This need to match the MHC between the donor and the recipient
necessitates tissue typing of the donor and the recipient.
This patient has developed renal failure
and needs a kidney transplant.
He has been typed for
HLA-A, HLA-B and HLA-DR.
And as we can see, this particular individual
is HLA-A2, A5, B7, B13 and DR2, DR1.
Here we have a number of different
patients that are awaiting a transplant.
They are placed on a
register with many others.
Each of whom are likely to have different
HLA types as shown on this slide.
When tissue typing occurs, a potential donor
is HLA typed and each kidney is sent to
a hospital where a good HLA match patient
is waiting to have the graft transplanted.
A blood sample from the donor
is also sent to the hospital.
In the cross match, donor B-cells are
mixed with recipient’s serum.
In this case, preformed antibodies
are binding the donor cells.
This transplant cannot take place.
However here we see that the recipient has no antibodies
against donor cells and the transplant can go ahead.
Preformed anti-donor antibodies can result from pregnancy,
blood transfusion, or indeed a previous transplant.
Let’s look at the mechanisms of
action of immunosuppressive drugs.
These are almost always required, because
it’s almost impossible to get an identical
match between the donor and the recipient
unless there is an identical twin.
There is almost always some
mismatch as regards the MHC.
Here we can see an anti T-cell
receptor antibody that is used to
block the interaction between the T-cell receptor and the MHC.
The drugs, cyclosporine and FK506 inhibit
the calcineurin signaling pathway.
CTLA4-Ig interferes with the
co-stimulatory interaction between B7 and
CD28, thereby preventing co-stimulation
and activation of T-cells.
Both of these approaches, using
cyclosporine, using FK506, using CTLA4-Ig,
using anti T-cell receptors, at the end
of the day they have the same effect.
They block the activation of T-cells and block
the subsequent production of interleukin-2.
Antibodies against the interleukin-2 receptor can be used to
prevent T-cell stimulation by this particular cytokine.
Therefore signaling through the IL-2 receptor leading
to lymphocyte activation will be blocked.
The immunosuppressive drug rapamycin inhibits
mTOR which is involved in the signaling process.
And therefore, there is prevention
of proliferation of the lymphocytes.
And finally, azathioprine and mycophenolate can also interfere
with the proliferative process and
act as immunosuppressive drugs.
One normally thinks about the recipient
rejecting the graft, but the opposite situation
can occur when an individual is being given
a hematopoietic stem cell transplantation.
This can result in graft
versus host disease.
In this situation, you have an individual,
perhaps a patient with leukemia that is being
treated with radiation or with cytotoxic drugs
that is damaging their own immune system.
They are then given a transplant of hematopoietic
stem cells, perhaps from a bone marrow.
Could be from cord blood, could
be from peripheral blood.
These cells are of course immune system cells
that are being used for the transplantation.
And the donor T-cells can recognize the
foreign MHC on the recipient cells,
leading to the death of those cells and
causing graft versus host disease.