'Perfect mismatch' heralds revolution in transplant technology

Delegates to an international tissue-typing workshop in Melbourne this week were told of a remarkable discovery by the University of Perugia immunogeneticist that is beginning to revolutionise tissue- and organ transplantation -- and cure leukaemia.

For decades, immunologists have used MHC (major histocompatibility complex) typing to pursue 'perfect matches' between organ and tissue donors and recipients.

But two years ago, Prof Andrea Velardi's research team at the University of Perugia, in Italy, showed that a 'perfect mismatch' sometimes works even better -- a bone marrow transplant can actually cure the recipient's leukaemia.

One of the workshop's organisers, Prof Jim McCluskey, of the Department of Microbiology and Immunology at the University of Melbourne, said that the Italian group had found a way to use of a cluster of killer immunoglobulin-like receptor (KIR) genes on chromosome 19 to open the way to transplanting tissues or organs across "quite profound mismatches" between MHC antigens.

Many of the MHC genes, which cluster on a 4-megabase region of human chromosome 6, are highly polymorphic, complicating the process of finding donors to match patients requiring bone-marrow, heart, lung, kidney or pancreas transplants,

Since the discovery of the MHC in the early 1970s, immunologists have always sought a donor who matches the recipient at six critical loci to achieve a perfect match, on the assumption that the recipient's immune system would be likely to reject the graft if just one of the six loci was mismatched.

Relatives, particularly siblings, are the most likely sources of a perfect match; if there is no familial 'match', immunologists must then search bone-marrow registries around the world for an unrelated individual who, by chance, matches at all six loci.

Although 10 million individuals are now listed on tissue-typing databases around the world, the odds against finding a perfect match increase with the rarity of a patient's MHC 'signature'.

As a last resort, physicians have sometimes attempted bone-marrow transfers that mismatch at several -- if not all -- critical MHC loci. McCluskey said it was a "frustrating reality" that although most mismatched donor-recipient combinations have done badly, a few fare surprisingly well.

Velardi's group has now identified a mechanism that helps explain the favourable outcome of the occasional 'perfect mismatch' -- an epistatic interaction between the KIR genes on human chromosome 19, and the six critical MHC loci on chromosome 6.

In the wake of Velardi's discovery, immunogeneticists have been trying to bring some predictability to the outcome, by investigating other factors that also make a difference between a 'perfect mismatch', and a 'taboo mismatch'.

McCluskey said no national databank of stem cell transplanted donor-recipient pairs provided sufficient statistical power to establish such correlations. Immunologists from the international community must pool their data sets and expertise -- and this week's Melbourne workshop is one of most important forums for establishing international research collaborations.

The project is being coordinated by Prof Effie Petersdorf at the world's premier bone-marrow research institute, the Fred Hutchinson Cancer Research Centre in Seattle, Washington.

McCluskey said the KIR complex of genes on chromosome 19 are highly polymorphic, like the MHC proteins whose activity they modulate.

"Each KIR gene codes for a polymorphic receptor protein dedicated to recognising a different type of HLA protein," he said. "The crazy thing is that if the recipient has the 'right' HLA molecule, and the donor has the right KIR receptor, you can deliberately set up a mismatch, and the graft will be accepted, because natural killer (NK) cells expressing particular KIR proteins kill off any host white cells lacking the appropriate MHC proteins."

The grafted bone marrow must first be completely depleted of normal T-cells, which would otherwise immediately attack host cells with mismatching MHC antigens, causing a graft-versus-host reaction.

As a bonus, if a leukaemia patient receives a mismatched bone marrow graft, NK cells in the graft will also destroy the host's cancerous white cells since they also lack the appropriate MHC antigens complementary to the KIR receptors, thus curing the leukaemia.

"But before we can proceed, we need to get a couple of concepts right -- we need to 'mismatch' very carefully," McCluskey said. "The opportunity for 'matched mismatches' represents a paradigm shift, because the whole field has been driven by perfect matching.

"If you can't find a perfect match, you can actually mismatch the entire haplotype. Often, there may be no 'mismatch' that works either -- but we're still making inroads into the problem [of lack of suitable donors]."

Fighting infections

Another exciting discovery is that KIR genes influence, in a statistical sense, our ability to fight infections. Prof Mary Carrington at the National Cancer Institute in Frederick, Maryland, has shown that individuals with certain KIR haplotypes who contract HIV infections have a tendency to progress much more slowly to full-blown AIDS.

"The KIR genes seen to come in two 'flavours' -- they either super-activate natural killer cells and T-cells, or inhibit their activity," McCluskey said. "If the super-activating response dominates, the patient clears more of the virus, and progresses more slowly to AIDS. We're hoping that we might see the same effect in hepatitis C infections."

Another very strange result is that that the KIR genes also appear to influence the incidence of pre-eclampsia in pregnancy, which can result in dangerous elevation of maternal blood pressure.

"NK cells occur in the placenta, and drive its vascularisation using their KIR molecules to recognize MHC molecules -- if there are only a few activating KIR molecules, vascularisation is inhibited and there is a higher risk if pre-eclampsia," McCluskey said. "So on the one hand, KIR-expressing cells drive placental vascularisation, but at the same time, KIR-expressing cells appear to control viral eradication in HIV-AIDS and hepatitis C. It's an incredible example of dual evolutionary forces shaping genetic variation."

McCluskey said immunologists are now working intensively to determine whether particular KIR genotypes factor in susceptibility to autoimmune diseases like rheumatoid arthritis, lupus, and diabetes.

"We're now beginning to understand why all immune systems are different," he said. "For example, we still don't understand why some teenagers who contract Epstein-Barr virus develop severe glandular fever and enlarged lymph nodes, while others remain asymptomatic. This is likely to be due to genetic variation in immune genes, perhaps even the KIR and MHC combinations.

"Individuals also vary widely in their response to other viral infections, like influenza. The explanation probably lies in a mosaic of interactions between MHC genes, activating and inhibitory KIR genes, and strong-versus-weak responder variants of interferon genes and tumour necrosis factor (TNF) genes."