Describe As autografts are recognised by the immune

Describe and discuss the categories of
solid organ allograft rejection, and the means by which they may be limited

For patients
with end stage organ failure the gold standard of treatment is an
allotransplant of the failing organ. Kidneys, pancreas, heart, lung, liver and
intestines are all routinely transplanted. Restrictions to solid-organ
transplant include a lack of suitable organs available, and the risk of
rejection of the transplanted organ. An immunological basis for allograft
rejection was first proposed in the 1930s by Gorer gorer. Medewar further
cemented the idea by showing that rejection of skin grafts displayed
specificity and memory for the donor tissue with second allografts from the
same donor being rejected faster than the previous allograft. Further work in the 1960s

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There are three
main classes of antigens that are involved in initiating the immune response
that leads to rejection. Those are the major histocompatibility complex (MHC)
antigens, the minor histocompatibility antigens and blood group antigens.  While MHC antigens (human leukocyte antigens,
HLA) are considered the primary transplantation antigens, blood group antigens
are the first consideration for any transplant. This essay will focus on the
impact MHC antigens have on solid organ allograft rejection.

Rejection Classification

Rejection occurs
due to an immune response being mounted against the transplanted organ. There
are three types of transplant; autografts, allografts and xenografts (1,2). Autografts describe the
transplant of tissue or organs from one part of the body to another (1). As autografts are recognised
by the immune system as ‘self’, i.e. not foreign, there is no risk of
rejection. Allografts are defined as transplants of tissues or organs between
two individuals of the same species. Allograft rejection is defined as an
immune response mounted by a recipient against donor antigens that result in allograft
loss. Rejection of allografts can be classified as hyperacute, accelerated, acute
and chronic (1,2). Classification criteria are
based upon histopathology and time of rejection post-transplant rather than by
rejection mechanism.

Hyperacute
rejection can occur within minutes or up to 24 hours post-transplant, with the
causative agent being the presence of pre-existing antibodies against HLA. Clinically,
hyperacute rejection is characterised by endothelial cell injury, platelet
margination, complement activation and thrombosis within allograft vasculature
following anastomosis Gautreaux. The transplanted organ will suffer
irreparable ischemic damage following hyperacute rejection. While there is no
effective treatment for hyperacute rejection, with appropriate
pre-transplantation testing hyperacute rejection is now extremely rare,
particularly in kidney transplants. Accelerated vascular rejection is similar
to hyperacute rejection in that it is aggressive, mediated by pre-existing antibodies
(albeit at a lower circulating titre than those found in hyperacute), and has
no standard therapy. The timeline for accelerated rejection is within two weeks
of transplant.

Acute rejection
is defined as allograft failure within 6 months of transplantation and can be
either T-cell (cellular rejection) or antibody mediated (AMR). The clinical
characteristic of acute rejection is necrosis of allograft endothelial cells
Gautreaux. While hyperacute rejection is shown histologically via vasculature
thrombosis, acute rejection more typically presents with vasculitis.

Acute cellular
rejection (ACR) is the most common form of early onset acute rejection and can appear
from 5-7 days post-transplant. ACR is mediated by lymphocytes, specifically T-
and NK-cells, that infiltrate the allograft parenchyma. Untreated ACR can lead
to irreversible histological damage to the transplanted organ through the
activity of complement. Long-term, continuous ACR may lead to chronic
deterioration that eventually results in chronic rejection.

Chronic
rejection is the greatest barrier to long-term allograft and patient survival
and is defined as delayed loss of allograft function months or even years
following transplant. Chronic rejection describes the long-term deterioration
of tissue due to continual immune activation against the allograft.  In cardiac and kidney transplants chronic rejection
histologically manifests as a narrowing of the allograft arteries. This
arterial narrowing is termed obliterative arteriopathy and results from a
build-up of smooth muscle cells and connective tissue within the vascular lumen
Gautreaux. Obliterative arteriopathy is
not such a risk in lung transplants as the lung is not particularly
vascularised. 

Graft versus
host disease (GvHD) is unlike the other forms of rejection in that it is donor
immune cells that recognise the recipient as foreign and mount a response. For
GvHD to occur viable donor lymphocytes must be transplanted alongside
non-immune cells. As such GvHD is commonly associated with haematopoietic stem
cell transplantation however can also occur in patients who have intestinal or
liver transplants. This is because both bowel and liver possess an abundance of
immune cells that are transplanted into the recipient alongside the required
organ. Clinically GvHD presents with a wide range of symptoms affecting skin,
liver and intestine Mazariegos.  Symptoms
may include skin rash or blistering, GI tract ulceration, liver dysfunction or
mouth and tongue lesions Mazariegos. GvHD following solid organ transplant is
associated with a significant mortality. Studies by Hawksworth et.al. and
Clouse et.al. showed that intestinal transplant patients had a survival rate of