,ALEXANDRIA UNIVERISTY

,FACULTY OF MEDICINE
PATHOLOGY .
DEPARTMENT

objectives
1. Immune system.
 2. Cause of graft rejection.
3. Important definitions.
4. Types of graft rejection.
5. Treatment of graft rejection.

Immune System
The immune system defends the body against disease.
Lymphocytes are one type of white blood cell that helps
the body resist infection by recognizing harmful foreign
substances, such as bacteria, and eliminating them. The
ability of the vertebrate immune system to distinguish self
from non self depends largely on a group of protein makers
(antigens) known as the major histocompatibility complex
(MHC). These markers are present on the surface of every
cell are slightly different in different individuals. The genes
that code for these proteins are found linked together on
one chromosome (chromosome 6 in humans).
 In humans the MHC is called the HLA (human leukocyte
antigen) group. HLA is determined by five different linked
genes. These genes are all polymorphic ,within the
population there are multiple alleles at each locus.
Because of the polymorphism of the HLA genes, it is
difficult to find identical matches among strangers. If a
tissue or organ is taken from a donor and transplanted to
the body of an unrelated host, several of the HLA antigens
are likely to be different.The host's immune system regards
the graft as foreign and launches an effective immune
response called a graft rejection.T lymphocytes attack the
transplanted tissue and can destroy it within a few days.
The T-cells cause cells in the transplanted tissue to lyse, or
produce cytokines that cause necrosis of the transplanted
tissue.

• Autologous Graft = Autograft

One site to another site in/on the same host
• Syngeneic Graft = Syngraft
Genetically identical but different individual hosts
(identical twins, clones)
• Allogeneic Graft = Allograft
Same species but genetically different individuals
(different people)
• Xenogeneic Graft = Xenograft
Different species
Primarily use of pig heart valve in humans
 Before transplants are performed, tissues from the patient
and from potential donors must be typed and matched as
well as possible.

GRAFT REJECTION TYPES

1.HYPERACUTE – Immediate rejection
2.ACUTE – Cellular
3.CHRONIC – Fibrosis

1-Hyperacute rejection
Hyperacute rejection is a complement-mediated
response in recipients with pre-existing antibodies to the
donor ( ABO blood type antibodies) Hyperacute rejection
occurs within minutes and the transplant must be
immediately removed to prevent a severe systemic
inflammatory response. Rapid agglutination of the blood
occurs.This is a particular risk in kidney transplants.
For other organs, hyperacute rejection is prevented by
transplanting only ABO-compatible grafts. Hyperacute
rejection is the likely outcome of xenotransplanted organs

2-Acute rejection
Acute rejection usually begins one week after
transplantation.The risk of acute rejection is highest in the
first three months after transplantation. However, acute
rejection can also occur months to years after
transplantation. A single episode of acute rejection is not a
cause for concern if recognised and treated promptly, and
rarely leads to organ failure. But recurrent episodes are
associated with chronic rejection .
 Tissues such as the kidney or the liver which are highly
vascularized (rich in blood vessels), are often the earliest
victims of acute rejection. Damage to the endothelial lining
of blood vessels is an early predictor of irreversible acute
transplant rejection.
The diagnosis of acute rejection relies on clinical data,
including patient signs and symptoms, laboratory testing
and a tissue biopsy. There areThree main
histological features.: 1-
the presence of T-cells infiltrating the transplanted tissue;&
may be eosinophils, plasma cells and neutrophils.
2-structural injury to the transplanted tissue; the
characteristics of this injury will depend on the type of
tissue being transplanted.
3- injury to the blood vessels in the transplanted tissue.

3-Chronic rejection
Chronic rejection describe loss of function in
transplanted organs, associated with fibrosis of the internal
blood vessels of the transplanted tissue. now termed
chronic allograft vasculopathy. IN chronic rejection the
rejection is due to a chronic immune response against the
transplanted tissue.. This usually leads to need for a new
organ transplant after a decade or so.

Treatment of rejection
Chronic transplant rejection is irreversible and cannot be
treated effectively. The only definitive treatment is re-
transplantation, if necessary. This would typically be ten
years after a transplant, and this may entail returning to a
transplant queue.
Acute transplant rejection can be treated using
chemotherapeutic drugs designed to suppress the immune
system . Acute rejection is normally treated initially with a
short course of high-dose corticosteroids, which is usually
sufficient to treat successfully. If this is not enough, the
course can be repeated or a triple therapy regimen can be
used, consisting of a corticosteroid plus a calcineurin
inhibitor ( Cyclosporin A – cyclic peptide that binds with cyclophilin
together they inhibit calcium/calmodulin activation ) and an anti-
proliferative agent. Antibodies against specific components
of the immune system can be added to this regimen ,
especially for high-risk patient.Acute rejection refractory to
these treatments may require blood transfusions to remove
antibodies against the transplant.
Treatment is usually necessary for the life of the
recipient.

IMMUNOSUPPRESSION
1. Corticosteroids
* Lysis of mature cortical T cells.
* Activation of endogenous nucleases (cleave DNA).
* Block cytokine gene transcription.
* Inhibition of IL-1, IL-6, and TNF production.

2.Metabolic Toxins
 General group of toxins that inhibit
Lymphocyte growth.
• Azathioprine
• Cyclophosphamide
• Hydroxychloroquine
• Cyclosporin
• Calcineurin
3.Iratiation
T cells are particularly sensitive to Gamma
radiation treatments.
4.Induce tolerance
Multiple blood transfusions prior to transplant
induces generalized tolerance.
5.Antibodies
• Antibodies to T cell surface markers
• Mouse derived monoclonal antibodies to CD3
• Antibodies to B cells inhibit Abs synthesis
• Can also remove Ab by plasmapheresis
References
• Aust doctors hail teen's transplant 'miracle' Sean
Rubinsztein-Dunlop, ABC News (Australia),
January 24,2008
• Demi-Lee Brennan has changed blood types and
immune system Kate Sikora, Daily Telegraph,
January 25, 2008