Description of various immunological mechanisms involved in the rejection of transplants. Lecture notes for medical, dental and allied health sciences undergraduate medical students.

1. Transplantation immunology

2. Transplantation
❑ Graft or Transplant: Transfer of living
cells, tissues and organs from one part
of the body to another or from one
individual to another.

3. Types of grafts
• Autologous graft (autograft) – in the same individual: from one site to
another one
• Isogenic (isograft) – between genetically identical individuals
• Allogeneic (allograft or homograft) – between different members of the
same species
• Xenogeneic (xenograft) – between mmbers of different species

4. Autograft
• The transfer of self tissue from one body site to another in the same
individual
• Due to the genetic homology of the tissue, the immune system does not
respond to it
• Use: synthetic implantation
➢ skin grafts
➢ bone marrow transplantation
➢ hair

5. Allograft
• Definition:The transfer of organs or tissue from human to
human.
• Allografting transplantation has many applications.

6. Xenotransplantation
Definition: – the transfer of tissue from one
species to another
Usually refers to the implantation of animal
tissue in humans
➢ provides a new source of organs for humans
➢ many different types of tissue can be
transplanted:
e.g. heart, kidney, liver or lung

7. Immunological basis of graft rejection

8. Transplantation antigens
• Major histocompatibility antigens (MHC molecules)
• Minor histocompatibility antigens
• Other alloantigens

9. Histocompatibility Complex (MHC)
– gene complex whose alleles encode polymorphic cell surface
glycoproteins
– nomenclature
• HLA: human leukocyte antigen
• SLA: porcine leukocyte antigen
• H-2: mouse MHC
• RT1: rat MHC

10. Major histocompatibility antigens
• Main antigens of grafts rejection
• Cause fast and strong rejection
• Difference of HLA types is the main cause of human grafts
rejection

11. Major Histocompatibility Complex
(MHC):
– Class I antigens: constitutively expressed on
surface of most cells
– Class II antigens: expressed on cells of
lymphoid system
– Expression of MHC molecules can be
upregulated by ischemia, etc.
– nomenclature
• HLA (human) class I: A, B, C; class II: DR, DQ
• H-2 (mouse) class I: K, D, L; class II: IA, IE

12. Short arm of Chromosome 6

13. Comparing MHC Class I and II
Properties Class I Class II
ANTIGENS HLA-A, B, C HLA-D-DR/Q/P
TISSUE On virtually B-cell, dendritic
DISTRIBUTION all cells cell, macrophage
FUNCTIONS Endogenous Ag Exogenous Ag
presented to CD8 presented to
(cytotoxic) T-cells CD4 (T-helpers)

15. Minor histocompatibility antigens
• Also cause grafts rejection, but slow and weak
• Mouse H-Y antigens encoded by Y chromosome
• HA-1～HA-5 linked with non-Y chromosome

16. Other alloantigens
• Human ABO blood group antigens
• Some tissue specific antigens

17. • Cell-mediated Immunity
• Humoral Immunity
• Role of NK cells
Mechanism of allograft rejection

18. Cell-mediated Immunity
• Recipient's T cell-mediated cellular immune response against
alloantigens on grafts

20. Features of CMI
• Slow and weak
• Late phase of acute rejection and chronic rejection
• Coordinated function with direct recognition in early
phase of acute rejection

21. • Important role in hyperacute rejection
(Preformed antibodies)
– Complements activation
– ADCC
– Opsonization
Humoral immunity

22. Role of NK cells
• Cytokines secreted by activated Th cells can promote NK
activation

23. • Host versus graft reaction (HVGR)
– Conventional organ transplantation
• Graft versus host reaction (GVHR)
– Bone marrow transplantation
– Immune cells transplantation
Classification of Allograft Rejection

24. Host versus graft reaction (HVGR)
• Hyperacute rejection
• Acute rejection
• Chronic rejection

25. • Occurrence time
– Occurs within minutes to hours after host blood
vessels are anastomosed to graft vessels
Hyperacute rejection

