Investigating the genetic basis of Graft versus Host Disease

Reading time: 5 minutes

Kate Secombe

The treatment for many blood cancers can be invasive and have a range of side effects. One such side-effect is known as Graft versus Host Disease (GvHD). While GvHD invokes a range of unwanted symptoms, we currently do not fully understand how and why it develops. New research by Kuba and colleagues from Palacky University in the Czech Republic has offered insights into the potential genetic basis behind its development.

Treating blood cancers with stem cells

Some blood cancers, including leukemias and lymphomas, are treated via an allogeneic hematopoietic stem cell transplant (HSCT). Briefly, this is the transfer of blood stem cells from a healthy donor to the patient. In order to accept the donation, the patient will usually undergo high-intensity chemotherapy or radiotherapy conditioning treatment before the transplant. This conditioning treatment works to destroy cancer cells from the body, and weaken the patient’s immune system. This weakened immune system is less likely to reject the donor’s stem cells. Once the donor cells are in place, they will grow and produce new blood cells, in some cases providing a long-term cure for cancer.

However, a potential side effect of this treatment is known as Graft versus Host Disease (GvHD). This is where particular immune cells (known as T cells) that are in the stem cell transplant from the donor (also called “the graft”), attack the patient’s healthy cells. In some cases, this can be life-threatening, involving symptoms such as skin rashes and diarrhea, and more chronically, liver damage.

We can’t predict who will develop GvHD

A key issue with the effective treatment of GvHD is that there is currently no clear way to predict who will develop GvHD, and how severe it will be. It is thought that one may have a higher risk if the stem cell donor is of a different sex than the patient, and there are careful regulations around who may become a stem cell donor. In order to reduce the risk of developing these severe side effects, patients and donors are carefully matched. One important match is the human leukocyte antigen (HLA) type. The HLA system is a gene complex that encodes the major histocompatibility complex protein, which is responsible for the regulation of the immune system. At least three locations of the HLA gene are compared using blood samples, and a perfect match is preferred. 

In spite of a perfect HLA match, many patients develop either acute or chronic GvHD. Acute GvHD occurs less than 100 days post-HSCT, and chronic GvHD occurs beyond 100 days post-HSCT. These subtypes are identified by different symptoms, with acute GvHD characterized more by the skin, liver, and gastrointestinal damage, as mentioned above, whereas chronic GvHD can, and often does affect multiple organ systems. While the exact pathology and development processes of GvHD is still being determined, we do know that there is a clear inflammatory basis such as an increase in production of chemical messengers that promote further inflammation.

This increase in inflammation is due to the drugs used in conditioning regimes. The high-intensity chemotherapy (such as cyclophosphamide) and radiotherapy agents cause cell death and damage to the patient’s DNA. This can lead to the induction of inflammatory processes.

NF-kB: is inflammation the key to predicting GvHD?

NF-kB is one transcription factor that can start these inflammation processes. Transcription factors are proteins that work to either increase or decrease the production, or transcription, of certain molecules. NF-kB in particular is known to play a role in regulating the immune response to infection and is known to induce the expression of a variety of pro-inflammatory proteins. Many studies have shown that altered NF-kB activation is an important contributor to the development of various inflammatory diseases.

The authors of this research suggested that as the drugs used in HSCT conditioning lead to the secretion of pro-inflammatory cytokines and chemokines, a close investigation of NF-KB in GvHD would be useful. In addition, previous studies have shown that inhibiting c-Rel (a member of the NF-kB complex) reduces GvHD symptoms while also preserving the beneficial effects of the treatment.

Can one tiny change in our DNA change much?

Kuba and colleagues investigated two single nucleotide polymorphisms (SNPs) of NF-kB in the setting of GvHD. SNPs are a common type of genetic variants with an estimate of 4-5 million SNPs found in a person’s DNA. Each SNP represents differences in a single nucleotide.  While most SNPs have no consequences, some have been under investigation for their important effects. The authors selected two SNPs within the genes for NF-kB (with the names rs3774937C/T and rs3774959 A/G) that previous studies had suggested may be relevant to this situation.

The researchers looked at the association of these two SNPs with the occurrence of both GvHD and transplant-related mortality. They studied 109 patients whose graft came from an HLA-identical donor. In this patient cohort, 27.5% developed acute GvHD and 34.4% developed chronic GvHD. DNA from the patient’s blood was analyzed for these SNPs. While the presence of both SNPs were strongly associated with acute GvHD, there was no association with treatment-related mortality or chronic GvHD. It is possible that other factors, such as demographics and other genetic factors play a role in the development of treatment-related mortality or chronic GvHD.

This research has provided further evidence that inflammatory processes are important in the development of acute GvHD, and that these inflammatory processes could have a genetic basis. More research in a larger patient group is required to confirm these results. Additionally, this research includes a patient cohort that received a similar conditioning chemotherapy regimen. Understanding how different conditioning regimens may affect these correlations could provide more insights.  

Edited by Prathyusha Konda

Main work discussed:

Kuba A, Raida L, Mrazek F, et al. NFKB1 gene single-nucleotide polymorphisms: implications for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2020;99(3):609–618. doi:10.1007/s00277-020-03935-5

Other reading:

Toubai T, Sun Y, Reddy P. GVHD pathophysiology: is acute different from chronic?. Best Pract Res Clin Haematol. 2008;21(2):101–117. doi:10.1016/j.beha.2008.02.005

Lv X, Qi J, Zhou M, et al. Comparative efficacy of 20 graft-versus-host disease prophylaxis therapies for patients after hematopoietic stem-cell transplantation: A multiple-treatments network meta-analysis [published online ahead of print, 2020 Mar 20]. Crit Rev Oncol Hematol. 2020;150:102944. doi:10.1016/j.critrevonc.2020.102944

https://www.lls.org/treatment/types-of-treatment/stem-cell-transplantation/graft-versus-host-disease

https://www.cancerresearchuk.org/about-cancer/coping/physically/gvhd/about

Image:

Photo by National Cancer Institute on Unsplash

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