Transplantation

TRANSPLANTATION
SUBMITTED BY:
MUGDHA SHARMA
2084044
MSC. BIOTECH 2ND SEM
SUBMITTED TO:
Dr. SAMRITI DHAWAN

TOPICS
• Introduction
• History
• Clarification of grafts
• Transplantational Antigens
• Role of MHC in Transplantation
• Immunology of Allogeneic Transplantation
• Types of Graft Rejection
• Immunology of Xenogeneic Transplantation
• Organ Transplantation

Introduction
• Transplantation is the process of taking tissues or
organs (or even cells) and placing them into the
same or different individual.
• GRAFTS: The tissues, organs or cells(viable tissue
organ or cell) that are transferred from one
individual to another .
• DONOR: The individual who donates the graft.
• RECIPIENT: The individual who receives the
graft.
https://images.app.goo.gl/MQxWFMSWR8T5y5xR7

HISTORY
Peter
Medawar
Father of
transplantation
Joseph E. Murray
First successful
identical twin
transplant of a
human kidney, in
1954
Dr. Thomas E.
Starzl
First successful
liver transplant, in
1967
E. Donnall
Thomas
First successful
bone marrow
transplant, in
1968
Christain
Banard
First heart
transplantation, in
1967
Skin rejection
allograft 1944
Source: google photos

Classificationof grafts
(on the basis of their origin & identity of recipient)
Autograft
Autologous graft
ISOGRAFT
Syngenic graft
ALLOGRAFT
Allogeneic graft
XENOGRAFT
Xenogeneic graft
These are graft
transplants
from one region
to another on
the same
individual.
• It involves the
transfer of graft
between genetically
identical (syngenic)
individuals of the
same species.
• Possible between
genetically identical
twins or genetically
identical mice.
A graft
transplanted
between two
genetically non-
identical
individuals of
the same
species
These are graft
transplants
between
individuals of
different
species

Autograft Isograft Allograft Xenograft
https://pathologia.ed.ac.uk/topic/transplantation-immunology/

TRANSPLANTATIONANTIGEN
• These are those antigens (proteins) that are present on cells (or tissue surface) and are
responsible for either the acceptance or the rejection of the graft
• These antigens induce the immune response in the host that may cause the rejection of the
transplanted tissue
• Graft is permanently accepted only when essentially all of its transplantation antigens
(such as histocompatibility antigens) are present in the recipient.
• Graft having transplantation antigens that are different from the transplantation antigens
of the recipient, an immune response that leads to the rejection of the graft takes place.
• The molecules that are recognized as foreign (antigen) on an allograft are referred to as
alloantigens
• The molecules present on a xenograft are called xenoantigens.
• Autograft and isograft survive because they evoke little or no immune response whereas
allograft and xenograft are rejected under normal conditions.

Autografts and isografts are usually accepted,
owing to the genetic identity between graft and
host
An allograft is genetically dissimilar to the host,
it is often recognized as foreign by the immune
system and is rejected.
Xenografts exhibit the greatest genetic disparity
and therefore engender a vigorous graft rejection.
Source: The Elements of Immunology – Fahim Halim Khan

• The transplantation antigens are products
of genes called histocompatibility genes
• One set of histocompatibility genes, called
major histocompatibility complex (MHC)
genes, specify the cell surface molecules
that elicit the most rapid allograft rejection.
The MHC antigens are termed as human
leukocyte antigen or HLA complex in humans
(the genes of which reside on chromosome 6)
and H-2 complex in mice (located on
chromosome 17).
https://youtu.be/t9TvTmddanE

• MHC proteins are cell surface transmembrane
glycoproteins that are present on all host cells and are
involved in interaction with the cells of immune system.
• MHC genes are inherited from both parents and are
expressed codominantly.
• Transplantation is governed mainly by allogenic differences
in histocompatibility antigens (HLAs) between donor and
recipient.
• Genes for HLA are located in the MHC on chromosome 6.
• Class 1 and Class 2 HLA genes exhibit enormous
Polymorphisms
• Class 1 antigens are found on all nucleated cells. Present
antigenic peptides to CD8+ cells.
• Class 2 antigens are found on macrophages, dendritic cells,
B cells. Present antigens to CD4+ cells.
• Matching the donor and recipient at the HLA locus
improves graft acceptance.
Human MHC on the short arm of
chromosome 6

theroleofMHCin transplantation.
Source: The Elements of Immunology – Fahim Halim Khan

