ORGAN TRANSPLANTATION

HISTORICAL BACKGROUND

• Failed initially due to lack of appreciation of immune response

• 1954 – renal transplant between identical twins

• 1960 – first immunosuppressive drugs were used

• 1980s – more powerful ciclosporin permitted transplantation of liver, heart, lungs, pancreas

CLASSIFICATION OF GRAFTS

• AUTOGRAFT – from one part of the body to another e.g. skin

• ALLOGRAFT – between members of the same species e.g. human to human

• ISOGRAFT – between identical twins• XENOGRAFT – between different species e.g.

pig to human• STRUCTURAL GRAFTS – biological (arterial and

heart valve grafts) or synthetic (Dacron)

• ORTHOTOPIC – diseased organ is removed and replaced by the transplanted organ in the normal anatomical position e.g. heart, lung, liver

• HETEROTOPIC – the transplanted organ is placed in a different position to the normal anatomical position e.g. kidney and pancreas

ORGAN DONORS

• 2 sources:– LIVING – Applies mainly to kidney transplantation,

where the donor can maintain adequate renal function with only one kidney

– DECEASED – those who have sustained lethal brainstem injury following a head injury, intracranial haemorrhage or primary brain tumour

• ASYSTOLIC DONATION – organs are removed from the donor after cardiac arrest; possible for kidney and liver

EXCLUSIONS TO ORGAN DONATION

There are three main reasons why a potential donor may be unsuitable:

1. Potential transmission of infection – hepatitis B, C and HIV

2. Malignancy – except low-grade primary brain tumours

3. Impaired function of donor organ – e.g. heart with severe coronary artery disease

ORGAN PRESERVATION

• Organ must be maintained in its optimum state

• Achieved by combination of – cooling the organ to 4°C to reduce metabolic

activity and– Perfusing it with and storing it in a preservation

solution that acts as a buffer and prevents cell swelling by osmosis

ISCHEMIA TIMES - TERMINOLOGY

• WARM ISCHEMIA – Donor warm ischemia – starts from the time of

asystole until cold perfusion begins– Recipient warm ischemia – starts from the

removal of the organ from ice until reperfusion• COLD ISCHEMIA – time between the end of

donor warm ischemia until the onset of recipient warm ischemia

ORGAN RECIPIENTS

• No one should undergo transplantation unless fit enough to withstand the operative procedure

IMMUNOLOGY

• Major histocompatibility complex (MHC)– When an organ is transplanted, it is recognized as

foreign by the host’s immune system and the rejection response is initiated

– This recognition is initiated by an interaction between T cells and histocompatibility antigens on the surface of the donor organ

– The MHC is a group of genes that encode molecules (antigens) expressed on the surface of cells

• Human leucocyte antigen system– This system describes the locus on chrmosome 6

containing the genes encoding the MHC antigens

ORGAN MATCHING

• 3 LEVELS:1. ABO matching2. Lymphocytotoxic cross-matching3. MHC matching

ABO MATCHING

• Required for all transplants• Presence of preformed ABO antibodies means

that the transplanted organs must be ABO compatible

• Crossing the ABO barrier results in hyperacute rejection

LYMPHOCYTOTOXIC CROSS-MATCH

• To detect circulating antibodies in the recipient against donor HLA antigens, a direct lymphocytotoxic cross-match is performed

• Donor cells (lymphocytes) mixed with recipient sera in the presence of complement and observing for cytolysis

MHC MATCHING

• In order to minimize the immune response to an organ allograft, the recipient’s MHC antigens can be matched to the donor

• Perfect matching comes from an identical twin

REJECTION

• Hyperacute rejection• Acute rejection• Chronic rejection• Graft versus host disease

HYPERACUTE REJECTION• Occurs immediately• Preformed antibodies to donor HLA I antigens• Intravascular thrombosis and interstitial

haemorrhage• Is prevented by ensuring compatibility

ACUTE REJECTION• Occurs within 6 months• T-cell dependent• May be cell-mediated, antibody mediated or

both• Mononuclear cell infiltration of graft• Treated by increasing immunosuppressive

therapy

CHRONIC REJECTION• Occurs after months to years• Antibodies• Risk factor – recurrent acute rejection• Myointimal proliferation – ischemia and

fibrosis

GRAFT VERSUS HOST DISEASE• Some donor organs (liver and small bowel)

contain large numbers of lymphocytes• These may react against HLA antigens

expressed by recipient tissues• Characteristic rash on palms and soles

IMMUNOSUPPRESSIVE THERAPY

• Is a balance between giving enough drug to prevent rejection, but not too much to cause infection

• Usually consists of a steroid (e.g. prednisolone), an antinucleotide such as azathioprine and an inhibitor of T-cell activation such as ciclosporin

COMPLICATIONS

• EARLY: may be related to the four components of transplant surgery:1. The surgical operation – wound infection,

anastomotic breakdown2. The quality of the organ – long cold ishemia

time, less well performance3. The immunological response 4. The effects of immunosupression – infective

complications (wound, chest, viral)

• LATE:1. Immunological complications – acute and

chronic rejection2. Immunosuppressive complications – drug side-

effects, infection, malignancy3. Recurrent disease – e.g. hepatitis B and C may

re-infect a transplanted liver