26. • Mechanisms
– Preformed antibodies
• Antibody against ABO blood type antigen
• Antibody against HLA antigen

27. • Occurrence time
– Occurs within days to 2 weeks after
transplantation, 80-90% of cases occur within 1
month
Acute rejection

28. • Mechanisms
–Vasculitis
• IgG antibodies against alloantigens on endothelial cell
–Parenchymal cell damage
• Delayed hypersensitivity mediated by CD4+Th1
• Killing of graft cells by CD8+Tc

29. • Occurrence time
– Develops months or years after acute rejection
reactions have subsided
Chronic rejection

30. • Mechanisms
– Not clear
– Extension and results of cell necrosis in acute rejection
– Chronic inflammation mediated by CD4+T cell/activated
macrophages
– Organ degeneration induced by non immune factors

31. Graft versus host reaction (GVHR)
• Graft versus host reaction (GVHR)
– Allogenetic bone marrow transplantation
– Rejection to host alloantigens
– Mediated by immune competent cells in bone marrow
• Graft versus host disease (GVHD)
– A disease caused by GVHR, which can damage the host

32. Graft versus host disease

33. Conditions
• Enough immune competent cells in grafts
• Immunocompromised host
• Histocompatability differences between host and
graft

34. • Bone marrow transplantation
• Thymus transplantation
• Spleen transplantation

35. Acute GVHD
• Endothelial cell death in the skin, liver, and
gastrointestinal tract
• Rash, jaundice, diarrhea, gastrointestinal
hemorrhage
• Mediated by mature T cells in the grafts

36. • Acute graft-versus-host reaction with
vivid palmar erythema

37. Chronic GVHD
• Fibrosis and atrophy of one or more of the organs
• Eventually complete dysfunction of the affected organ

38. Both acute and chronic GVHD are commonly
treated with intense immuno-suppresion
• Uncertain
• Fatal

39. Tissue matching
• ABO and Rh blood typing
• Crossmatching (Preformed antibodies)
• HLA typing
– HLA-A and HLA-B
– HLA-DR
– Microcytoxicity assay

40. • Microcytoxicity assay for
MHC haplotypes
• If antigen is present on
cell, complement will
lyse it, and it will uptake
dye (blue)
• Donor 1 has antigens in
common with recepient

41. Mixed Lymphocyte Reaction:
DonorRecipient
(Irradiate) Cell Proliferation
❑ Strong Proliferation--->High incompatibility
❑ Weak proliferation--->Low incompatibility
❑ No proliferation---> 100% compatibility
❑ Helps to identify any antigenic differences between
donor and recipient
+

42. Immunosuppressive Therapy
• Cyclosporine
– Inhibit NFAT transcription factor
• Azathioprine, Cyclophosphamide
– Block the proliferation of lymphocytes
• Ab against T cell surface molecules
– Anti-CD3 monoclonal Ab----Deplete T cells
• Anti-inflammatory agents
– Corticosteroids----Block the synthesis and secretion
of cytokines

43. Monoclonal antibodies
• an antibody produced by a single clone of cells or cell line and
consisting of identical antibody molecules.

47. Producing Monoclonal Antibodies
1. Inject a mouse with a specific antigen to stimulate its immune
system to produce necessary antibodies.
2. Extract mouse spleen cells (containing B-lymphocytes) and
culture them in the lab.
3. Extract mouse tumour cells, which grow continuously, and
culture them in the lab.
4. Mix spleen cells and tumour cells on the same plate and
culture.

48. Producing Monoclonal Antibodies
5. Add polyethylene glycol – this causes some B-lymphocytes to fuse
with tumour cells to produce a hybrid cell called a hybridoma.
6. Grow the cells under conditions that allow only hybridoma cells to
survive.
7. Extract the cells, culture them separately and test the medium
around each cell for the specific antibody of interest.
8. Culture the cells making the desired antibody and use as needed.