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TRANSPLANTATION GENETICS

M.Tevfik Dorak, MD, PhD

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Various histocompatibility loci play a role in transplantation genetics. The most important one in the determination of the fate of a transplanted cell/tissue/organ is the major histocompatibility complex (MHC). The MHC exists in all vertebrates examined to date (from the Xenopus and shark to humans) and similar histocompatibility systems exist even in invertebrates. The MHC was first identified through tumor transplantation studies in mice by Peter Gorer in 1937. This is why it is called a histocompatibility complex but it has many more biological functions (for details, click here). George Snell, Jean Dausset and Baruj Benacerraf received the Nobel Prize in 1980 for their contributions to the discovery and understanding of the MHC in mice and humans (other noteworthy names in the HLA field are Jon van Rood, Adriana van Leeuwen, Jan Klein, Walter Bodmer, John Trowsdale and Peter Parham). The MHC is the most polymorphic expressed genetic system. This looks like a price to pay in transplantation for the other biological functions of the MHC (e.g., avoidance of inbreeding). The main function of the classical MHC antigens is peptide presentation to the immune system to help distinguishing self from non-self (even protists have systems to recognize self and non-self). It is called human leukocyte antigens (HLA) in humans and consists of three classical regions: class I (HLA-A,B,Cw), class II (HLA-DR,DQ,DP) and class III (no HLA genes). HLA matching also has some relevance in blood and blood products transfusion under special circumstances.

Histocompatibility systems:

MHC

mHAg (minor histocompatibility antigen)

Sex-linked histocompatibility systems (H-Y antigen coded by SMCY)

Blood groups

MHC typing:

Cellular (mixed lymphocyte reaction for HLA-Dw, primed lymphocyte test for HLA-DP)

Serological (HLA-A,B,C,DR,DQ)

Molecular (HLA-A,B,C,DR,DQ,DP)

Other histocompatibility tests:

Mixed Lymphocyte Reaction (MLR)

Lymphocyte cross-matching

Other cellular assays to detect the precursor frequency of (cytotoxic or helper) lymphocytes sensitized against the mismatched HLA antigen

Donor sources:

Patients themselves (autologous)

HLA-identical siblings (allogeneic)

HLA-mismatched siblings or other related/unrelated subjects

HLA-matched unrelated donors

Cadaver donors (HLA-matched or mismatched)

Cloned human embryos, tissue engineering? [see Sci Am April 1999 issue]

Most commonly used transplantations:

Bone Marrow Transplantation (Hematopoietic Stem Cell Transplantation): HLA matching is an absolute requirement, and even mHAg differences may result in immunological complications. Associated with graft-versus-host disease (GvHD; an attack of immunocompetent donor cells to immunosuppressed recipient cells), engraftment failure and high probability of rejection (reverse of GvHD). The first two complications correlate with the degree of histocompatibility (so does the infection risk). Thus, its use is limited by the availability of HLA-matched donors. The alternatives are autologous BMT, cord blood/fetal liver stem cell transplantation, and xenogenic transplantation. Cord blood stem cell transplantation has been clinically evaluated and the GvHD incidence is much lower than in conventional BMT. This is due to the lower immunogenicity and lower immune capability of the umbilical cord cells. Likewise, intra uterine BMT can be attempted to exploit the immaturity of the fetus' immune system. It is also possible to use gene therapy to lower the risk of immunological complications due to HLA-mismatching (such as the addition of adenovirus E3 genes which hide the cells from the immune system "stealth technology").

Pancreatic islet cell transplantation: For the treatment of Insulin-Dependent Diabetes Mellitus.

Cornea transplantation: HLA matching is not very relevant (at least HLA-DR) mainly because of the lack of vascularization of the cornea but also because of the immunological privilege of the cornea.

Solid organ transplantations: Kidney, Liver, Heart, Lung, Pancreas, Intestine. HLA matching is not crucial but beneficial.

Internet Resources

Transplantation in Merck Manual

Organ Transplantation (Kimball)

HLA Typing & Organ Transplantation by Bainbridge et al (PPT)

MHC and Transplantation Chapter in Online Immunology Textbook

MHC Diversity .. Structure and Function of MHC Proteins

HLA-Related Links

M.Tevfik Dorak, M.D., Ph.D.

Last updated on 9 November2006

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