• MHC genes are inherited from both parents
and are expressed codominantly.
• Co-dominant expression means that animals
of F1 generation of A and B (A × B) will
express both A-strain and B-strain alleles
• This conclusion is based on the result of
experimental transplantation between
inbred strains of mice.
• Grafts between individuals of the same
inbred strain of species are always accepted.
• Grafts of tissues or organs between
individuals of genetically diff erent inbred
strain of same species of mice are always
rejected.
• Inbred strain (A × B) will never reject graft s
from either parents (A or B). This is because
A × B animals see both A and B tissues as
self.
Grafts between individuals of the same inbred strain of
species are always accepted.
Grafts of tissues or organs between individuals of genetically diff
erent inbred strain of same species of mice are always rejected.

If an inbred mouse of strain A is grafted with skin from strainB,primary graft rejection, known as first-set rejection
Immunologic memory is
demonstrated when a second
strain-B graft is transferred to a
previously grafted strain A mouse
a graft-rejection reaction develops
more quickly, with complete
rejection occurring within 5–6
days;this secondary response is
designated second-set rejection
The skin first becomes revascularized between days 3 and 7; as the reaction develops, the vascularized transplant
becomes infiltrated with lymphocytes, monocytes, neutrophils, and other inflammatory cells
There is decreased vascularization of the transplanted tissue by 7–10 days, visible necrosis by 10 days, and complete
rejection by 12–14 days
https://youtu.be/4E4K5jeAkR0

IMMUNOLOGY OF A L LOG E N E I C TRANSPLANTATION
• Immune response to alloantigens of a graft can be both
cell-mediated and antibody-mediated
• T-cell responses and antibodies are more important for the
rejection of transplanted grafts

PresentationofallogeneicMHCtoTcells
MHC, which are expressed on allogeneic tissues……ALLOGENEIC MHC
MOLECULES
are presented to host T cells in two different ways;
DIRECT PRESENTATION INDIRECT PRESENTATION
Intact allogeneic MHC molecule
plus foreign peptides are directly recognized by
self-T cells in direct presentation.
Processed allogeneic MHC is
recognized by host T cells in an
indirect presentation.

• Self-T cells selected recognize and respond to self-MHC molecule plus foreign peptide.
• Some of these T cells, can cross-react with foreign MHC plus foreign peptide displayed
on donor cells and elicit a T-cell response.
• The same TCR which recognizes self-MHC plus foreign peptide may also recognize one
or more (foreign) allogeneic MHC molecules
DIRECT PRESENTATION
• Recognition of an intact MHC molecule
displayed by donor APC in graft.
• All allogeneic MHC molecule with
bound peptide can mimic that
determinant formed by a selfMHC
molecule plus peptide.
Involves the recognition of intact MHC molecules (together with associated
peptides)displayed on allogeneic donor cells.
https://marlin-prod.literatumonline.com/cms/attachment/cf8540f5-b9a9-4231-b902-28d32a64726d/gr1_lrg.jpg

A T-cell receptor normally recognizes self-MHC plus foreign
peptide.
• Allogeneic MHC molecules together with bound peptides
mimic the structure of self-MHC + foreign peptide.
• the host T cells elicit a strong immune response leading to
graft rejection.
• This recognition of allogeneic MHC–peptide complex by T
cells, results from the fact that T cells that can respond to self-
peptide + allogeneic MHC are not entirely removed from the
T-cell repertoire and hence respond to the allograft
Each allogeneic MHC molecule may be recognized by and
responded to by many different TCR molecules on different T
cells in vivo
As many as 2% of an individual’s T cells are capable of directly
recognizing & responding to a single foreign MHC molecule.
The Elements of Immunology – Fahim Halim Khan

