Transplantation and graft rejection involves complex immune mechanisms. There are different types of grafts including autografts, isografts, allografts, and xenografts which elicit varying immune responses. Major histocompatibility antigens are the main antigens that cause fast and strong rejection through direct or indirect antigen recognition. Graft rejection is classified as hyperacute, acute, or chronic rejection based on timing and mechanisms involving antibodies, T cells, and inflammation. Prevention strategies aim to minimize rejection by controlling these immune responses.

1. TITLE: - TRANSPLANTATION AND GRAFT REJECTION
By,Getahun.A 2024
JimmaUniversity
InstituteofHealthSciences
DepartmentofMedicalBiochemistry
AssignmentfortheCourseImmunology

2. Outline of presentation
 Introduction
 Immunologic basis of graft rejection
 Recognition of graft/transplant antigens
 Classification of allograft rejection
 Mechanism of allograft rejection
 Graft versus host reaction
 Prevention and therapy of allograft rejection
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3. Objectives
 Name the different types of grafts
 Distinguish among the rejection reactions
 Differentiate between host VS graft rejection
 Understand the molecular basis of immune response
 Understand how transplant antigens are recognized
 List mechanisms used to minimize rejection
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4. Introduction
 Transplantation: refers to the act of transferring cells tissues
or organs from one site to another.
 Graft: implantation/transfer of healthy organs, tissue or cells
to replace the diseased or damaged once to establish health
and normal functioning.
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5. Introduction …
 1908: Alexis Carrel reported the first systematic transplantation.
 1935 the first human kidney transplant attempted by a Russian
surgeon failed because of mismatch of blood type between donor
and recipient.
 1944: Medawar showed that skin allograft rejection is a host
versus graft response.
 1954: Joseph E. Murray the 1st successful human kidney
transplant b/n identical twins was accomplished in Boston, USA
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6. Introduction …
 1967: Thomas E. Starzal, the first successful liver transplant
was done.
 1967: Christian Barnard, the first heart transplantation.
 1968: E. Donnall Thomas, the first successful bone marrow
transplant.
 Nowadys kidney, pancreas, heart, lung, liver, bone marrow,
and cornea transplantation are done with ever increasing
frequency.
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7. Types of grafts
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8. Types of grafts……
 The degree of immune response to graft varies with the type
of graft:
 Four type of graft:-
 Autograft
 Isograft
 Allograft &
 Xenograft
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9. Types of grafts……
 Autograft: self tissue transferred from one body site to
another in the same individual. Eg. transfering healthy skin to
burned area in burn pts and use of blood vessels to replace
blocked coronary arteries.
 Isograft: is tissue transferred b/n genetically identical
individuals (monozygotic twins).
 Allograft: is tissue transferred b/n genetically different
members of the same species.
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10. Types of grafts……
 In humans, organ grafts from one individual to another are
allografts unless the donor and recipients are identical twins.
 Two major problems arise in allogeneic transplantation:
 Transplant rejection
 Graft Versus Host (GVH) disease
 Xenograft: is tissue transferred b/n different species (eg. The
graft of a baboon/pig heart into a human).
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11. Immunologic basis of graft rejection …
 Immune system do not stimulate the immune response against
all the antigens present in the graft,
 and no graft rejection even when the donor and recipient are
not syngeneic. This is called as graft acceptance.
 Acceptance of an autograft is completed within 12-14 days .
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12. Immunologic basis of graft rejection …
 First set rejection of an allograft begins 7-10 days after
grafting, with full rejection occurring by 10- 14 days.
 Second-set rejection occurs within 3-4 days after a second
graft with the same antigenic specificity as the first is
placed in the same host.
 The cellular infiltrate that invades an allograft contains
lymphocytes and other inflammatory cells.
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13. Immunologic basis of graft rejection…
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14. Immunologic basis of graft rejection …
 Graft rejection:-occurs when a transplanted organ or tissue
fails to be accepted by the body of the transplant recipient.
Causes of graft rejection
MHC genes
Different MHC Ags within species& individuals
T Lymphocytes recognize transplanted organ as foreign&
release cytokines that lyse cells.
Graft failure
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15. Immunologic basis of graft rejection …
 Graft rejection depends on host recognition of the grafted tissue
as foreign.
 The antigens responsible for such rejection are those of the MHC
(HLA) system.
 Rejection is a complex process in which both cell mediated
immunity and circulating Abs play a role.
