IMMUNOLOGY OF TRANSPLANT

REJECTION
(Dr. Al-Farah)
Learning objectives
 Define Major Histocompatibility Complex (MHC).
 Classify MHC proteins.
 Define transplantation.
 Discuss the importance of MHC in transplantation.
 Define allograft rejection.
 Classify types/patterns of transplant rejections.
 Discuss HLA typing in the lab in association with transplantation.
Introduction: MHC Molecules

 When disease associated proteins occur in a cell they are broken into pieces
by the cells proteolytic machinery. Cell proteins become attached to antigen
fragments and transport them to the surface of the cell, where they are
"presented" to the bodies defence mechanisms. In every cell in your body,
antigens are constantly broken up and presented to passing T cells
 These transport molecules are called the Major Histocompatibility Complex
(MHC) proteins. Without these, there would be no presentation of internal or
external antigens to the T cells.
 The importance of MHC proteins is that they are present on every cell of a
body and allow T cells to distinguish self from non-self.
Introduction: MHC Molecules
Major Histocompatibility Complex (MHC)

 In humans the MHC molecules are called human leukocyte antigens (HLA).
 MHC molecules are membrane- bound proteins. Recognition by T cells requires
cell-cell contact
 The function of MHC molecules is to display peptide fragments of protein
antigens for recognition by antigen-specific T cells.
 Summary: Significance of the
MHC

1. Role in immune response

The T Cell Receptors can only recognize and bind a peptide antigen if the antigen
(pathogen) is bound first to “self” proteins i.e. MHC proteins otherwise no immune
response can occur.

2. Role in predisposition to disease

Particularly in autoimmune diseases.

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Significance of the MHC

2. Role in organ transplantation

 The success of organ transplants is, in large part, determined by the
compatibility of the MHC genes of the donor and recipient.
 The role of MHC, therefore, is particularly important in organ transplantation,
where non-self, normally allogeneic organs from one individual are
transplanted into another individual. Antigen presentation by MHC can
initiate various types of immunological rejection of transplants.
 The combination of HLA alleles in each individual is called the HLA
haplotype. Any given individual inherits one set of HLA genes from each
parent and expression of these genes is codominant (i.e., the proteins encoded
by both the paternal and maternal genes are produced).

 The HLA system is highly polymorphic, meaning that there are many alleles of MHC
genes (in the thousands) in humans AND no two individuals (other than identical twins)
are likely to express the same MHC molecules, and therefore grafts exchanged between
these individuals are recognized as foreign and attacked by the immune system
 Among siblings in a single family, there is a 25% chance for both haplotypes to be
shared, a 50% chance for one haplotype to be shared, and a 25% chance for no
haplotypes to be shared.
 Types of MHC proteins

 The genes encoding HLA molecules are clustered on a small

segment of chromosome 6

Types of MHC molecules:

 On the basis of their structure, cellular distribution and function,
MHC gene products are classified into two major classes.
• Class I MHC molecules
• Class II MHC molecules
STRUCTURE Major Histocompatibility complex proteins

Class I MHC proteins are Class II MHC proteins are only

found on the surface of ALL found on the surface of
nucleated cells B lymphocytes, macrophages
and other antigen presenting cells

ALL MHC proteins are embedded in the cytoplasmic membrane of

cells and project outward from the cell surface
Comparison of MHC class1 & MHC class 2
Transplantation
 Transfer of living cells, tissues and organs from one part
of the body to another or from one individual to another is
called Transplantation

 Organ transplantation is a medical procedure in which

an organ is removed from one body and placed in the
body of a recipient, to replace a damaged or missing
organ
 Graft : Implanted cell, tissue or organ

 Donor : Individual who provides the graft

 Recipient or host : Individual who receives the graft

 Self tissue is transferred from one body site to another
 Antigen present in autograft is same as that present in body; so immune system
recognizes the autograft antigen as a self antigen No immune response
is elicited.

 Autograft survive throughout the life.

 E.g., - Transferring healthy skin to burned area,
- Use of healthy blood vessels to replace blocked coronary arteries,
- Plastic surgery of skin
 It is also called Syngeneic graft
 Tissue is transferred between genetically identical individuals of
same species.
 In isograft the histocompatibility antigens are identical hence the
graft survives and not rejected.
 E.g, In human isograft can be performed between two twins.
 Also called homograft.
 Tissue is transferred between two genetically different members of
same species
 In allograft histocompatibility antigens are dissimilar (degree of
difference could be from mild to severe) hence immune response is
elicited and graft is rejected
 Allografts are usually rejected unless the recipient is given
immunosuppressive drugs.
 E.g, In humans graft is transferred from one
individual to another
 Also called Heterograft
 Tissue is transferred between two different species
 In xenografts histocompatibility complex antigens are so
different that the graft is more vigorously rejected
 E.g., Porcine (pig) heart valve transplant to humans.
Transplant Rejection

 A major barrier to transplantation is the process of

rejection, in which the recipient’s immune system
recognizes the graft as being foreign and attacks it.

