Some of the recipient DCs that have entered into the allograft may engulf allocells and
then migrate to peripheral lymphoid tissue of the recipient to activate both host CD4+
and CD8+ T cells that have receptors to allo-peptides (which are now displayed on self
MHC molecules) ((This is similar to the cross-presentation discussed earlier eagrding
virally infected cells)). The generated effector helper T cells and CTL cells migrate to the
allograft
Note: The host dendritic cells that present allo-peptides on host MHC I and II also
provide co-stimulators needed for the activation of host T cells .
A-Role of Allo-Reactive CTL Generated By The Indirect Pathway In
Allograft rejection
The CTLs that are activated by the indirect pathway and are specific for allo-peptides that
are displayed by host MHC-I molecules.
However, in the allograft, these host CTL cannot recognize and kill cells in the allograft
because the allo-peptides against which HOST specific CD8 T cells were activated are
displayed by DONOR MHC-I………… (the generated allo-reactive CTL are specific for allopeptides provided that these allopeptides are displayed on HOST MHC-I but NOT ON
DONER MHC-I…….
So that why the generated host allo-reactive CLT ( by the indirect pathway) will not be
able to recognize and kill cells of the allografts………simply because they can not
recognize these allo-peptides when presented by allo- MHC-I (donor MHC-I) expressed
on the of the allograft cells
Accordingly, it is likely that CLT cells generated by the indirect pathway DO NOT play a
major role in allograft rejection ( In contrast of host CLTs generated by the direct
pathway, which is believed play a major role in
acute allo-graft rejection)
B- Role of Allo-Reactive Helper T Cells Generated By The
Indirect Pathway In Allograft rejection
Once these alloreactive helper T cells of the recipient enter the allograft, they can
activate host macrophages in allograft that display the same allo-peptides displayed
on host ( recipient) MHC-II.
The host activated macrophages found in the allograft starts secreting cytokines and
chemokines resulting in a delayed-type hypersensitivity (DTH) reaction
(inflammation ) that slowly destroys the allograft
Accordingly, it is most likely that allo-reactive Helper T cells generated by the
indirect pathway play a major role in
chronic allograft rejection
The mixed lymphocyte reaction (MLR) is an in vitro model of T
cell recognition of alloantigens
In this model, T cells from one individual (Recipient/Host) are cultured with leukocytes
of another individual (Donor) in the presence of adjuvant, and the responses of the T
cells are assayed.
The magnitude of this response is proportional to the extent of the MHC differences
between these individuals and is a rough predictor of the outcomes of grafts exchanged
between these individuals.
The model is just like a test to measure HISTOCOMBATIBILITY between donor and the
recipient
Role of antibodies In Graft Rejection:
Antibodies are involved in both Hyperacute or acute rejection allograft
rejection
IMMUNE MECHANISMS OF GRAFT REJECTION
On the basis of clinical and pathologic features Graft rejection is classified into
1- Hyperacute, 2- Acute, and 3- Chronic. Each type of rejection is mediated by a
particular type of immune response.
1- Hyperacute rejection occurs within minutes of transplantation:
It is characterized by thrombosis of graft vessels and ischemic necrosis of the graft.
Hyperacute rejection is mediated by circulating antibodies, specific for alloantigens on
allograft endothelial cells, that are present before transplantation.
These preformed antibodies may be natural IgM antibodies specific for
A- Blood group antigens (discussed later)
B- Antibodies specific for allogeneic MHC molecules that are present because of
exposure to allogeneic cells due to blood transfusions, pregnancy, or prior organ
transplantation.
These antibodies bind to antigens in the graft vascular endothelium and activate
the complement and clotting systems, leading to injury to the endothelium and
thrombus formation.
Why hyperacute rejection is not a common problem in clinical transplantation?
because every recipient is tested for blood type and for antibodies against the cells of
the potential donor. (The test for antibodies is called a cross-match.)
2- Acute rejection occurs within days or weeks after transplantation
It is the principal cause of early graft failure. It is mediated mainly by
A- Recepinet T cells, which react against alloantigens in the graft.
These T cells may be CTLs that directly destroy graft cells, or
 T cells may react against cells in graft vessels as wells, leading to vascular damage.
B- Alloantibodies
Mainly alloantibodies directed specifically against the vascular alloantigen of the
allograft.
In this reaction, injury to graft vessels is caused mainly by complement activation by the
classical pathway.
Current immunosuppressive therapy is designed mainly to prevent and reduce acute
rejection by blocking the activation of alloreactive T cells
3- Chronic rejection
It is an indolent (slow) form of graft damage that occurs over months or years, leading to
progressive loss of graft function.
Chronic rejection may be manifested as
A. Fibrosis of the graft
B. Gradual narrowing of graft blood vessels
Chronic rejection is believed to be mediated by T cells that react against graft
alloantigens and secrete cytokines ( most likely alloreactive helper T cells)
These cytokines stimulate the proliferation and activities of fibroblasts and vascular
smooth muscle cells in the graft.
 Chronic rejection is called graft arteriosclerosis.
Note: As treatment for acute rejection has improved, chronic rejection is becoming the
principal cause of graft failure
PREVENTION AND TREATMENT OF GRAFT REJECTION
Preventing and treating the rejection of organ transplants is mainly mediated by
immunosuppression, designed mainly to inhibit either:
1- T cell activation (of the host/recipient) (All kinds of T cells)
2- Effector functions of activated T cells (effector T cells of the host/recipient) (All kinds
of effector T cells)
The most useful immunosuppressive drug in clinical transplantation is
Cyclosporine that has allowed the transplantation of heart, liver, and lung.