 The relative contribution of these two mechanisms to rejection
vary among grafts.
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16. Immunologic basis of graft rejection …
 Cell mediated graft rejection occurs in two stages:
 A sensitization phase, in which Ag reactive lymphocytes of
the recipient proliferate in response to allantingens on the
graft.
 An effector phase, in which immune destruction of the grafts
takes place.
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17. Immunologic basis of graft rejection …
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18. Transplantation antigens
 Major histocompatibility antigens (MHC molecules)
 Main antigens of grafts rejection
 Cause fast and strong rejection.
 difference of HLA types is the main cause of human grafts
rejection
 Minor histocompatibility antigens
 Also cause grafts rejection,
 but slow and weak
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19. Transplantation antigens…
 Other alloantigen's
 Human ABO blood group antigens
 Some tissue specific antigens
• Skin＞kidney＞heart＞pancreas ＞liver
• Vascular Endothelial Cell (VEC) antigen
• Skin-specific (SK) antigen
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20. Recognition of graft Ags
 For transplantation rxn to happen the transplantation Ags must
be recognized.
 There are 2 ways for recognition:
 Direct Recognition
 Indirect Recognition
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21. Direct Recognition
 Recognition of an intact MHC molecules dispalyed by donor
APC in the graft.
 Host T cells recognize HLA molecules on the surface of APC
of the donor.
 Host T cells recognize the donor dendritic cells within the
grafted organ or after these cells migrate to the draining lymph
nodes.
 Both host CD4 and CD8 T cells are involved in the reaction.
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22. Indirect recognition
 Uptake and presentation of allogeneic donor MHC molecules by
recipient APC in “normal way”.
 Recognition by T cells like conventional foreign antigens
 Host CD4 T cells recognize donor HLA after they are processed
and presented by the hosts APC.
 Basically, donor MHC moles recognition is handeled like any other
foreign Ag.
 This recognition activates DTH
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23. Indirect recognition…
 Indirect presentation may result in allorecognition by CD4 T
cells.
 This is because alloantigen is acquired primarily through the
endosomal vesicular pathway and is therefore presented by
class II MHC molecules.
 Some antigens of phagocytosed graft cells appear to enter the
class I MHC pathway of antigen presentation and are
indirectly recognized by CD8 T cells.
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24. Recognition of graft Ags…
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25. Recognition of graft Ags…
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26. Difference between direct & indirect recognition
Direct
Recognition
Indirect
Recognition
Allogeneic MHC
molecule
Intact allogeneic
MHC molecule
Peptide of allogeneic
MHC molecule
APC
s
Recipient APCs arenot
necessary
Recipient APCs
Activated T cells CD4＋T cells and/or
CD8＋T cells
CD4＋T cells and/or
CD8＋T cells
Roles in rejection Acute rejection Chronic rejection
Degree of rejection Vigorous Weak
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27. Classification of allograft rejection
 Two major problems arise in allogeneic transplantation:
1. Transplant rejection
 Host versus graft reaction (HVGR) Conventional organ
transplantation
2. Graft Versus Host (GVH) disease
 Graft versus host reaction (GVHR)
 Bone marrow transplantation
 Immune cells transplantation
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28. Host versus graft reaction (HVGR)
 Host via graft rejection refers to the immune response of the
recipient's body against transplanted or donated tissue.
 When the immune cells in the host recognize the graft as
foreign, they attack the grafted cells,leading to graft rejection.
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29. HVGR…..
 Graft rejection can occur with any tissue graft or organ
transplant.
 Symptoms of graft rejection may vary depending on the
specific organ or tissue involved.
 Chronic graft rejection can lead to organ failure after
several year
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30. HVGR…..
 On the basis of the morphology and the underlying
mechanism, rejection reactions are classified as :
1. Hyperacute rejection
2. Acute rejection
3. Chronic rejection
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31. Hyperacute rejection
 Occurs within minutes or hrs after transplantation, due to the presence of
preformed antidonor Abs in the recipients circulation.
 Preformed antibodies generally arise from; past blood transfusion, multiple
pregnancies, previous transplantation.
 Antibody against ABO blood type antigen
 Antibody against VEC antigen
 Antibody against HLA antigen
 Leading to C activation, neutrophil margination,
 inflammation, thrombosis formation.
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32. Steps in Hyperacute rejection
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33. Acute rejection
 Occurs within days of transplantation in the untreated pt, manifests
commonly in the first 6 months after transplantation
 Is a combined process in which both cellular and humoral tissues play a
part.