INDIRECT PRESENTATION
• Involves the processing of a donor’s MHC protein molecules by the recipient’s antigen-
presenting cells and their subsequent display with self-MHC.
• This self-MHC + foreign peptides (derived from donor MHC) present the antigen to self-T
cells.
• MHC molecules are processed like any other foreign peptide (through the endosomal
pathway) and presented on the antigen-presenting cell surface together with class II MHC
molecules.
https://marlin-prod.literatumonline.com/cms/attachment/cf8540f5-b9a9-4231-b902-28d32a64726d/gr1_lrg.jpg

• This presentation of alloantigens occurs usually by class
II MHC molecules and hence TH cells of the host are
stimulated, though cross-priming of Tcyt cells
• Some alloantigens can enter the class I MHC pathway in
antigen-presenting cells.
• Experiments in class II MHC knockout mice have
confirmed the indirect presentation of alloantigens.
• These mice express only class I MHC molecules on their
cells. Skin grafts from mice that express only class I
MHC molecules have activated the recipient’s TH cells
and B cells, apart from Tcyt cells.
• These results imply that class I MHC molecules are
taken up by the recipient’s antigen-presenting cells,
which process and present them to THcells, apart from
other cells.

T-CELLRESPONSETOALLOANTIGENSINVITRO:
MIXEDLEUKOCYTEREACTION
• Graft rejection is often a T-cell mediated response and we can actually see if the donor cells
can activate recipient T cells to divide.
• The mixed leukocyte reaction (MLR) is a useful in vitro model of T-cell recognition of
allogeneic MHC gene products and is used as a predictive test of cell-mediated graft
rejection or acceptance.
• MLR is induced by incubating cultured mononuclear leukocytes (which include T cells, B
cells, NK cells, phagocytes and dendritic cells) from the donor with mononuclear leukocytes
derived from the recipient.
“If two individuals have a difference in alleles of MHC and hence are incompatible for transplants, a
large proportion of mono-nuclear cells will be stimulated to divide over a period of 3-7 days.”
proliferative response indicates that the recipient will react to allogeneic antigen
not suitable for transplantation.

Histocompatibility is inversely proportional to the clonal expansion of lymphocytes in the MLR.
MLR
One-way MLR Two-way MLR
one-way MLR, treated donor cells serve exclusively as
stimulator cells and recipient cells as responder cells.
In two-way MLR, mononuclear leukocytes from a donor
and a recipient are mixed in culture and both sets of
leukocytes proliferate.
Donor leukocytes are prevented from proliferating by γ-
radiation/treatment with an antimitotic
drug such as mitomycin C.
These donor cells which now cannot undergo mitosis
are then incubated with recipient leukocytes.

If recipient cells respond,
CD8+ T cells differentiate into Tcyt cells specific for allogeneic MHC, and
CD4+ T cells differentiate into TH cells of both TH1/TH2 types that secrete cytokines.
The responding T cells recognize specific MHC molecules on the stimulator cells.
Tcyt cells recognize class I MHC molecules on stimulator cells namely;
• HLA-A, HLA-B and HLA-C in humans.
• H-2k, H-D or HL in mice.
TH cells, stimulated in allogeneic MLR are specific for;
• class II MHC molecules I-A and I-E in mice.
• HLA-DP, HLA-DR and HLA-DQ in humans.
• The stimulation of T cells in an MLR reaction requires both MHC–peptide complex and its
costimulating signal.
• The full differentiation of Tcyt cells requires stimulation by allogeneic class I molecules, as well
as costimulators of antigen-presenting cells or cytokines by TH cells.
• Full activation, proliferation and differentiation of CD4+ T cells can be induced only by
professional antigen-presenting cells that express allogeneic class II MHC molecules and also
provide costimulatory signal

