00:01
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.
00:25
And as we can see, this particular individual
is HLA-A2, A5, B7, B13 and DR2, DR1.
00:34
Here we have a number of different
patients that are awaiting a transplant.
00:41
They are placed on a
register with many others.
00:44
Each of whom are likely to have different
HLA types as shown on this slide.
00:51
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.
01:08
A blood sample from the donor
is also sent to the hospital.
01:13
In the cross match, donor B-cells are
mixed with recipient’s serum.
01:18
In this case, preformed antibodies
are binding the donor cells.
01:23
This transplant cannot take place.
01:27
However here we see that the recipient has no antibodies
against donor cells and the transplant can go ahead.
01:36
Preformed anti-donor antibodies can result from pregnancy,
blood transfusion, or indeed a previous transplant.
01:47
Let’s look at the mechanisms of
action of immunosuppressive drugs.
01:51
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.
02:01
There is almost always some
mismatch as regards the MHC.
02:08
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.
02:19
The drugs, cyclosporine and FK506 inhibit
the calcineurin signaling pathway.
02:30
CTLA4-Ig interferes with the
co-stimulatory interaction between B7 and
CD28, thereby preventing co-stimulation
and activation of T-cells.
02:48
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.
03:00
They block the activation of T-cells and block
the subsequent production of interleukin-2.
03:06
Antibodies against the interleukin-2 receptor can be used to
prevent T-cell stimulation by this particular cytokine.
03:19
Therefore signaling through the IL-2 receptor leading
to lymphocyte activation will be blocked.
03:27
The immunosuppressive drug rapamycin inhibits
mTOR which is involved in the signaling process.
03:36
And therefore, there is prevention
of proliferation of the lymphocytes.
03:41
And finally, azathioprine and mycophenolate can also interfere
with the proliferative process and
act as immunosuppressive drugs.
03:52
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.
04:04
This can result in graft
versus host disease.
04:09
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.
04:22
They are then given a transplant of hematopoietic
stem cells, perhaps from a bone marrow.
04:28
Could be from cord blood, could
be from peripheral blood.
04:32
These cells are of course immune system cells
that are being used for the transplantation.
04:40
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.