IMMUNOLOGY OF TRANSPLANT REJECTION Flashcards
Autologous grafts - Grafts transplanted from ___________ to _________ in __________
one part of the body
another
the same individuali
Syngeneic grafts (Isografts) - Grafts transplanted between __________ of —————-
two genetically identical individuals
the same species
Allogeneic grafts (Allografts) - Grafts transplanted between _________ of _____________
two genetically different individuals
the same species
Xenogeneic grafts (Xenografts) - Grafts transplanted between ________ of ————-
individuals of different species
IMMUNE RESPONSES TO TRANSPLANTED TISSUES
Transplant rejection caused by genetic differences between donor and recipient
•_______ and __________________
Alloantigens
•Antigens which _____________________________
HLA and blood group antigens
IMMUNE RESPONSES TO TRANSPLANTED TISSUES
Alloreaction
•__________ to _________
Alloreactions in transplantation
•______________ (transplant rejection)
•______________
Immune response; an alloantigen
Host-versus-graft
Graft-versus-host
Cells of Immune response to transplant
_____ Cells
____ cells
____________ cells
______ (Most important)
T
B
Antigen presenting
MHC
T cells
Arise in _____ from ______ derived precursors
Each T-Cell has a unique ___________(______)
thymus; bone marrow
T Cell receptor (Clone)
T cells
Subtypes
CD 4 T cells – ______ specific immune response
CD8 T cells - Precursors of CTL – Class ____ MHC
Antigen
1
B cells
Arise and mature in _________
Express ______ on their surface
bone marrow
BCRs
B cells
When BCR is stimulated the B cell secrete _______ of (same or different?) specificity as their BCRs
antibodies
Same
Antigen presenting cells
Most important
Activate ____ cells
They ____ antigen and _____ it on _______
T
Endocytose; display
MHC molecules
Antigen presenting cells
T cells recognize and interact with ___________ to become activated
antigen MHC
MHC complex
Encode molecules crucial to the _________ and _________ of immune response
The HLA complex on chromosome ____ contains over ____ genes
initiation and propagation
6; 200
MHC complex
The HLA genes that are involved in the immune response fall into two classes, _____ and ______, which are structurally and functionally (similar or different?)
I and II
Different
Tissue compatibility is determined by genes of the __________________
major histocompatibility complex
The MHC
In humans this is referred to as __________________ system, and are clustered on the (short or long?) arm of chromosome ____
Human Leucocyte Antigen (HLA)
Short; 6
The MHC
The HLA region is a _______genic system that encodes structurally _____logous cell surface glycoproteins that exhibit ____________
Multi; homo
polymorphic alleles
HLA class I molecules are expressed on _______________ cells
most nucleated
HLA class I:
HLA – ____
HLA – ____
HLA – ____
A
B
C
HLA class II:
HLA – ____
HLA –____
HLA – ____
DR
DQ
DP
HLA class II molecules are expressed on a subset of cells of the immune system:-
______ cells, ____ cells, _________ cells, —————.
These are collectively referred to as —————- cells.
Dentritic
B
activated T
Macrophages
antigen presenting
HLA antigens
The biological function of the HLA molecules is to _____________ to T-cells, thereby playing a central role in T-cell – mediated adaptive immunity
present peptide antigens
Types of MHC
There are ______ classes of MHC molecules.
three
Types of MHC
There are three classes of MHC molecules.
Class I- encodes glycoproteins expressed on the surface of __________ cell; the major function of the class I gene is ———————- as to ————- -cells
nearly all nucleated
presentation of peptide antigens
cytotoxic T
Types of MHC
There are three classes of MHC molecules.
Class II- encodes glycoproteins expressed primarily on _______cells, examples: macrophages, dendritic cells and B-cells, where they present _____________ to ____ helper cells.
antigen-presenting
processed antigenic peptides
T
Types of MHC
There are three classes of MHC molecules.
Class III- encodes various secreted proteins that have immune function including components of the —————- ; C2,C4, Factor B, &TNF, and molecules involved in inflammation.
complement system
Function of MHC
Function of MHC
The function of both class I and class II molecules is the _______________ to _____ cells, a process that initiates the adaptive immune response
presentation of short, pathogen-derived peptides
T
Function of MHC
Class I – Detects ______ and _______ that would indicate an intracellular pathogen such as virus or intracellular bacteria; Recognised by ______ cells and provide a surveillance mechanism to target infected cells for destruction
cytosolic and foreign proteins
CD 8 T
Function of MHC
Class II system is designated to sample extracellular proteins by extracellular proteins by specialized _______
Class II are recognized by ________ cells and allow for the generation of immune response to invading pathogens
APC’s
CD 4 helper T
Class I
The class I genes code for the _________ of the ______ molecule
the ß chain of the class I molecule is encoded by a gene on chromosome ____, the ________ gene.
polypeptide chain
class I
15; beta2-microglobulin
Class I
There are some _____ class I genes in the HLA region; three of these, _____,______ ,_______ , the so-called ______, are the main actors in the immunologic transplant reaction
20
HLA-A, B, and C
classic
Class II
The class II genes code for the __________ polypeptide chains of the class II molecules .
alpha and ß
Class II
The designation of their loci on chromosome ___ consists of three letters: the first (___) indicates the _____, the second (____,____,___,_____, or _____) the _______, and the third (___ or ____) the ______ ( or ____, respectively).