CELL MEDIATED RESPONE TO
ALLOGRAFTS IN VIVO
• MHC molecules play a central role in initiating graft rejection (or acceptance) in
vivo.
• MHC molecules are presented by both direct and indirect pathways of allogeneic
presentation.
importanceofMHCmoleculesin allograftrejectionwas established by the fact that graft s between congeneic
strains of inbred mice were rejected when strains diff ered only in class I or class II MHC
alleles but not other genes.
Donor and recipient APCs are likely to be involved in graft rejections.
Mostimportantantigen-presentingcellsarelikelytobe
dendriticcells

• Donor antigen-presenting cells may stimulate T cells entering the graft through the blood
supply.
APCs T CELLS
• Alternatively, a donor’s antigen-presenting cells may migrate from the graft into the lymph and
reaching lymph nodes, where they activate naïve alloreactive T cells by direct presentation of
allogeneic MHC.
APCs GRAFT LYMPH LYMPH NODES NAÏVE ALLOREACTIVE T CELLS
Antigen-presenting cells of the graft that pass into the host are called passenger leukocytes.
• Similarly a recipient’s antigen-presenting cells may enter
the graft and pick up donor alloantigens or alternatively
the recipient or host antigen-presenting cells may also
pick alloantigens entering lymphoid tissues, process them
and present them to alloreactive T cells.
• However, the donor antigen-presenting cells may or may
not play a vital role in graft rejection.
Stimulates
Activates

TYPESOF GRAFTREJECTION
Hyperacute
graft rejection
Acute graft
rejection
Chronic graft
rejection
Graft vs host
disease
https://www.stomponstep1.com/transplant-rejection-hyperacute-acute-chronic-graft-versus-host/

HYPERACUTE GRAFT REJECTION
The hyperacute rejection mechanism is initiated by pre-existing antibodies.
• Hyperacute graft rejection occurs almost immediately after transplan-
tation, usually within 24 hours.
• This rejection is either due to preformed anti-MHC antibodies, natural
antibodies to blood type antigens, or those antibodies that are formed in
response to previous blood transfusions or previous transplants or
developed during pregnancy to the baby’s paternal MHC antigens.

pre-existing antibodies against the donor’s endothelial antigens enter the
graft
antibodies bind endothelial antigen
Complement activation and damage toendothelial cells
damaged endothelial cells secrete the Von-Wil-lebrand factor
mediates platelet adhesion and aggregation
process of platelet aggregation and the loss of anticoagulating factor
from endothelial cells contributes to thrombosis and vascular occlusion
depriving the graft of blood supply and leading to irreversible
ischaemic damage to the graft

ACUTE REJECTION GRAFT
Acute rejection usually begins after the first week of transplantation.
• It is mediated primarily by effector T cells, though macrophage
activation and antibodies also play a role.
• Within the T-cell response, both TH and Tcyt cells may contribute
to acute rejection.
Acute rejection is mediated by T cells.
• T-cell response occurs to responding alloantigens, including MHC molecules, alloantigens on
vascular endothelium cell as well as on other cells of the graft . Since, it takes a few days to
generate effector T cells (as well as B cells), acute rejection starts aft er a week of transplantation.
• The activated Tcyt cells cause direct lysis of graft cells,
• TH-cell-generated cytokines recruit and activate inflammatory cells such as macrophages which
cause necrosis.
• An acute rejection shows histologically different patterns as compared to a hyperacute rejection.
Acute rejection is characterized by necrosis of graft vessel walls, with acute inflammation which
is distinct from the thrombotic blocking of blood vessels without necrosis of blood vessel wall
observed in hyperacute rejection.

1. Alloreactive Tcyt cells directly lyse graft
endothelial cells.
2. Alloreactive TH cells summon and activate
mac-rophages and initiate grafted tissue
injury by delayed-type hypersensi-tivity.
3. Alloreactive antibodies bind to the
endothelium.
4. Activate the complement pathway.
5. Injure graft blood vessels.

