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