| link to discussion of them. |
| The MHC of humans is now completely sequenced! A consortium of laboratories reports in the 28 October 1999 issue of Nature that they have determined the sequence of 3,673,800 nucleotides on chromosome 6 that encode the genes of the MHC as well as many other genes involved in immune function. |
The class I transmembrane proteins are encoded by three loci: HLA-A, HLA-B, and HLA-C.
| Link to schematic of the HLA-A2 molecule (92K) |
Class I molecules are expressed at the surface of almost all the cells of the body (except for red blood cells and the cells of the central nervous system).
Class II molecules consist of two transmembrane polypeptides: an alpha chain and a beta chain. The alpha and beta chains are encoded by clusters of loci in the region of chromosome 6 designated HLA-D.
Class II molecules are not as widely expressed in the body as the class I molecules are. However, cells where inflammation is occurring express class II strongly and provide a powerful stimulus to the immune system.
The genes of the MHC are the most polymorphic known. Over 40 different alleles have been found in the human population at HLA-B; some 20 at HLA-A. Of course, any one human can inherit a maximum of two alleles at each locus.
The diversity of alleles in the population makes possible thousands of different combinations. In a study of 1000 blood and organ donors in San Francisco that were typed for HLA-A and HLA-B,
Most tissue typing is done using serological methods: antibodies specific for those HLA antigens that have been identified in the human population. A reaction between cells of the subject and, for example, anti-HLA-A28 antibodies and HLA-A9 antibodies - but no other antibodies - establishes the phenotype.
At the present time, routine typing is limited to establishing the phenotype at HLA-A, HLA-B, and HLA-DR.
Coming into wider use is DNA typing, especially for HLA-D antigens. It promises to improve the sensitivity and specificity of tissue typing.
So what hope do these data hold for the dialysis patient awaiting a kidney transplant?
If the patient has a large family of willing donors, the odds for a good match are not bad because of the tight linkage of the HLA loci.
Assuming that no crossing over occurs within the HLA region of either the mother's or the father's two number 6 chromosomes, there are four possible combinations in which they may transmit their alleles to their children. So even if the parents carry different alleles at each locus (which is often the case), there is a 1:4 probability that any one of their children will be an exact match with any other. (Only the HLA-A and HLA-B antigens are shown here, but the tight linkage of the entire HLA region makes it likely that all the loci on each chromosome will be passed on as a block.)
But,| Number of HLA mismatches |
% kidneys surviving after 5 years |
|---|---|
| 0 | 68 |
| 1 | 61 |
| 2 | 61 |
| 3 | 58 |
| 4 | 58 |
| 5 | 57 |
| 6 | 56 |
Allografts that contain T cells of the donor can cause graft-versus-host disease (GVHD). The T cells in the transplant see the host as "foreign" and proceed to mount a widespread attack against the tissues of the host.
GVHD is an especially serious problem with grafts of bone marrow (the source of all blood cells) and cord blood. Even when the donor and recipient have identical HLA alleles, grafts of bone marrow often cause GVHD because of differences in their minor histocompatibility antigens.
Many cancer patients (leukemia, breast cancer) are now deliberately treated so vigorously with radiation and chemotherapy that their bone marrow is destroyed along with their cancer cells. In order to survive, these patients must be given stem cells to repopulate their marrow after their therapy.
Control of GVHD - like control of graft rejection - depends on the use of immunosuppressive agents.
Immunosuppression is the treatment of the patient with agents that inhibit the immune response. Presently the major players are:
These are relatives of the purines used in DNA synthesis. Because they interfere with DNA synthesis, they interfere with the rapid cell proliferation needed for immune responses. Azathioprine (trade name = Imuran) is a widely-used purine analog.
Unfortunately, these drugs also interfere with the many other tissues that depend on rapid cell division (e.g., lining of the intestine, hair follicles) so they have many unpleasant side effects. Therefore, the search for agents that specifically target immune cells goes on.
These are natural products isolated from microbial cultures. They also interfere with the transcription factors needed by T cells to turn on their genes for activation, e.g., for IL-2 secretion, (but not by the same mechanism as the corticosteroids).
FK506 is also known as tacrolimus (trade name = Prograf). The trade name for cyclosporine is Neoral.Rapamycin is also known as sirolimus and will be sold under the trade name Rapamune.
The immune system is vital to protect us against infectious agents (bacteria, viruses, fungi). So infection is a frequent side effect of immunosuppression in transplant recipients. Fortunately, the infections can usually be controlled by the appropriate antibiotic, antiviral drug, etc.
From 1% to 5% or more of transplant recipients will develop cancer within a few years of receiving their allograft. This may not seem to represent a great risk, but it does represent a 100-fold increase in risk compared to the general population. Allograft recipients are particularly prone to developing lymphomas, usually a cancer of a B cell. They do so at a rate some 350 times higher than the occurrence of these tumors in the general population.
Curiously, transplant recipients do not seem to be at any greater risk for developing the most common types of cancer in the rest of the population: cancers of the lung, breast, colon, and prostate.The chief culprit seems to be the immunosuppression that these patients have been receiving. In most cases, stopping the immunosuppression leads to regression of the cancer, but - often - rejection of the transplant as well.
The choice is usually clear for patients with allografted kidneys; they can go back on dialysis and anticipate receiving another kidney at a future date. But what of the cancer patient with a heart transplant?
Although organ transplants have helped thousands of people, much remains to be done. In particular, ways need to be found to
Xenotransplantation is the use of organs from other animals. A number of attempts have been made to use hearts, livers, and kidneys from such primates as chimpanzees and baboons - so far with limited success. One reason is that xenotransplants usually are attacked immediately by antibodies of the host resulting in hyperacute rejection. But perhaps the use of pigs as organ donors will be feasible.
However, pigs contain retroviruses (called PERV = porcine endogenous retrovirus) and there is fear that these might infect the human recipient (in much the same way that a primate retrovirus seems to have made the jump to humans in the form of HIV, the cause of AIDS).
Only a few transplants of pig tissue into humans have been done to date: skin grafts and grafts of pancreatic islets. A larger number of people have been temporarily hooked up to pig organs or "bioreactors" containing pig cells to provide support for their failing spleen, liver, or kidneys.
Most of these recipients have been monitored for signs of infection by PERV and - even though PERV can infect human cells growing in culture - there is no evidence that any of these people exposed to pig tissue have become infected.
Many factors are involved in immune privilege, such as
The cells in many privileged sites express FasL on their surface. When threatened by a cytotoxic T cell, they avoid being killed by forcing the T cell to commit suicide by apoptosis. The cytotoxic T cells express Fas on their surface. When they engage (with their T cell receptor [TCR]) a privileged cell expressing FasL, instead of killing the target, the target kills them!
| Link to more of the story of the role of Fas and FasL in apoptosis. (but note: the example you will see is the reverse of the story here; that is, the cytotoxic T cell is using its own FasL to kill a target cell that is not expressing FasL. |
| More |
Animals often contain latent viruses in their cells. If their cells are transplanted into humans, could these viruses infect the patient? start an epidemic?
The danger seems greater for xenotransplants from other primates. (There is some evidence that the retrovirus HIV arrived in humans from a primate host.)
However, retroviruses have also been found in some pigs. One of these is able to infect human cells grown in tissue culture.
For these reasons, many biologists are urging that transplant surgeons proceed cautiously with xenotransplants.
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