transplantation

Dr. Ahmed Adil Immunology 3rd class-college of Medicine
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Transplantation
Transplantation is a widely used treatment for replacement of nonfunctioning
organs and tissues with healthy organs or tissues. It is the process of taking cells,
tissues or organs called graft from one individual (Donor) and placing them into a
usually different individual (Recipient).If the graft placed in its normal anatomic
location,this is called Orthotopic transplantation and if it is placed in different
location called Heterotopic transplantation.
The success of tissue and organ transplants depends on the donor s and recipient s
human leukocyte antigens (HLA) encoded by the HLA genes which are highly
polymorphic among members of the same species. If the HLA proteins on the
donor s cells differ from those on the recipient s cells, an immune response occurs
in the recipient and transplantation fails.
An autograft (transfer of an individual s own tissue to another site in the body) is
always permanently accepted, it always "takes" A syngeneic graft is a transfer of
tissue between genetically identical individuals, i.e., identical twins, and almost
always "takes" permanently. A xenograft , a transfer of tissue between different
species, is always rejected by an immunocompetent recipient.
An allograft , is a graft between genetically different members of the same species,
e.g., from one human to another.
Dr. Ahmed Adil Immunology 3rd class-college of Medicine
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Allograft Rejection
Allografts are usually rejected by a process called the allograft reaction unless the
recipient is given immunosuppressive drugs. The severity and rapidity of the
rejection will vary depending on the degree of the differences between the donor
and the recipient at the MHC.
The acceptance or rejection of a transplant is determined by the class I and class II
MHC proteins on the donor cells, with class II playing the major role.
In addition to the MHC encoded by the HLA genes, there are an unknown number
of minor antigens encoded by genes at sites other than the HLA locus.
These minor antigens can induce an immune response that can result in slow
rejection of a graft. The cumulative effect of several minor antigens can lead to a
more rapid rejection response.
Dr. Ahmed Adil Immunology 3rd class-college of Medicine
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Recognition of alloantigen ( MHC in graft) by recipient T cells
Allogeneic MHC molecules of a graft can be presented for recognition by the
recipient T cell (alloreactive T cell) in two ways:
1- Direct recognition of alloantigens proteins.
In which T cells of the recipient recognize the intact ,unprocessed MHC
molecules in the graft as foreign Ag. This seems to be puzzling because T cells can
recognize Ags only when they are presented in association with MHC (MHC
Restriction).The only accepted explanation is MHC molecules are normally
contain bound peptides to which contributes that alloreactive T cells can recognize
graft MHC directly.
2- T cells of the recipient can recognize the graft MHC molecules only in the
presenting allogeneic graft MHC to recipient T cells) and it looks as the same as
foreign Ag. Minor histocompatibility Ag can also be presented to the recipient T
cell.
Regardless of which pathway, the initial immune response occurs in lymph nodes
draining the graft . APCs carrying the allogeneic Ag. must migrate from the graft
to lymph nodes.
Dr. Ahmed Adil Immunology 3rd class-college of Medicine
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The alloantigens activate T cells, both helper and cytotoxic, which bear T-cell
receptors specific for the alloantigens , but CD8+ cytotoxic T cells do most of the
killing of the allograft cells.
Foreign MHC proteins (graft) typically activate many more T cells (they elicit a
much stronger reaction) than do foreign proteins that are not MHC proteins like a
microbial Ags this is because:
1-Allogeneic MHC(donor) on the surface of APC may combine with different
cellular peptides of the donor. Since there are thousand different types of MHC
types, the peptide –MHC complex will looks different types to recipient TCR .
2-The donors self-proteins , MHCI and MHCII can shed and subsequently
processed by recipient APC.
3-APC of the graft can present the recipient’s protein and activate the immune
response (because the recipient s proteins are recognized as foreign when presented
by a foreign MHC protein).
Dr. Ahmed Adil Immunology 3rd class-college of Medicine
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4-Many of T cells that respond to allogeneic MHC are memory T cells even in first
exposure , because of antigenic mimicry between the allograft Ags and the Ags of
some microbes that previously infected the recipient.
Activation of alloreactive B cells &production of alloantibodies :
Abs against the graft Ags also contribute to rejection. The most recognized Ag by
alloantibodies(recipient) are the donor HLA including both MHCI &MHCII
proteins .The sequence of producing alloantibody is following the classical
antibody that B cell recognize foreign MHC ,internalize and processed these
proteins and present them to TH cells and subsequently activate more B cells and
plasma cells to produce Abs against the graft that have the same effect of antibody
against foreign Ags like activation of complement system, activation of PMN &
Macrophages and NK cells through Fc receptor.
Graft –Versus –Host Reaction (GVH)
Graft may be rejected due to the immune response of the donor grafted organ
against host foreign Ags, e,g., in bone marrow taransplant.
This reaction occurs because grafted immunocompetent T cells proliferate in an
immunocompromised host and reject cells with "foreign" proteins, resulting in
severe organ dysfunction. The donor s cytotoxic T cells play a major role in
destroying the recipient s cells and many GVH reactions end in overwhelming
infections and death.
There are three requirements for a GVH reaction to occur:
(1) The graft must contain immunocompetent T cells
(2) The host must be immunocompromised
Dr. Ahmed Adil Immunology 3rd class-college of Medicine
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(3) The donor T cells recognize the recipient MHC proteins as foreign.
A Fetus Is an Allograft that Is Not Rejected:
A fetus has MHC genes inherited from the father that are foreign to the mother, but
allograft rejection of the fetus does not occur in spite of The mother forms
antibodies against the foreign paternal MHC proteins; therefore, the reason is not
that the mother is not exposed to fetal antigens. One possible explanation is that the
trophoblast layer of the placenta does not allow maternal T cells to enter the fetus.
Immunopathology of allograft rejection:
1- In an acute allograft reaction, vascularization of the graft is normal initially, but
in 11–14 days, marked reduction in circulation and mononuclear cell infiltration
occurs, with eventual necrosis. This is called a primary (first-set) reaction.
A T-cell-mediated reaction is the main cause of rejection of many types of grafts,
e.g., skin, but antibodies contribute to the rejection of certain transplants, especially
bone marrow.
2- If a second allograft from the same donor is applied to a sensitized recipient, it is
rejected in 5–6 days. This accelerated (second-set) reaction is caused primarily
by presensitized cytotoxic T cells (CD8).
3- Hyperacute rejection can occurs within minutes of engraftment due to the
reaction of preformed anti-ABO antibodies in the recipient with ABO antigens on
the surface of the endothelium of the graft. Hyperacute rejection is often called the
"white graft" reaction, because the graft turns white as a result of the loss of blood
supply .