Mechanism of action of cyclosporine:
Cyclosporine blocks the T cell phosphatase (called calcineurin) that is required to activate
the transcription factor NFAT (nuclear factor of activated T cells)
Inhibition of NFAT stops transcription of cytokine genes in Host/recipient T cells that play
a major role in graft rejection
Many other immunosuppressive agents are now used either together with adjuncts
cyclosporine to or instead of cyclosporine
Immunosuppressive Drugs
Side effects of drugs used to inhibit graft rejection in the
host/donor
All of these immunosuppressive drugs carry the problem of nonspecific
immunosuppression ( shut down of the host immune system)
Accordingly, patients receiving these drugs as part of their post-transplantation
treatment become susceptible to infections, particularly infections by intracellular
microbes, and demonstrate an increased incidence of cancers, especially tumors
caused by oncogenic viruses.
The matching of donor and recipient HLA alleles by tissue typing
had an important role in minimizing graft rejection in the days
before cyclosporine became available for clinical use.
Although immunosuppression is so effective that HLA matching (
histocompatibility) is not considered necessary for many types of organ
transplants, especially because recipients often are too sick to wait for the
closest match.
Although this may be associated with a serious risk in terms of the
suppression of the host’s/recipient’s immune systems that makes the recipient
very susceptible to infection and maybe cancer development especially those
caused by oncogenic viruses.
The long-term goal of transplant immunologists is to induce
immunological tolerance specifically ( in the host/recipient) for
the graft alloantigens.
If this is achieved, it will allow graft acceptance without shutting off any other immune
responses in the host.
Attempts to induce graftspecific tolerance are ongoing in experimental models (e.g., by
stimulating alloreactive T cells to become regulatory cells).
A major problem in transplantation is the shortage of
suitable donor organs.
Can Xenotransplantation be a possible solution for this problem????
Experimental studies with xenotransplants have shown that hyperacute rejection is a
frequent cause of the loss of these grafts.
The reason for the high incidence of hyperacute rejection of xenografts is:
I- Natural Antibodies:
The host/recipient often contain antibodies that react with cells from other species.
These antibodies, like antibodies against blood group antigens discussed
subsequently, are called “natural antibodies”
They called natural antibodies because their production does not require prior exposure to
the xenoantigens.
What Produces Natural Antibodies?
These natural antibodies are produced against bacteria that normally inhabit the gut and
that the antibodies cross-react with cells of other species.
II- Xenografts also are subject to acute rejection, much like allografts.
Attempts are ongoing to genetically modify xenogeneic tissues in ways that prevent
their rejection by recipients of other species.
TRANSPLANTATION OF BLOOD CELLS AND BONE MARROW CELLS
Transplantation of blood cells, called blood transfusion
It is the oldest form of transplantation in clinical medicine.
The major barrier to transfusion is the presence of foreign blood group antigens, the
prototypes of which are the ABO antigens. These antigens are expressed on red blood
cells, endothelial cells, and many other cell types.
ABO molecules are glycosphingolipids containing a core glycan with sphingolipids
The names A and B refer to the terminal sugars of glycosphingolipids.
These terminal sugars are:
 Nacetylgalactosamine……A
found in people with A blood group
 Galactose………..B
found in people with B blood group
AB means that both are present ( like the case of people with AB blood group)
O means that neither is present ( like the case of people with O blood group)
Individuals expressing one blood group antigen are tolerant to that antigen
but contain antibodies against the other
Blood Group
Antibodies found
A
anti B antibodies
B
anti A antibodies
AB
NEITHER anti A NOR Anti B antibodies
O
Both anti A and Anti B
It is believed that these antibodies are produced against similar antigens that are
expressed by intestinal microbes and cross-react with the ABO blood group antigens
.
The preformed antibodies react against transfused blood cells expressing
the target antigens, and the result may be a severe transfusion reaction.
This problem is avoided by matching blood donors and recipients, a standard
practice in medicine.
Because the blood group antigens are sugars, they do not elicit T cell responses.
Blood group antigens other than the ABO antigens also are involved in transfusion
reactions, and these usually are less severe
Hematopoietic stem cell transplantation
Hematopoietic stem cell transplantation is being used increasingly to:
1. Correct hematopoietic defects or
2. To restore bone marrow cells that have been damaged by irradiation and
chemotherapy for cancer.
Either whole bone marrow cells or enriched populations of hematopoietic stem
cells derived from a donor’s blood or bone marrow are injected into the circulation
of a recipient. Hematopoietic stem cells then home to the marrow.
The transplantation of bone marrow cells poses many
special problems.
1. Before transplantation, some of the bone marrow of the recipient has to
be destroyed to create “space” to receive the transplanted marrow Cells
2. This depletion of the recipient’s marrow inevitably causes deficiency of
blood cells, including immune cells.
3. The immune system reacts very strongly against allogeneic bone marrow
cells, so that successful transplantation requires careful HLA matching of
donor and recipient
4.
If mature allogeneic T cells are transplanted with the marrow cells, these
mature T cells ( of the doner can attack the recipient’s tissues, resulting in a
serious clinical reaction called graft-versus-host disease.
5.
Even if the graft is successful, recipients often are severely immunodeficient
while their immune systems are being reconstituted.
Despite these problems, there is great interest in hematopoietic stem cell
transplantation as a therapy for a wide variety of diseases affecting the
hematopoietic and lymphoid systems.