Transplant Medicine the Major Histocompatibility Complex (MHC)

Transplant Medicine

The Major Histocompatibility Complex (MHC) contains over 128 functional genes. This is the densest part of the human genome and is responsible for most autoimmune diseases. This region also determines vaccine responsiveness, adverse drug reactions, disease progression and transplant rejection. The MHC genes are multigenic with a high degree of allelic polymorphism. There are over 7,500 different alleles and over 5,458 expressed MHC antigens currently known. (DeFranco, Locksley & Robertson, 2007). Genomic evolution and HLA screening have been extremely profitable to Transplant Medicine.

A brief analysis of MHC variability reveals two classes of antigens belonging to this complex; class I (A, B, and C) and II (DR, DQ, and DP). Both classes of molecules are expressed in a co-dominant fashion. These molecules are designed to recognize antigens that are foreign to the body and present them to the T cells. (Janeway, Travers & Walport, 2001)

The co-dominant mode of inheritance of MHC genes assures that each individual will have a distinct antigen on their cell surface. This forms the basis of graft rejection. Once a foreign antigen enters the human body, activation, proliferation and differentiation of lymphocytes into effector cells continues until the foreign antigen is eliminated, after which the immune system returns to its quiescent state and an immunologic memory is generated. (Janeway, Travers & Walport, 2001)

Tissue typing to match HLA antigens is an important step before transplantation. In general, the larger the number of matched MHC alleles between the donor and the recipient, greater are the chances of graft survival. However, routine HLA typing focuses only on HLA-A, B and DR antigens because these are the only loci that appear to predict the likelihood of graft rejection. (Janeway, Travers & Walport, 2001)

The extreme polymorphism of the MHC genes poses several challenges in recognizing the perfect donor, thus complicating HLA typing. The HLA nomenclature differs with the type of typing method used. Refinement of the serological typing of HLA antigens through the years has led to the identification of additional gene loci, which were previously thought to yield one antigen. For example, the B. 60 and B. 61 antigen were previously thought to be one antigen, the B. 40, based on their common ability to bind to a shared public epitope. Moreover, serology does not recognize heterogeneity of HLA antigens, as confirmed by DNA sequencing. Thus serological nomenclature is not representative of the true heterogeneity of the HLA system. HLA typing through this method may lead to a greater risk of graft rejection. (Badders, Houp, Sholander, Leffell & Zachary, 2010)

Further more, three different nomenclatures exist for defining HLA antigens. It is important to be able to appreciate the differences of each molecular typing nomenclature and to know which system is being used in the laboratory. Failure to do so may result in missed recognition of a donor specific antibody. (Badders et al., 2010)

Apart from the likelihood of graft rejection, recipients are faced with several challenges, such as prolonged waiting times and donor shortage, especially for sensitized individuals since they have additional immunological barriers. From 2000-2008, a total of 243,662 candidates were on the waiting list for kidney transplantation, with only 62,622 available donors in the United States. The broadly sensitized patients have average waiting times twice that of un-sensitized patients. It has been observed that the proportion of patients that are broadly sensitized have been increasing through the years. (Reinsmoen, Lai, Vo & Jordan, 2012)

Sensitization to HLA antigens occurs through exposures from blood and platelet transfusions, pregnancy and previous transplants. Examining the sera of patients against cells from a panel of HLA typed donors can identify sensitized individuals. The results are used to calculate panel reactive antibodies (PRA) or the percentage of population that the anti-human antibody, present in the blood, reacts with. Sensitized individuals have a higher PRA and are less likely to receive organ transplants due to an increased risk for immediate graft rejection. (Reinsmoen et al., 2012)

Calculated PRA and virtual cross-match have proven to be an important means to identify compatible donors for sensitized patients. The histocompatibiilty and immunogenetic laboratories use strategies to identify unacceptable HLA antigens for each prospective donor. These antigens are then registered on the database so that individuals expressing these antigens are not considered as compatible donors for a given patient. The computer then performs a virtual cross-match with the registered donors against every blood group-eligible patient on the transplant list. (Reinsmoen et al., 2012) In a study by Appel et al. (2006), virtual crossmatch increased the donor pool for sensitized patients waiting for lung transplants, thus decreasing the average waiting time and death for such patients. The study also concluded that virtual crossmatch eliminates the need for pre-transplant crossmatch and is an effective approach for thoracic organ transplantation.