 T cell, macrophage and Ab mediated, inflammation
 Vasculitis
 IgG antibodies against alloantigens on endothelial cell
 Parenchymal cell damage
 Delayed hypersensitivity mediated by CD4+Th1
 Killing of graft cells by CD8+Tc
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34. Chronic rejection
 Chronic rejection develops months to years after acute
rejection episodes have subsided.
 Chronic rejections are both antibody-and cell-mediated.
 The use of immunosuppressive drugs and tissue-typing
methods has increased the survival of allografts in the first
year,
 but chronic rejection is not prevented in most cases.
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35. Chronic rejection…
 Chronic rejection appears as fibrosis and scarring in all
transplanted organs,
 Extension and results of cell necrosis in acute rejection
 Chronic inflammation mediated by CD4+ T cell, MΦ,
 & DTH reaction
 Organ degeneration induced by non immune factors
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36. Graft versus host reaction (GVHR)
 GVH reaction occurs in any situation in which immunologically
competent cells or their precursors are transplanted into
immunologically suppressed or deficient recipient (host).
 The grafted cells survive and react against the host cells, instead of
host reacting against the graft.
 Allogenetic bone marrow transplantation.
 Rejection to host alloantigens.
 Mediated by immune competent cells in bone marrow.
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37. Graft versus host reaction (GVHR)…
 Graft versus host disease (GVHD)
 A disease caused by GVHR, which can damage the host
 Conditions :
 Enough immune competent cells in grafts.
 Immunocompromised host Histocompatability differences between
host and graft.
 Bone marrow transplantation -Thymus transplantation
 Spleen transplantation - Blood transfusion of neonate
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38. Graft versus host reaction (GVHR)…
 In most cases the reaction is directed against minor histocompatibility
antigens of the host.
 Endothelial cell death in the skin, liver, and gastrointestinal tract
 Rash, jaundice, diarrhea, gastrointestinal Hemorrhage.
 Chronic GVHD
 Fibrosis and atrophy of one or more of the organs
 Eventually complete dysfunction of the affected organ
 Both acute and chronic GVHD are commonly treated with intense
immunosuppresion.
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39. Mechanism of allograft rejection
 Cell-mediated Immunity
 This mechanism of rejection refers to the immune response
that involves
 the activation of T cells, particularly cytotoxic T cells, to
recognize and attack foreign cells or tissues.
 Recipient's T cell-mediated cellular immune response against
alloantigens on grafts.
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40. Mechanism of allograft rejection…
 Humoral Immunity -Important role in hyper acute rejection.
 ADCC
 Complement activation
 Opsonization
 Enhancing antibodies /Blocking antibodies
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41. Mechanism of allograft rejection…
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 Donor-Specific HLA Antibodies (DSA):
 DSA are antibodies produced by the recipient's immune
system in response to the presence of foreign HLA antigens on
the transplanted organ.
 These antibodies can recognize and bind to the HLA antigens
on the endothelial cells of the graft, initiating the rejection
process

42. Mechanism of allograft rejection…
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 Complement Activation:
 Binding of DSA to the graft endothelial cells can activate the
complement system, leading to the formation of membrane
attack complexes (MACs) and subsequent tissue damage.
 MACs can directly lyse the endothelial cells and cause
inflammation, further contributing to graft rejection

43. Mechanism of allograft rejection…
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 Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC):
 DSA can also trigger ADCC, a process in which immune cells,
such as natural killer (NK) cells and macrophages, recognize
and bind to the Fc portion of the DSA.
 This interaction activates the immune cells, leading to the
destruction of the graft endothelial cells.

44. Mechanism of allograft rejection…
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 Antibody-Dependent Cellular Phagocytosis
(ADCP):
 In ADCP, immune cells, particularly macrophages, recognize
and engulf the DSA-coated graft endothelial cells, leading to
their destruction.

45. Transplant Tolerance and Minimizing
Rejection
Method of increasing graft survival
 Minimization of the HLA disparity b/n donor and the recipient
by better HLA matching.