6
D; class
M, O, P, Q, or R; family
A or B; chain
ß
Class II
HLA-DRB, for example, stands for class II genes of the R _____ coding for the ____ chains.
family
ß
HLA typing
Serology:
An effective method for typing for purposes of _______
Simplicity and (low or high?) cost
Requires viable ________
Equivalent to (low or high?) resolution DNA typing
family donors
Low ; lymphocytes
Low
HLA typing
Genomic DNA typing:
Based on ________ of the DNA segment
______ technology
3 levels of resolution: _____,______ and _________
nucleotide sequence
PCR
low, intermediate and high
Donor
The best donor for transplant is a ————- matched ________ identified in family study
genotypically
sibling
Donor
HLA-____,______,_____ (low or high?) resolution typing (2- digit DNA typing or serology) is enough to confirm genotypic identity for sibling donors.
Related donors can be identified in ____-____ % of cases
A,B,DR
Low
20-30
HLA matching: Unrelated Donor
When ________________________
Good risk patients
HLA-____,____,___,____,_____ – allele matched may produce comparable _______________
no HLA matched sibling donor is available
A,B,C,DR,DQ
disease-free survival rates
HLA matching: Unrelated
Donor
Matched Unrelated Donor identification has been facilitated by ____________
Bone Marrow Worldwide Registries
The immunology of transplant rejection
Foreign invaders are presented to the immune system in the form of small molecules called ________.
Identification of these _________ will trigger an immune response and will stimulate the production of_________ that mark infected cells for ______ by the immune system and help amplify the immune response.
antigens
non-self antigens
antigen specific antibodies; destruction
The immunology of transplant rejection
The Human Leukocyte Antigen (HLA) complex is a group of genes that encode the proteins responsible for ________________________.
These proteins are found on the surface of _____ cells and act as ‘ _______ ’ telling the immune system ____________
identifying foreign agents to the immune system
all; self-markers
not to trigger a response.
Mechanism of rejection
Graft rejection occurs when the ________ immune system attacks the _________ and begins ________________________.
The immune response is usually triggered by the presence of the ______’s own unique set of ________, which the recipient’s immune system will identify as _______.
recipient’s
donated graft
destroying the transplanted tissue or organ
donor’; HLA proteins; foreign
Mechanism of rejection
The degree of similarity between the HLA genes of the donor and recipient is known as __________________
the more ____________ the donor and the recipient, the more ______ the recipient’s immune system should be of the graft.
histocompatibility
genetically compatible; tolerant
Mechanism of rejection
However, unless the donor and recipient are __________ (e.g. as in __________) there will always be _______________.
genetically identical; identical twins
some degree of rejection.
Mechanism of rejection
As well as nonself HLA proteins, other ___________ on the donor graft can also be identified as a foreign antigen and illicit an immune response.
surface proteins
Graft versus host reaction’ occurs when (mature or immature?) immune cells already present in the __________ attacks the _________ of the __________.
Mature ; donor graft
healthy cells of the recipient
Graft versus host reaction, where the donor graft is described as being “immune- _________” (i.e. capable of _________________________) is a particular risk with__________________ and can also occur following ___________
competent
producing an immune response
stem cell transplants
blood transfusions.
Hyperacute rejection
This occurs within ______ or ______ after a transplantation and is caused by the presence of ____________________ of the recipient, that match the foreign antigens of the donor, triggering an immune response against the transplant.
These antibodies could have been generated as a result of prior _________ , prior _________ or _________.
minutes or hours
preexisting antibodies
blood transfusions
transplantations or multiple pregnancies
Hyperacute rejection
The antibodies react with cells in the _______ of the graft, causing ______ to form, which will ____________ from reaching the graft resulting in immediate rejection of the transplant.
blood vessels
blood clots
prevent blood supply
Acute rejection
This occurs within the first ________ after transplantation.
__________________ will occur in all transplantations, except between _________.
6 months
Some degree of acute rejection ; identical twins
Acute rejection
Recipients are most at risk in the first _______, but rejection can still occur at a later stage.
3 months
Acute rejection is caused by the formation of _______ following the detection of ______ antigens in the donated graft.
If diagnosed early enough, acute rejection can be treated by _______________ and permanent damage to the graft can be avoided in some cases.
antibodies; non-self
suppressing the immune system
Chronic rejection
_______________ of ____ rejection can ultimately lead to chronic rejection of the graft and failure of the transplant.
Repeated episodes; acute
Chronic rejection commonly manifests as ______ of the tissue or organ which can occur ______ to ________ after acute rejection has subsided.
scarring
months to years
cure for chronic rejection is ????
