Nine-year-old Laura Mosley has been battling leukemia for most of her short life. The chemotherapy she underwent destroyed her bone marrow’s ability to produce blood cells, so she had to have a bone marrow transplant. Blood-forming cells from another person were injected straight into her bloodstream. She responded well, and her blood cell counts steadily rose. Then a few months later, her body began to reject the marrow. Despite all the tests that had been done beforehand to make sure that the transplant would be successful, the donor’s cells apparently didn’t match her cells closely enough. Laura is now back on the waiting list. Her family members, friends, and even people in her community gotten tested to see if they might be a match for her, but so far, she has had no luck.
Finding someone with a matching tissue type is very difficult, much more so than finding someone with a matching blood type. Tissue type depends on a set of proteins called Human Leukocyte Antigens, or HLA. These antigens can be found on the surface of nearly every cell in the body, including blood cells. They serve as “self” markers, meaning that they allow the body’s immune cells to differentiate between the body’s own cells and foreign cells, like bacteria or viruses. If the free-floating immune cells ever encounter a cell without the right HLA markers, they recognize the cell as foreign and attack it. Thus, HLA is an indispensible component of the immune system. Unfortunately, it also complicates tissue transplants. If the donor HLA type is not similar enough to the recipient’s HLA type, the recipient’s immune cells will attack the blood cells that have formed from the donor’s marrow.
The oldest way to type potential donors’ tissue is serotyping, a technique based on antibody-antigen recognition. Antibodies are proteins produced by the body. These proteins are designed to bind specific antigens, almost like a lock (the antibody) and a key (the antigen). Once the antigen-antibody complex is formed, the antigen is marked for destruction. A person with a specific antigen on their cells will not produce the antibody that binds with it; otherwise the antibodies would attack the body’s own cells! So let’s say that we are looking for a donor with the antigen HLA-B21. We would take a sample of the potential donor’s serum, which is what you get when you take the cells and clotting factors out of the blood. Then we would add an antibody that is known to bind with antigen HLA-B21 to the serum. If we observed evidence of binding, like clumping of the sample or a color change, then we would know that HLA-A is present in the sample. If it is present in the sample, then it is present on all of potential donor’s cells.
Serotyping antibodies have become more and more refined over time, and are increasingly sensitive to slight differences between different types of antigen. But there are limitations to this technique. Serotyping does not preclude the possibility that the transplant will be rejected, as was the case with Laura. The differences between antigens are often so minute that they will bind with the same antibody. Thus, the donor and recipient antigens appear to be the same, when in fact they are “subtypes” of a particular antigen. The differences between the two subtypes may be enough to activate the recipient’s immune response.
Another higher-resolution technique based on DNA matching is now the preferred method for tissue typing. Three or more different loci (or regions) on the gene that codes for HLA are examined. A perfect match at these loci is ideal, though nearly impossible to find, unless the patient has an identical twin. Of course, most people do not have a twin, so they look for a match among their relatives. According to the National Marrow Donor Program, however, the chance that a patient will find a match this way is only 35 percent, so most patients rely on unrelated volunteers. Sadly, only four out of ten people looking for an unrelated donor actually get a transplant. Part of the reason that it’s so difficult to find a suitable match is that there are many different forms of the HLA gene. These forms, or alleles as they are called, arose when the DNA sequence that makes up the HLA gene mutated. These mutations may have occurred long ago or recently. Perhaps the gene is still mutating. Whatever the case, new alleles continue to be identified. It is these different alleles that account for the antigen subtypes. For instance, if a certain allele is found at loci A, then the individual has a particular subtype of HLA-A.
Of the 40 percent of patients who do get find an unrelated donor, practically none of them manage to find a perfect match. Some of these recipients survive; others do not survive or they require a second transplant. The question now is, how much mismatching can the body tolerate? The National Marrow Donor Program conducted a study in order to answer this question. Data was obtained from 3857 transplantations. It was found that mismatches at a single HLA-A, -B, -C, or –DRB1 locus (7/8) was associated with lower survival rate. Of the patients who had a single mismatch at these loci (7/8), 43% survived, compared with a 54% survival rate for perfect matches (8/8). Mismatching (7/8) at these loci is also associated with complications, like “treatment-related mortality” or and Graft-Versus-Host-Disease. Mismatched alleles at the HLA-DQ or –DP loci did not appear to have an effect on survival rate. There were no differences in the survival rates of patients whose donors had been selected using high-resolution DNA typing, or low-resolution serological typing. indicating that allele matching is just as valid a method of tissue typing as antigen matching, contrary to many researchers' opinions.
By AB
No comments:
Post a Comment