Matching

By Dom Spinella

Your immune system is a wonderous collection of white blood cells and other cell types that interact with each other to defend you against invasion by microbes, viruses, fungi and toxins. Without it, you would quickly succumb to these invaders. This defensive army is on constant patrol for “foreign” molecules  collectively known as ‘antigens’ – proteins, sugars, and other substances that are not supposed to be there, and it attacks them with a variety of weapons including T-cells that can directly destroy foreign tissues, and B-cells that make antibodies which attach to antigens and mark them for destruction.

As you probably remember from your high school biology, all tissues and organs are made of cells.  And like icebergs floating in polar seas, these cells have thousands of different kinds of molecules embedded in their surface.  These are mostly proteins although some of these proteins have other kinds of molecules like sugars or lipids attached to them.  They all have a function and their presence is in part what differentiates, say, a blood cell from a kidney cell, from a liver cell, etc.  These “cell surface” proteins are encoded by our genes which, of course, are inherited from our parents.  Now, these proteins can differ slightly between individuals because of sequence differences in the DNA of the genes that encode them.  These genetic variations, called “alleles,” are collectively what makes us individuals who differ from each other.   But the immune system did not evolve with transplants in mind and unfortunately, many of those genetic differences lead to variations in antigens that can be recognized as foreign and attacked. Unless we are dealing with transplants between identical twins, there are many such antigenic variants that differ between the donor and recipient.  However, there are two that are particularly important:  The ABO blood group antigens and the HLA antigens.   

The ABO antigens are what make up the “blood types” that we are all familiar with.  Although they are often called blood group antigens because they are found on red blood cells and are of critical importance when receiving a blood transfusion, the ABO antigens are also found on other tissues as well – including kidney tissue.  They are actually short chains of sugar molecules called “oligosaccharides” that are affixed to cell surface proteins.   People with an A blood type have at the end of the chain the “A sugar” (OK, N-acetyl galactosamine if you must know) and recognize the “B-sugar” (galactose if you’re a geek like me) as “foreign”; people with type B blood have the B-sugar at the end of the chain and recognize the A sugar as foreign; people with type AB blood have both sugar types and recognize neither as foreign, while people with type O blood have neither sugar and recognize both as foreign.  The reason why the ABO antigens are so critical to both transfusion and transplant is that these same sugar antigens are also present on many common bacteria that inhabit our gut and other tissues.  Our immune systems encounter them frequently and continually produce large quantities of antibodies in response.  So if you are, say, of blood type O, you already have antibodies to the A and B antigens – even before you receive a transfusion or a transplant. If you now receive a transfusion of an incompatible blood type, those antibodies will attack the transfused cells, causing them to clump together and clog up blood vessels and capillaries leading a what’s called a “transfusion reaction” which can be fatal.  Similarly in the case of an organ transplant, those same antibodies will attack the A or B antigens on the organ and quickly lead to its destruction – a phenomenon called “hyperacute rejection.”  So the first component of “matching” is to ensure ABO blood type compatibility.

The next order of business to determine compatibility involves the “Human Leukocyte Antigens” or HLA.  These are group of cell surface proteins that are actually important parts of the immune system.  We need not go into their function here but it is important to know two things.  First, these are extremely potent antigens and provoke a very vigorous response. When the immune system rejects an organ, it is usually the HLA antigens that are the main target.  There  are 12 HLA genes closely linked to each other, but three of them are particularly relevant to kidney transplantation:  HLA-A, HLA-B and HLA-DR.  Second, each one of these genes has many variants (alleles) that lead to subtle differences in the protein structure that can provoke an immune response.  Most people inherit different variants of all three genes from each parent meaning that they have six different variants – two for each gene one from mom and the other from dad.   In general, the more matches between the donor and recipient, the better for the long-term survival of the transplant, and you may hear people say they have “6 out of 6” matches, or “3 out of 6 matches”  (usually because their donor was a parent or sibling). However, most transplants between unrelated donors and recipients will have few or no matches at all (I myself have a transplant from my brother-in-law with 0/6 matches).  

Modern immunosuppressive drugs  can prolong the survival of such mismatched transplants, but it may require more intense immunosuppression and more frequent monitoring for rejection.  There are many other factors that affect long-term survival of the transplant as well – including age of the donor, whether a living or deceased donor, and the overall health of the recipient, the length of time on dialysis prior to transplant, etc. While HLA matching is not essential for transplant eligibility, what IS critical is to ensure that there are no pre-existing antibodies in the recipient to the HLA variants of the prospective donor.  That can occur because of prior transplant, transfusion, or pregnancy.  Even some viral infections can give rise to anti-HLA antibodies.  Therefore all potential donors and recipients are “cross-matched.”  There are a number of ways to perform cross-matching.  Often, the blood cells of the prospective donor and recipient are mixed in a test tube to make sure that there is no immune reaction on the part of the recipient to the prospective donor’s blood cells (which also express HLA antigens.)

So there you have it:  Matching basically determines whether the donor and recipient have compatible blood types, and if the recipient has any pre-existing immune reactivity against the donor’s HLA antigens.  Finally, the degree of HLA mismatch is determined, not as a precondition for transplant, but to give the nephrology team an idea of the level of immune suppression that will likely be necessary to forestall rejection and keep the new kidney healthy for as long as possible.

Keep in mind however, that most centers do “paired transplants” such that even if your donor is not a match for you, there may be another patient for whom he/she IS a match and who has a potential donor in the same situation — not a match for them, but a match for you.