2. Transplantation; Is the transfer of organs,
tissues or cells (hematopoietic stem cells)
from one part of the body to another, or
from
one person to another person.
3. Transplantation involves;
Solid organ transplants, example kidney, heart,
pancrease,liver, and lungs
Cell transplant, example hematopoietic stem
cells transplants.
4. Transplantation is potentially life saving
treatment for;
End stage organ failure.
Cancers.
Autoimmune diseases.
Immune deficiencies and a variety of other
diseases.
5. Compatibility of immune molecules determines
successful transplants, these immune molecules
includes HLA antigen, ABO blood grouping
antigen, MIC antigen and KIR
The HLA system is the largest immunologic
barrier to successful allogerneic organ
transplantation, an allogerneic response may
result in graft rejection in solid organ and stem
cell tranplantation or graft-versus- host disease
in stem cell transplantation
6. HISTOCOMPATIBILY SYSTEM
The classical (transplant) HLA antigens also
known as major histocompatibility antigens,
include the class І (HLA-A,B and C and class ІІ
(HLA-DR, DQ and DP).
Genes coding for the MHC molecules are found
on short arm of chromosome 6.
7. • The MHC molecules control the immune
response through recognition of "self" and
"non-self" and consequently serve as targets
in transplantation rejection.
• MHC was originally discovered as
transplantation antigens, that predominantly
determine the compatibility of tissues
between different individuals.
8. Cont…
• The MHC class І and class ІІ molecules are the
most immunogenic antigen that are
recognized during rejection of an allogeneic
transplant.
• It consist of cell surface protein that play a
central role in immune recognition and
initiation of immune responses.
9. Cont…
Class І heterodimer are co -dominantly found
virtually in all nucleated cells.
Class II heterodimer are co-dominantly
expressed primarily in antigen presenting cells,
e.g dendritic cells,monocytes, macrophages
and B lymphocyte.
10. Cont…….
Because of the ubiquitous presence of these
protein on the surface of nucleated cells and
their extensive degree of polymorphism an
allorgeneic response may result in graft
rejection, solid –organ and stem cell
transplantation.
11. Cont….
HLA genes are inherited as haplotypes from
parental chromosomes, meaning that offspring
receive one maternal and one paternal HLA
haplotype
12. A.Minor Histocompatibility antigen
• mHAs are non-HLA proteins that demonstrate
polymorphism in amino acid sequence within
a species
• These receptors are found on the cellular
surface of donated organs and induce an
immunological response in some organ
transplants.
13. Cont.,
• The immune response is mediated by CD4
and/or CD8 T cells recognizing a variant
protein in the context of the recipient MHC
molecule.
14. Cont.,
• Even when a transplant donor and recipient
are identical with respect to their major
histocompatibility complex genes, the amino
acid differences in minor proteins can cause
the grafted tissue to be slowly rejected hence
its name.
15. MIC Antigens
• MHC class I-related chain A, proteins are
expressed on endothelial cells, keratinocytes,
fibroblasts, dendritic cells, epithelial cells and
monocytes but they are not expressed on T or
B lymphocytes.
• MICA antibodies have been associated with
rejection episodes and decreased graft
survival.
16. B. ABO BLOOD GROUPING ANTIGEN.
ABO system consists of anti-A and anti-B,and
have a greater impacts on clinical
transplantation.
Anti-A and anti-B develop in individuals
lacking the corresponding blood group
antigen.
17. ABO blood group incompatibility is a barrier
to solid-organ transplantation, because these
antibodies can bind the corresponding antigen
that are expressed on vascular endothelium.
Binding activates the complement cascade
which can lead to hyperacute rejection of the
transplanted organ.
18. C. KILLER IMMUNOGLOBIN-LIKE
RECEPTORS.
• Is another polymorphic genetic system that
impacts allogeneic transplantation.
• It regulate the activity of natural killer
(NK)lymphocytes.
• KIRs have activating and inhibitory receptors.
• These receptors vary in number and type in
individual NK cell.
19. Cont,,,,,,
• Normally, a NK cell encounters self class I
MHC proteins as it circulates in the body
• If a NK cell encounters a cell lacking or having
decreased class I (MHC) expression, inhibitory
receptors are not occupied.
• Inhibitory signal loss occurs, resulting in NK
cell activation.
20. Cont,,,,,
• The regulatory role of KIRs has been exploited
in haploidentical stem cell transplantation.
• For recipients who lack a corresponding class I
MHC protein can results in alloreactivity by
NK cells that repopulate the recipient after
transplant.
• A graft-versus-leukemia reaction is an
example.
21. ALLORECOGNITION
• Is the ability of an individual organism to
distinguish its own tissue from those of
another. It is genetic relatedness of the donor
and the recipient.
