Anthony Nolan is proud to facilitate three stem cell transplants a day. Though they give patients a vital second chance of life, they can also lead to severe post-transplant complications including relapse, graft vs host disease (GvHD) and infections. But what if we could identify specific genes in the donor which help reduce the risk of these complications and give patients a better chance of survival?
Dr Jonathan Kay, our Science Communications Manager explains our latest research, recently published in the journal, Bone Marrow Transplantation.
How is Anthony Nolan answering this question?
Researchers at the Anthony Nolan Research Institute have highlighted important differences in a set of genes which seem to play a role in reducing the risk of these complications. They are called Killer-cell Immunoglobulin-like Receptor genes, or KIR genes and for patients with acute myeloid leukaemia (AML), they may help in protecting against potentially fatal post-transplant infections.
What are KIR genes and why are they important?
There are 15 KIR genes which all make receptors found on the surface of natural killer or NK cells, a type of white blood cell that forms part of our immune system. Binding between KIR receptors and their targets helps NK cells to judge the health of other cells and in turn either activate or reduce our immune responses. By helping to detect and remove abnormal cells, such as those infected with virus, these complex interactions are also important in combatting infections following transplant.
We inherit our KIR genes in clusters known as ‘haplotypes’ because they are positioned very closely to each other. There are two possible haplotypes: the KIR A, which has a simple, fixed set of KIR genes, and KIR B, which is more variable and has at least one of six specific KIR genes. We inherit two copies of these haplotypes, one from each of our parents.
Depending on how these genes are arranged in the cluster, they can also be divided into centromeric (Cen) or telomeric (Tel) motif groups. The group of KIR genes nearer to the middle of chromosome 19 make up the Cen motif whereas those found towards the end of the chromosome comprise the Tel motif. This was an important distinction for the findings of this study.
What happened in the study?
Anthony Nolan’s recent study examined the outcomes of stem cell transplants for 119 AML patients against the haplotypes of their donors. These patients had all undergone a transplant from an Anthony Nolan donor, and been given the same full-intensity conditioning therapy and treatment to reduce the risk of GvHD beforehand. This ensured the group was as clinically similar as possible. Blood samples from each of the corresponding donors were analysed to determine their KIR haplotype status. Could the presence of either the KIR A or KIR B haplotype lead to more cases of relapse or serious infections after transplant?
What did the study show?
Firstly, when a donor had two copies of the KIR A haplotype, there was less than a 10% chance of the patient not surviving the first year after transplant, for reasons other than relapse. This is called non-relapse mortality (NRM). However, the presence of at least one KIR B haplotype in the donor more than tripled this risk to almost 30%.
Secondly, it highlighted the importance of how KIR genes are arranged in the haplotype. It showed that the presence of a centromeric (Cen) KIR B motif can have a negative impact. The one-year NRM rate rose from around 10% when the donor who had no Cen-B motifs, to 33% when they had one motif, and up to 42% when they had two motifs.
This also had an impact on the overall survival seen after five years. Approximately half the patients with a Cen-A donor were still alive compared to only one third of patients with donors who had at least one Cen-B motif. However, the presence of a Cen-B motif appeared to have little effect on the rates of relapse.
To assess which post-transplant complications impacted on overall survival, the researchers looked at the number of patients who died from serious infections. When the transplant used a donor with at least one Cen-B motif, patients were more likely to get an infection which they were unable to recover from.
What does it mean for the future?
This work shows the potential benefit of considering KIR genes as a factor when selecting stem cell donors. The presence of donor Cen-A motifs appears to protect patients with AML and reduces the risk of serious infection.
However, these findings need to be put in context. While this data looks promising, other studies have shown different results in terms of the impact KIR genes can have on transplant success. This is why careful consideration was taken to define a group of AML patients who all had similar treatment programmes.
Clearly, there’s still much to learn about the role of KIR genes in this process. But this study has shown the need to apply these findings to a larger group of patients, with a broader range of blood cancers and treatment plans.
Will Bultitude, lead author of the study, agrees a more thorough investigation is necessary into the role KIR genes play in improving transplant outcomes.
‘Working with HLA and KIR highlights the level of immune system complexity we are dealing with when trying to find the best donors for our patients. Fortunately, many donors on the Anthony Nolan register have the desirable Cen-A motif combination. By uniting high resolution HLA and CMV matching with guided selection of KIR genes in the future, we can hopefully really home in on what makes the optimum donor in some transplant settings’.‘
This project looked at whether genes were present or absent from donors’ genomes. Now we’re investigating whether ultra-high resolution DNA sequencing for KIR, much like we already do for HLA, will improve these models. Hopefully we will gain even more insight into how best to help our patients, not only by improving how we select donors, but also by looking at how we can use KIR genes in NK cell therapies’.
Watch this space!
This work was funded by Anthony Nolan and by a grant from the National Institutes of Health, USA. If you or someone close to you is going through a stem cell transplant and would like more support, our Patient Services team are here to help. Find out more at anthonynolan.org/Patients