00:01
Rejection can be due either to a direct
or an indirect alloantigen recognition.
00:11
In direct alloantigen recognition,
the allogeneic antigen presenting
cell in the graft shows the allogeneic
MHC to a alloreactive T-cell.
00:29
The T-cell in the recipient recognizes unprocessed
allogeneic MHC molecules on the graft APC.
00:38
So the graft from the donor will most
often have some foreign MHC molecules.
00:47
It’s almost impossible to completely match between the
donor and the recipient across all of the MHC molecules.
00:55
Remember there will be six different MHC
Class I’s, six different MHC Class II’s.
01:03
So matching perfectly is incredibly
difficult and incredibly rare.
01:09
So usually there will be this recognition of
allogeneic MHC, and here we see it occurring in a
direct way where the recipient’s T-cells directly
recognize the foreign MHC on the donor cells.
01:26
There is also indirect alloantigen
presentation which occurs.
01:33
This is due to uptake and processing of the allogeneic MHC
molecules by the recipient’s antigen presenting cells.
01:44
And peptides derived from the allogeneic MHC
molecule are shown to the T-cells in the recipient.
01:52
So there is presentation of processed
peptide of the foreign allogeneic
MHC molecule bound to the recipient’s own self MHC molecules.
02:04
So fragments of the foreign MHC being shown by the
recipient’s MHC to the T-cell receptor on their T-cells.
02:14
And both of these processes take place following
transplantation unless there is an absolutely perfect match.
02:22
Let us now look at the activation
of alloreactive T-cells.
02:27
There will be a sensitization phase,
where the donor dendritic cells
and recipient dendritic cells will
show donor alloantigen to T-cells.
02:42
There’ll be transport of those alloantigens
to the lymph nodes with activation of T-cells.
02:49
The generation of effector T-cells
in the recipient by both the direct
and indirect antigen presentation
pathways that we’ve just explored.
03:01
And both recipient CD4 T-cells and recipient
CD8 T-cells will become activated.
03:11
Those recipient effector T-cells
can then migrate to the allograft.
03:18
And there will be activation of the effector T-cells by
alloantigens, by foreign antigens from the donor tissue.
03:27
And this can result in graft rejection with
killing of target cells and cytokine secretion.
03:36
Let’s have a look in a little bit more detail at the
precise events in the immunological rejection of a graft.
03:44
And we’re going to use a
liver graft as an example.
03:47
So there’ll be both donor and
recipient antigen presenting cells.
03:51
And in the presence of co-stimuli, Th0 cells can be
differentiated into other populations of T-cells.
04:00
These will include T-regulatory
T-cells that can be produced, and
would actually be beneficial in
preventing the rejection of the graft.
04:11
But the balance overall is towards the generation
of T-cells that contribute towards graft rejection.
04:18
In the presence of interleukin-12, Th0
cells will differentiate into Th1 cells.
04:26
These Th1 cells produce gamma
interferon which cause the upregulation
of MHC Class I and MHC Class II molecules on the donor cells.
04:38
Interleukin-2 is also produced by Th1 cells,
which will cause the activation of cytotoxic
T-lymphocytes, which can recognize peptides
presented by the MHC Class I molecules.
04:51
Gamma interferon from Th1 cells will cause activation of
macrophages with the secretion of the cytokines IL-1 and TNF-α.
05:04
These cytokines are pro-inflammatory and will
contribute towards the rejection process.
05:10
Interleukin-4 will cause Th0 cells
to differentiate into Th2 cells
which secrete interleukin-4, interleukin-10 and interleukin-13.
05:23
These help activate B-cells to differentiate
into plasma cells and to secrete antibodies.
05:31
Natural killer cells can then
recognize the antibody coated donor
cells, and mediate ADCC (antibody
dependant cellular cytotoxicity).
05:45
Complement can also bind to these
antibodies and become activated via
the classical pathway, and again
contribute towards the graft rejection.
05:56
Here we can see the acute rejection
in a heart transplant recipient.
06:01
There is a cellular infiltrate of
both lymphocytes and macrophages.