CHRONIC GRAFT REJECTION
Chronic rejection of an allograft is a slow process taking months or years
Chronic rejection may be cell-mediated or antibody mediated.
When mediated by antibodies, antibodies alone or an antigen–antibody complex may
cause damage to grafted tissue leading to graft rejection.
The main feature of chronic
rejection is the thickening of blood
vessel walls which eventually get blocked
Graft arteriosclerosis
Graft arteriosclerosis is the blocking of an artery due to smooth
muscle proliferation and production of collagen by fibroblasts.
This process results in fibrosis which can cause ischeamia and
cell death.
Chronic rejection is characterized by fibrosis with loss of normal organ structures.
Some scientists suggest that chronic rejection is a form of delayed-type hypersensitivity.

smooth muscle proliferation of the intima of blood vessels, is induced by
cytokines secreted by lymphocytes
cytokines, particularly IFN-γ, stimulate macrophages
secrete platelet derived growth factor (PDGF) and
transforming growth factor-β (TGF-β)
TGF-β induces smooth muscle proliferation (which causes graft
arteriosclerosis)
PDGF induces fibroblast proliferation
Fibrosis is the result of fibroblast proliferation and secretion of
collagen throughout the graft
The formation of scar tissue or fibrosis throughout the grafted
organ or tissue is another feature of chronic rejection.

G R A F T V E R S U S H O S T DISEASE (GVHD)
• GVHD reactions are an expression of T-cell function.
• GVHD reactions are usually directed against minor histocompatibility antigens.
• GVHD can also occur when other organs such as lungs, alimentary tract and liver (which
contains a number of T cells) are transplanted.
• GVDH could be:
Acute Chronic
• manifested as early as 8 to 10 days after
transplantation by a measles-like skin rash,
diarrhoea, gastrointestinal tract haemorrhage
and jaundice.
• Target organs: Liver, skin, gastrointestinal tract
• Causes; Necrosis
• manifests 3 months after
transplantation
• Target organs: Lver, gastrointestinal
tract, skin, lungs, without necrosis
• Causes: atropy & fibrosis

I MM UN O L O G Y O F X E NO G E NE I C T RA N S P L A
NT A T I O N
• The lack of availability of donor organs has led to the need of source of donor organs
has focused the attention on other mammals such as non-human primates, baboons,
chimpanzee, monkeys and pigs.
• The major immunologic barrier with xenotransplantation is that immune rejection is
quite vigorous even in the presence of immunosuppressive drugs.
• The immune reaction that results in xenograft rejection are:
1. hyperacute xenograft rejection,
2. delayed xenograft rejection and
3. acute T-cell-mediated rejection.

HYPERACUTE XENOGRAFT REJECTION
• Karl Landsteiner in 1901 was the fi rst to describe the existence of separate blood groups in humans.
• The naming A, B, AB and O of the blood groups was done by Von Dungren and Hirszfi eld in 1910.
• A vast majority of pig organ xeno-grafts are rejected because humans have natural anti-pig antibody against a
cell surface antigen that is analogous to the human blood group H antigen, but has galactose (pig) instead of
fucose (human).
• Xenograft rejection occurs mainly by hyperacute mechanism.
D E L A Y E D X E N O G R A F T R E J E C T I O N
• Even when hyperacute xenograft reaction is prevented by immunosuppressive therapy, xenograft are still rejected
within 4 to 5 days of transplantation. This form of rejection is called delayed xenograft rejection.
• Delayed xenograft rejection involves antibodies but not complement activation.
T - C E L L - M E D I A T E D X E N O G R A F T R E J E C T I O N
• Grafts from xenogeneic species such as pig induces a similar T-cell response as human allogeneic transplants
• Human T cells are activated by pig MHC molecules presented both by direct and indirect pathways. T-cell activation
leads to cell-mediatedrejection of xenografts.
• Pig tissues might contain retro-viruses called porcine endogenousretrovirus and there is a fear that these might infect
the human recipient.

