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9.1 What is the major histocompatibility complex and what is its function?
The major histocompatibility complex or MHC is located on the short arm of chromosome 6 and includes the genes that encode for the principal molecules of the human immune system. Within this complex are the genes that code for HLA molecules that can be divided into two regions: the class I region, where HLA-A, B, and C genes are located; and the class II region, which contains the HLA-DR, DQ, and DP genes. There is also a class III region which does not contain any HLA genes but genes encoding complement factors (C3 and factor B), tumour necrosis factor (TNF) alpha, heat shock proteins (HSP), and other genes involved in immune function.
9.2 What are the main functions of HLA class I and HLA class II antigens?
The main function of HLA molecules is the presentation of foreign molecules, in the form of peptides, to the immune system. In this way T-lymphocytes, cells of the adaptive immune response, can be activated. Pathogens that reside inside cells, such as viruses, are degraded by intracellular structures known as proteasomes, some of the genes of which are located within the MHC. The peptides produced by this degradation are between eight and ten amino acids in length, just the right length to be loaded into the peptide binding groove of HLA class I molecules. These newly formed HLA class I molecules containing antigenic peptide are transported to the cell 4 surface and present their peptides to predominately CD8 positive (cytotoxic) T-lymphocytes. Pathogens that reside outside the cell, such as bacteria, can be taken up by phagocytosis or pinnocytosis and degraded in the endosome, normally by acid digestion. The peptides produced are of varying length and are loaded into the peptide binding groove of an appropriately complementary HLA class II molecule. These newly formed HLA class II molecules are transported to the cells surface where they present their peptides to predominately CD4 positive (helper) T-lymphocytes.
9.3 What is the importance of HLA typing in solid organ transplantation?
The importance of the HLA system in transplantation was first seen in renal transplantation where it was observed that graft survival was improved in transplants between siblings when compared to unrelated or deceased solid organ donors. In solid transplants between parents and children where only one HLA haplotype is shared, graft survival was observed to be at a level between that seen in identical sibling and deceased donor transplants. Data from all solid organ transplants centres worldwide have all shown the benefits of HLA matching through analysis of the outcome of thousands of transplants. Independently many of these studies have shown a hierarchy in the effect of the different HLA loci on graft survival where HLA-DR matching is shown to the most beneficial when compared to HLA-A or B matching. The importance of HLA in solid organ transplantation differs with the type of organs transplanted. The immediate problem with transplanting an organ is the presence of preformed HLA and ABO blood group antibodies, which can cause the rapid rejection of the organ. Therefore, prior to transplantation every eff ort is made to detect and define donor specific antibodies and where possible the HLA type of the donor and recipient is matched to limit graft rejection.
9.4 What measures have transfusion services introduced to reduce the incidence of HLA-related adverse effects of transfusion?
Universal leucodepletion of all blood components in the UK was introduced as a measure to prevent transfusion transmitted vCJD but a number of studies have reported a that the incidence of FNHTR has been reduced since the advent of leucodepletion. The decrease in the number of leucocytes in each component transfused not only presents fewer targets for leukocyte reactive antibodies but also reduces the probability of sensitization in the non-sensitized patient. Leucodepletion can also reduce the likelihood of a patient being sensitized to produce HLA and HPA antibodies. Although there is no effective treatment of TA-GVHD and the mortality rate is extremely high, the introduction of universal leucodepletion in the UK has been associated with a significant reduction in the number of reported cases of TA-GVHD. However, the residual lymphocyte numbers may still be enough to initiate TA-GVHD. Transfusion related acute lung injury reduction measures introduced include: • The production of FFP from donations collected from male donors. • The use of male donor plasma to re-suspend pooled platelets. • The preferential recruitment of male apheresis donors. • HLA and HNA antibody screening of all new female apheresis donors added to the panel.
9.5 Why does xenotransplantation serve as an excellent model in our understanding of how our immune system responds to a foreign graft?
Xenotransplantation research has revealed how organs are rejected by hyperacute and acute rejection, and how the graft interacts with key soluble components of blood that will infuse it and potentially destroy it.