 Rejection is a process in which T lymphocytes and

antibodies produced against graft antigens react
against and destroy tissue grafts.
 The Immunology of Allogeneic Transplantation

The allo-reactive immune response is directed against transplantation

antigens .
Transplantation antigens
 Major transplantation antigens are MHC proteins

 Minor transplantation antigens are various normal body proteins that

have one or more amino acid acid differences from one person to
another
 Blood group antigens
Recognition of Alloantigens
 Direct Presentation
 Recognition of an intact MHC molecule displayed by donor APC in the graft

 Basically, self MHC molecule recognizes the structure of an intact allogeneic

MHC molecule
 Involves both CD8+ and CD4+ T cells
 Indirect Presentation
 Donor MHC is processed and presented by recipient APC

 Basically, donor MHC molecule is handled like any other foreign antigen

 Involve only CD4+ T cells.

 Antigen presentation by class II MHC molecules.

 The percentage of T cells activation that can recognize the
foreign antigens in a graft is much higher than the
percentage of T cells specific for any microbe or any
foreign proteins.

 IL – 2, IL – α, IFN – , and TNF -  are important

mediators of graft rejection.
 Used by immune system to reject allograft
 It is based on histopathological features or time duration of
rejection after transplantation

 There are three type of pattern

1. Hyperacute Rejection
2. Acute Rejection
3. Chronic Rejection
 Graft is irreversibly rejected within minutes to hours because vascularization is rapidly
destroyed. (Uncommon because of pretransplantation screening).
 Cause: It occurs because the recipient has pre-existing antibodies in circulation against
the graft due to ABO incompatibility, multiple pregnancies, prior transplantation, or
xenografts.

 Pathogenesis: Type II Hypersensitivity involving Ag-AB complexes that activates

complement system that targets the endothelium of small vessels; resulting in
thrombosis and fibrinoid necrosis and followed by ischemic necrosis of the transplanted
organ.
 The kidney is most susceptible to hyperacute rejection.
1) Preformed Ab,
2) complement activation,
3) Neutrophil margination,
4) Inflammation,
5) Thrombosis formation
 Most common transplant rejection.
 Definition—reversible reaction that occurs usually within days or weeks after a transplantation
 Combination of a Type IV and type II hypersensitivity reaction
 Vasculitis is a prominent feature. It is mediated by antidonor antibodies that attack the vessel wall, with subsequent
thrombosis and thickening of the arterioles. Vascular changes cause an ischemia of the transplanted organ.
 Interstitial accumulation of lymphocytes is a prominent feature. It is associated with parenchymal cell injury (e.g.,
tubular epithelium of kidneys or myocytes in the heart).
 Usually begin after the first week of transplantation if there is no immunosuppressant therapy
 Definition—irreversible reaction that occurs over months to years,
usually in patients that have survived acute rejection due to
immunosuppression therapy
 Occurs in most solid organ transplants
o Heart

o Kidney

o Liver

 Main pathologic findings related to release of cytokines by CD4 T cells

include:
 Atherosclerosis & proliferation of smooth muscle cells and fibroblasts
 Artherosclerosis
 Cell proliferation
 Concentric medial hyperplasia
 Occlusion
HLA TYPING IN THE
LABORATORY
 HLA Typing in the Laboratory
 Prior to transplantation surgery, laboratory tests, commonly called HLA
typing or tissue typing, are performed to determine the closest MHC match
between the donor and the recipient.

Methods used in the laboratory

1. DNA sequencing
 Highly specific and sensitive, use polymerase chain reaction (PCR)
amplification and specific probes to detect the different alleles.

2. Serologic assays
 Satisfactory in most instances but has failed to identify certain alleles, cells
from the donor and recipient are reacted with a battery of antibodies.
 HLA Typing in the Laboratory
3. Mixed lymphocyte culture (MLC) technique
 Peripheral blood lymphocytes from two individuals are mixed together in tissue
culture for several days. Lymphocytes from incompatible individuals will stimulate
each other to proliferate significantly (measured by tritiated thymidine uptake)
whereas those from compatible individuals will not.
HLA Typing in the Laboratory
4. Cross-matching
 Preformed cytotoxic antibodies in the Recipient’s serum

reactive against the graft are detected by observing the lysis

of Donor lymphocytes by the recipient’s serum plus
complement.
 Crossmatching is done to prevent hyperacute rejections from

occurring. Also include ABO blood group compatibility test

 Blood grouping
 Cytotoxic antibody testing
 Tissue matching
 Immunosuppressive measures (e.g., cyclosporine,
tacrolimus, sirolimus [rapamycin, Rapamune],
corticosteroids, azathioprine, monoclonal
antibodies, belatacept, and radiation)
THANK YOU