ORGANTRANSPLANTATION
https://images.app.goo.gl/TSnoHLHacHU43bfR7
Organs transplants are usually performed when the organ is
damaged or dysfunctional and there is threat to the patient’s
life and there is always a sense of urgency associated with
transplantation.
HEART TRANSPLANTATION
• Heart damage due to various types of diseases, or congenital or acquired defect
in heart circuitry or valves necessitates heart transplantation.
• Heart transplantation is an option for patients suff ering from the end stage of
coronary heart disease, congenital heart disease or arrhythmia. The donor
heart is preserved in special freezers and transplanted within four to six hours.
• The release of electric impulse from the pacemaker could damage the isolated
heart. The recipient’s heart is removed and patient is kept alive wholly
artificially by a heart–lung machine that circulates and aerates the patient’s
blood till the donor heart is transplanted.
• Though tissue HLA matching is desirable.

LUNG TRANSPLANTATION
• Lung transplantation is performed on patients with
respiratory insufficiency or failure.
• All the donated lungs are from brain-dead, heart-
beating donors.
• Donors must be non-smokers of less than 65 years of
age.
https://images.app.goo.gl/oSabtZ19Bws8sc4R9
KIDNEY TRANSPLANTATION
• The kidney was the first solid organ to be transplanted.
• Kidney transplantation is per-formed usually within 48 hours as a donor kidney cannot be
stored for more thantwo days. About half of all the kidneys transplanted come from brain-
dead individuals.
• Cause: Wide variety of diseases such as glomerulonephritis, drug-induced nephritis and
various other types of kidney disability diseases such as diabetes.

two main problems associated with kidney transplant.
1. First, kidneys are always in short supply because of
lack of donors.
2. The second problem is the large number of sensitized
recipients
• Tissue-typing procedure is performed to ascertain
that the patient has no antibodies or active cellular
mechanism directed against the potential donor
kidney.
• This typing includes HLA typing and functional
assays such as MLR
LIVER TRANSPLANTATION
• After kidney, liver transplantation is the second most common solid organ transplantation.
• In this case, the ABO group and size of the liver of the donor and the recipient are matched.
• Liver damage can occur due to variety of reasons such as cirrhosis, exposure to virus as in viral
hepatitis or ingestion of harmful chemicals, chronic alcoholism, hepatocellular carcinoma and
fulminant hepatic necrosis. A damaged liver usually regenerates itself once the cause or causative
agent has been cleared. If the liver fails to regenerate, it has to be transplanted

• The majority of liver transplants are used as therapy for
congenital abnormalities of liver.
• A liver donor is a cadaver.
• Liver transplantation is not an easy task as the liver is
so extensively vascularized; it immuno-logically
resists re-implantation
• Liver transplantation undergoes acute rejection in 50
per cent of the cases.
https://images.app.goo.gl/CZTk48z4tJSTKYrs8
SKIN TRANSPLANTATION
• Skin cells may be grown in culture to form artificial skin.
• Skin, by the virtue of its rich vascular bed of blood
capillaries and lymphatics, is highly immunogenic.
• The grafted skin does not grow on the recipient but acts as
a biological dressing till the body grows its own skin
tissues.
• Skin grafts are replaced from time to time as their cellular
contents become no longer viable.
https://images.app.goo.gl/rCGSzzU6eVPGfv427

References
• The Elements of Immunology – Fahim Halim Khan
• Immunology – Kuby (6th edition)
• https://pathologia.ed.ac.uk/topic/transplantation-immunology/
• https://www.stomponstep1.com/transplant-rejection-hyperacute-acute-chronic-graft-versus-host/
• https://www.google.com/url?q=https://slideplayer.com/slide/256888/&usg=AOvVaw1Og3lLvFy8uo
vqgvkvbOoy
• https://www.researchgate.net/figure/Pathways-of-Recognition-of-Allogeneic-MHC-Molecules-and-
Mechanisms-of-Graft-Rejection_fig3_273061651
• https://youtu.be/t9TvTmddanE
• https://images.app.goo.gl/MQxWFMSWR8T5y5xR7
• https://images.app.goo.gl/rCGSzzU6eVPGfv427
• https://images.app.goo.gl/CZTk48z4tJSTKYrs8
• https://images.app.goo.gl/24hQ2LUmsK6LuJFQ7

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