At present, there is no cure for chronic rejection other than removal of the graft.
Finding an eligible donor-recipient match
Compatibility between donor and recipient is assessed using a combination of tests, including:
ABO blood group compatibility – The donor and recipient are tested for ______________. This is the first test to be carried out as the transplant will be ___________ if the blood groups do no match.
In some transplants, for example _________ and also _______ transplants, ABO compatibility is not a necessity.
compatible blood groups
rapidly rejected
young children
bone marrow
Finding an eligible donor-recipient match
Tissue typing – A blood sample is taken from the ______ to identify the ______ present on the surface of the their cells to help find a ______ ______ donor.
The more alike the HLA types of the donor and recipient are the more likely a transplant will be successful. Family members, in particular ______, are often the best HLA matches due to their genetic similarity.
recipient; HLA antigens
histone compatible
siblings
Finding an eligible donor-recipient match
Cross matching – Blood samples are taken from ______________, and the _____ of the donor are mixed with the _______ of the recipient.
If the recipient’s antibodies attack the donor cells, transplantation will not be suitable due to increased risk of __________
both the recipient and donor
cells; blood serum
hyper-acute rejection.
Finding an eligible donor-recipient match
Panel reactive antibody test – The ___________ of patients awaiting transplantation are tested for __________ against a __________.
Previous exposure to foreign tissue, by blood transfusion, pregnancy or prior transplantations, are likely to increase the number of ________ in the blood.
blood serum
reactive antibodies ; random panel of cells
HLA antibodies
Finding an eligible donor-recipient match
Panel reactive antibody test:
The more HLA antibodies present, the (lower or higher?) the panel reactive antibody (PRA) level denoted to the patient, and the (smaller or greater?) the chance of graft rejection.
If PRA levels are high, it may be (more or less?) difficult to find a match and a higher dosage of __________ drugs may be required
Higher
Greater
More ; immunosuppressive
Serology screening – For patients undergoing stem cell transplantation __________________ will undergo pre-transplant serology screening. This is undertaken to detect the _________ of both the donor and a potential recipient against a number of _____________________, including viruses like HIV, Cytomegalovirus (CMV), and Epstein-Barr Virus (EBV), thus determining potential for __________ or _________ of the infection upon immunosuppression.
Individuals are often matched according to the _____ and _____ status.
they and their donor
immune status
clinically significant infectious organisms
re-infection or reactivation
CMV and EBV
Immunosupressive drugs
To reduce the risk of transplant rejection, patients are treated with immunosuppressive drugs that will ______________________.
Immunosuppressive drugs are given in ____ phases
•an initial _______ phase involving a (low or high?) dose, and a later ________ phase which involves using the drug in the long term at a (lower or higher?) dose.
dampen their immune response
two
induction; high
maintenance; lower
Immunosupressive drugs
The combination of drugs, and dosage given, will vary depending on the type of transplant and the chosen treatment regime.
If a patient experiences an episode of acute rejection, the drug combination is subject to _____ and the dosage is also likely to ____________.
_________ can also cause alternative drugs to be used.
change; increase
Side effects
_______, in the past, have been the most commonly used immunosuppressant drug. However, their use is being reduced due to the ____________ associated with them.
Steroids
adverse side effects
All current immunosuppressive drugs come with limitations.
One of the major limitations of these drugs is ______________.
As these immunosuppressive drugs are non-specific, they will reduce ______________ function leaving patients susceptible to opportunistic infection.
immunodeficiency
overall immune system
Additionally, many of these Immunosuppressive drugs are associated with adverse side effects, such as high __________, impaired _____ function, diabetes mellitus, and increased risk of _______ – to name just a few.
Patients are required to take a (small or large?) number of immunosuppressants each day for the rest of their lives, which can have a major impact on their health and lifestyle.
blood pressure; renal
cancer; large
Immunosuppressive drugs
A fine balance needs to be reached between _______________________ sufficiently to avoid rejection, preventing __________ , and maintaining __________________________.
suppressing immune function
drug toxicity
enough immune function to fight off disease
Future transplant therapies
Stem cells could have a major impact on ________ in the future beyond their current use in treating ____ disorders.
Pluripotent stem cells have the capacity to mature into any cell in the body, and this ability can be harnessed to _________________.
Moreover, the discovery that other cell types can be induced to _____________ means that the cells used to make the tissue could come _______________, thus circumventing the risk of rejection.
transplantation; blood
grow tissues and organs
have stem cell capacities
directly from the recipient themselves
Another future approach is the manufacture of organ scaffolds using _____________ and then __________ around these scaffolds to ____________ the tissue being replaced.
Bio- manufacturing of tissues and organs would not only ______________, if the patient’s own stem cells were used, but would also reduce the ____________________
3D printing
growing stem cells
artificially replicate
reduce the risk of transplant rejection
strain on the limited organ supply.