 Tissue Typing
 ABO and Rh blood typing
 Crossmatching (Preformed antibodies)
 HLA typing
 HLA-A and HLA-B
 HLA-DR
 Immunosuppressive Therapy
 Induction of Immune Tolerance
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46. Prevention and therapy of allograft
rejection…
 The primary consideration when selecting a suitable donor for
organ and tissue transplantation is to ensure compatibility for
ABO blood group antigens
 HLA matching is a secondary, but important,
 In practice, three of the HLA loci are usually typed and
matched for in kidney transplantation: HLA-A, HLA-B,
and HLA-DR
 For bone marrow transplantation, matching requirements are
more stringent to avoid both rejection of the stem cells and
GVH disease,
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47. Prevention and therapy of allograft
rejection…
 Tissue typing
 The role of the tissue typing laboratory in kidney transplantation is:
1. To determine the HLA type of the patient and of potential donors in order
to advise on the best match;
2. To perform a cross-match test to exclude the presence of existing
circulating antibodies against HLA alleles expressed by donor
lymphocytes; and
3. To identify the HLA specificity of circulating antibodies when patients
are found to be sensitized in order to pre- emptively exclude unsuitable
donor HLA types
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48. Prevention and therapy of allograft
rejection…
 Using immunosuppressive therapy
 Drugs such as Azathioprine, steroids, cyclosporine
 Anti lymphocyte globulins
 Monoclonal anti T cell Abs (eg. Monoclonal anti-CD3)
 Monoclonal Abs specific for the high affinity IL-2 receptor
 Monoclonal Ab for CAMs – anti ICAM-1 & anti LFA-1
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49. Prevention and therapy of allograft
rejection…
 Induction of Immune Tolerance
 Inhibition of T cell activation
 Soluble MHC molecules, CTLA4-Ig, Anti-IL2R mAb
 Th2 cytokines
 Anti-TNF-α，Anti-IL-2，Anti-IFN-γ mAb
 Blocking costimulatory signals at the time of transplantation can
cause anergy instead of activation of T cells reactive against the
graft.
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50. Treatment for Graft Rejection
Drug Mechanism of action
Cyclosporine
and FK 506
Blocks T cell cytokine production by inhibiting
activation of the NAFT transcription factor
Mycophenolate
mofetil
Blocks lymphocyte proliferation by inhibiting
guanine nucleotide synthesis in lymphocytes
Rapamycin Blocks lymphocyte proliferation by inhibiting IL-2
signaling
Corticosteroids Reduce inflammation by inhibiting macrophage
cytokine secretion
Anit-CD3
monoclonal Ab
Depletes T cells by binding to CD3 & promoting
phagocytosis or complement mediated lysis
Anti-IL-2
receptor Ab
Inhibits T cell proliferation by blocking IL-2 binding
CTLA4-Ig Inhibits T cell activation by blocking B7
costimulatory binding to T cell CD28; to induce
tolerance
Anti-CD40
ligand
Inhibits macrophage and endothelial activation by
blocking T cell CD40L binding to macrophage CD40
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51. Why fetus is not rejected by mother
 During pregnancy, the fetus is not rejected by the mother's
immune system due to a complex process called immune
tolerance.
 This mechanism allows the mother's immune system to
recognize the fetus as "self" rather than as a foreign entity.
 and prevents an immune response that could potentially harm
the developing baby.
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52. Cont.….
 some key factors that contribute to immune tolerance in
pregnancy:
 Maternal-Fetal Interface
 Unique Immune Adaptations
 Hormonal and Physiological Changes
 Regulatory T Cells
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53. Summary
 Transplantation of tissues from one individual to a genetically
non-identical recipient leads to a specific immune response
called rejection.
 Alloreactive T cells are principally responsible for allograft
rejection.
 Alloantigen-specific antibodies are responsible for hyperacute
rejection and acute humoral rejection.
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54. Cont.…
 The most important transplantation antigens, are derived from
the donor major histocompatibility complex (MHC),
 Two mechanisms for host T-cell alloantigen recognition are
known to exist
 Survival of allografts is prolonged using immunosuppressive
agents including anti-inflammatory agents, cytotoxic agents,
antimetabolites, and using agents that interfere with IL-2
production and cytokine-mediated signaling.
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55. References
 Text book of microbiology – Ananthanarayan &
Paniker’s, 9th edition.
 www.immunology.org/policy-and-public-
affairs/briefings-and- positions-statements/transplant-
immunology
 https://www.slideshare.net/mobile/ARYAGEORGE1/gr
aft-rejection
 https://www.slideshare.net/mobile/svasan3/transplant-
rejection
 www.quora.com/what-are-the-types-of-graft-and-their-
resources
 https://www.slideserve.com/kurene/immunology-of-
transplantation- malignancy
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56. Thanks
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