Module 9: Transplantation

Transplantation

The replacement of diseased organs by a transplant of healthy tissue

Autograft

tissue grafted back on to the original donor

Isograft

graft between syngeneic individuals(of identical genetic constitution) such as identical twins or mice of the same pure inbred strain

Allograft

graft between allogeneic individuals (members of the same
species but different genetic constitution), for example, human to human
and one mouse strain to another

Xenograft

graft between xenogeneic individuals (of different species),
for example, pig to human

What are the three types of rejection

Hyperacute, Acute, and Chronic rejection

Hyperacute rejection

occurring within minutes of transplantation
and resulting from pre‐existing anti‐donor antibodies in the recipient binding to blood vessel endothelium in the donated organ

Acute rejection

taking place days or weeks following transplantation
and mediated by lymphocytes

Chronic rejection

taking months or years to manifest itself and
involving mechanisms that are often somewhat poorly define

Role of Lymphocytes in first set rejection

to recognize foreign antigens on the transplanted organ, initiating an adaptive immune response that leads to graft damage

Because CD8 cytotoxic T‐cells play a major role in allograft rejection, murine models have indicated that in the absence of _____ allografts can be accepted indefinitely.

CD4 T-cells

Rejection can be mediated by CD4 T‐cells in the absence of ____

CD8 T-cells

Mechanisms of graft rejection

Cytotoxic T-cell killing, Antibody-mediated damage, and macrophage activation

_____ upregulates MHC expression on the target
graft cell, so increasing its vulnerability to CD8 cytotoxic cells

Interferon‐γ (IFNγ)

The MHC defined by

its ability to provoke the most powerful
rejection of grafts between members of the same species

This intensity of MHC‐mismatched rejection is a consequence of

the very high frequency of alloreactive T‐cells (cells that react
with allografts) present in normal individuals

What are the two main pathways of recognition of allogeneic MHC

Direct and Indirect

In the direct pathway of recognition of allogeneic MHC

large numbers of recipient alloreactive T‐cells recognize allo‐(graft) MHC on the surface of donor cells

In the indirect pathway of recognition of allogeneic MHC

a smaller number of recipient T‐cells recognize peptides derived from allo‐MHC (and allo‐minor
transplantation antigens) presented by self MHC
molecules on the recipient’s own antigen‐presenting cells

The role of Antibody in transplantation

Allogeneic cells can be destroyed by antibody‐mediated cytotoxic (type II hypersensitivity) reactions

In hyperacute rejection the antibodies that bind to blood vessel endothelium in the donated kidney…

activate the classical pathway of complement and initiate the blood clotting cascade

As a result of complement activation by antibodies…

the blood vessels become blocked with aggregated platelets, and neutrophils are also rapidly recruited

Acute rejection of a kidney is characterized by

dense cellular infiltration and rupture of peritubular capillaries

In acute rejection, _____ attack the graft cells whose MHC antigen expression has been upregulated by IFNγ

CD8+ cytotoxic T‐cells

Binding of ____ leads to the deposition of substantial amounts of complement component C4d in the peritubular capillaries

graft‐specific antibody

Immunoglobulin deposits on the vessel walls induce ______, leading to _______

platelet aggregation in the glomerular capillaries; acute renal shutdown

Chronic rejection involves ______ and is often associated with subendothelial deposits of _____ in the glomerular and peritubular capillaries

glomerular and tubular fibrosis; immunoglobulin and C4d

Because in Allograft transplants it is virtually impossible to completely match the donor and recipient, what is necessary to limit immunological rejection?

powerful and potentially toxic immunosuppressive drugs

The development of an immunological response requires the active
proliferation of _______ to give a population of sensitized cells large enough to
be effective.

a relatively small number of antigen‐sensitive lymphocytes

Because anti‐mitotic drugs are especially toxic for cells of the bone
marrow and small intestine and  the drugs used are not specific just for anti‐donor
lymphocytes, patients on immunosuppressive therapy tend to be _____

susceptible to opportunistic infections with a variety of viral, bacterial, fungal, and parasitic diseases

How in Immunosuppression employed

Induction therapy, Maintenance therapy, and Treatment of rejection episodes

Induction therapy

1. The aim here is to deliver intensive immunosuppression at the time of
transplantation to ensure that the immune system is stopped in its tracks
when being provoked by the arrival of the foreign graft.
2. Anti‐T‐cell antibodies and/or IL‐2 receptor antagonists are typically
employed.

Maintenance therapy

1. If immunosuppression is removed the donor organ or tissue will be
immunologically rejected. Therefore, transplant recipients usually need to be
maintained on immunosuppressive drugs for the rest of their lives.
2. A balance needs to be achieved between adequate dampening of the
immune response to prevent graft rejection while limiting drug toxicity and
maintaining sufficient immune responsiveness for the patient to combat
infection.
3. Typically, calcineurin inhibitors, purine metabolism inhibitors, and mTOR
inhibitors are used, often together with steroids

Treatment of rejection episodes

1. Humoral rejection can be treated with intravenous immunoglobulin,
plasmapheresis, and the anti‐CD20 antibody rituximab.
2. A variety of immunosuppressive anti‐T‐cell agents are also commonly
employed.

Stem cell therapy

The ideal transplant is one created entirely from cells of the recipient (an autograft), which would eliminate the need for immunosuppression. It is possible to isolate stem cells from various adult organs including bone marrow.