• An autograft is the transfer of tissue from
one area of the body to another of the same
individual
• A syngeneic graft/isograft is the transfer of
cells or tissues between identical twins.
22. Cont,
• An allograft is the transfer of cells or tissue
between two individuals of the same
species(most of transplantation fall under this
category)
• Xenograft is the transfer of tissue between
two individuals of a different species.
23. The recipient immune system recognizes foreign
HLA proteins via two distinct mechanisms;
Direct allorecognition
Indirect allorecognition
24. 1.Direct allorecognition
• Direct allorecognition, recipient T cells(CD 8)
bind and respond directly to foreign HLA
proteins on graft cells.
• Direct allorecognition is characterized by a
high frequency of responding T cells.
25.
26. 2.Indirect allorecognition
• Indirect allorecognition, foreign MHC antigens
are presented by phagocytic cells, and CD4 T cells
respond.
• Indirect allorecognition is analogous to normal
mechanism of recognizing foreign particles, as it
involves the uptake, processing, and
presentation of foreign HLA proteins by
recipient antigen-presenting cells to recipient.
27.
28. TRANSPLANT REJECTION
1.Hyperacute rejection
• Hyperacute rejection occurs within minutes to
hours after the vascular supply to the
transplanted organ is established.
• This type of rejection is mediated by
preformed antibody that reacts with donor
vascular endothelium.
29. • Also ABO,HLA and certain endothelial
antigens may elicit hyperacute rejection
• Binding of preformed antibodies to the
alloantigen activates the complement cascade
and clotting mechanisms and leads to
thrombus formation.
• The result is ischemia and necrosis of the
transplanted tissue.
30. 2.Acute Cellular Rejection
• Days to weeks after transplant, individuals
may develop acute rejection.
• It involve antibody as well.
• Acute rejection is characterized by
parenchymal and vascular injury.
31. Cont,
• Interstitial cellular infiltrates contain a
predominance of CD8-positive T cells as well
as CD4 T cells and macrophages
32. Cont……
• CD8 cells likely mediate cytotoxic reactions to
foreign MHC-expressing cells, while CD4 cells
likely produce cytokines and induce delayed-
type hypersensitivity (DTH) reactions.
33. 3.Chronic Rejection
• Chronic rejection results from a process of
graft arteriosclerosis.
• It is characterized by progressive fibrosis and
scarring
• Its impact includes development of chronic
rejection, including prolonged cold ischemia,
reperfusion, acute rejection episodes, and
toxicity from immunosuppressive drugs.
34. Graft- versus- host disease(GVHD)
• Is an immune-mediated disease resulting from
a complex interaction between donor and
recipient adaptive immunity. It is common in
stem cells transplants.
• Graft-versus-host reaction is common after
allogeneic bone marrow transplant.
35. Recipients of stem cell transplants for
hematologic malignancies typically have
depleted bone marrow prior to
transplantation, as a result of the
chemotherapy used to treat the malignancy.
Acute GVHD occurs during the first 100 days
post infusion and targets the skin,
gastrointestinal tract, and liver.
36. IMMUNOSUPPRESSIVE AGENTS
These are agents that are employed to
suppress anti-graft immune responses in
solid-organ and stem cell transplantation.
Immunosuppressive agents are used in
several ways, including induction and
maintenance of immune suppression and
treatment of rejection.
37. These immunosuppressive agents are like
• Corticosteroids act by blocking production and
secretion of cytokines, inflammatory mediators,
chemoattractants, and adhesion molecules
• These activities decrease macrophage function and
alter leukocyte-trafficking patterns. However, long-
term use is associated with several complications,
including hypertension and diabetes mellitus.
38. Cont..,
• Anti-metabolic agents interfere with the
maturation of lymphocytes and kill
proliferating cells.
• Azathioprine was the first such agent
employed.
39. Cont..,
• Calcineurin Inhibitors are compounds that
block signal transduction in T lymphocytes,
resulting in impairment of cytokine syntheses,
including IL-2, 3, 4, and interferon-gamma.
• Inhibition of cytokine synthesis blocks the
growth and differentiation of T cells, impairing
the antigraft response
40. Cont..,
• Monoclonal Antibodies Several monoclonal
antibodies that bind to cell surface molecules
on lymphocytes are used as induction agents
and to treat severe rejection episodes.
• Binding may modulate CD3 from the cell
surface, rendering the affected T cells
nonfunctional.
41. Cont..,
• Polyclonal Antibodies Two polyclonal anti-T-cell antibody
preparations are used to treat severe rejection.
• Thymoglobulin is an antithymocyte antibody and ATGAM is a
polyclonal antiserum. Both are potent immunosuppressive
agents that deplete lymphocytes from the circulation.
• A drawback associated with administration of polyclonal
antibody preparations is the development of serum sickness
due to antibody responses to the foreign immunoglobulin.
