TRANSPLANTATION NOTES

TYPES OF TRANSPLATATION

Transplantation can be carried out in two different types, Solid organ and bone marrow/cell
(link to lecture 2)

USE OF TRANSPLANTATION

-It is used to replace damaged organs/tissues( kidney,liver,cornea)

-To correct serious metabolic abnormalities( pancreas)
-To cure fatal disease ( heart, lung)
-Missing tissues( womb )
The treatment of organ transplantation is of choice for end stage failure of organs. A donor
graft include; kidney, liver, heart, lung, cornea, pancreas, skin and an allograft is a donor
( not self) recipient not genetically identical

TISSUES DERIVERENCE

-The tissues donated come from living donor related and non related people and dead
donors( non related kidneys)

LIMITATIONS

-shortage of organs
-half life of a transplant 10 years
-immunosuppressive drugs
-graft rejection
-The major obstacle to successful transplantation within a species is components the
recipients immune response

IMMUNE CELLS

-innate cells such as monocytes, macrophages, natural killer cells and granulocytes
-adaptive cells are immunoglobulin B lymphocytes and TCR T lymphocytes which recognise
‘non self’ antigens including bacteria and transplant tissue

COMPONENTS IN IMMMUNE SYSTEM REJECTION

-Cytokines( pro inflammatory)

-Complement
-Antibodies
-Clotting factors
TYPES OF REJECTION

-Hyperacute rejection (hours)

-Acute rejection(weks)
-Chronic allograft dysfunction – chronic rejection( years)

Hyperacute rejection

Leads to very early graft loss (48 hours), preformed antibodies-(Igm e.g ABO) , (IgG- e.g. HLA
class I, class II ). Antibodies present 1% of the population that can react to cell surface
carbohydrates(a-Gal), blood group antigen and MHC molecules. It also triggers the
activation of clotting ad complement cascade leading to intravascular thrombosis,
inflammation, Ischemia and subsequent necrosis as pre transplant cross match. Hyperacute
rejection is due to antibodies that react with endothelium causing hyperacute graft rejection

Acute Rejection

It causes parenchymal cell damage, inflammation and endothelialitis. Due to alloantigen

specific CD4+ and CD8+Tcells binding to alloreactive antibody on the endothelial cell
connected to the parenchymal cells.

Chronic Allograft Dysfunction

This causes slow deterioration of graft function and is typically irreversible and leads to the
complete loss of graft function. Also leads to non immune and immune( chronic rejection)
pathogenesis. The effects are chronic inflammatory reaction in vessel wall, intimal smooth
muscle cell proliferation and vessel occlusion. Alloantibodies also play part in chronic
rejection as they recruit inflammatory cells to the blood vessel wall of the transplanted
organ leading to increasing damage which enables immune effectors to enter the tissue of
the blood vessel wall and to inflict increasing damage

Themajor obstacle in transplantation success within a species is the immune response

induced by donor MC molecules( alloantigens)

ALLORECOGNITION

Is the recognition of donor MHC molecules by the recipients cells which two main types of
MHC molecule are class I and clas II. MHC class I includes all cells except RBCs and MHC class
II is APCs. MHC is important in graft rejection as it improves the survival of transplanted
kidneys.

RECOGNITION OF MHC BY T CELLS and MHC frequency

-T cells recognise donor MHC using T cell receptors TCR

-In T cell development TCR genes are rearranged and the TCR expressed on the cell surface.
-Each generated TCRs are inherently cross reactive and able to recognise alloMHC
molecules. A high frequency of alloreactive T cells also exist and if the recipient had around
1-10% recipient T cells, the donor might be rejected.
• Up to 1-10% of naïve T cells leaving the thymus exhibit recognise intact donor MHC
molecules (cross-reactive T cells)
• Both CD4 and CD8 human T cells display this cross-reactivity
• <0.01% are specific for any foreign antigen recognised in the context of self-MHC
molecules

SELF MHC-RESTRICTED T CELLS RECOGNISING ALLOGENEIC MHC

• TCR cross-reactivity
• Pathogen specific T cells cross-react with alloMHC
• 45% of viral-specific memory T cells specifically cross-react with at least one HLA
molecule
The recognition of donor MHC occurs on dendric cells and there are two sources of dendric
cells(DCs) in transplantation, donor DCs snd recipient DCs presenting Ag from the graft.

There are 3 ways of presenting alloantigens to the recipient T lymphocytes, through a direct
pathway, semi direct pathway, indirect pathway represented in early post-tx as acute or late
post-tx as chronic.

DIRECT PATHWAY OF ALLORECOGNITION

The direct pathway of allorecognition is formed by CD8+ cytotoxic T cell TCR being a donor
for MHC class I and CD4+ helper T cell in MHC class II as the classes would be the
allogeneic( donor) antigen presenting cell.
• Initial site of encounter: Peripheral LN
• “Passenger” donor DC
• Activation of recipient T cell with direct specificity
• High frequency of ‘direct’ recognising T cells exist pre-transplant
• Direct pathway declines with time as the DCs die
Some donors persist in the graft whilst most migrate out to dLNs. The direct pathway
declines with time as the DCs aree killed by NK cells.

INDIRECT PATHWAY

In indirect pathway, the removal of recipient DCs prolongs graft survival.

• Later site of encounter: Peripheral LN
• Involves the recipient DCs
• Recipient DCs presenting peptides derived from donor cells

T CELL WITH INDIRECT SPECIFICITY

• Recognised processed allogeneic MHC molecule presented as a peptide (similar to

recognition of foreign peptide/self-MHC complexes) on autologous APC
 • non detectable in non transplanted individuals but following transplantation
their frequency increases
• involved in chronic rejection.

THE SEMI-DIRECT PATHWAY

Consist of transfer of intact MHC class I and II allo MHC molecules to donor DCs.