Chronic graft-versus-host-disease, or GVHD, is an adverse consequence following hematopoietic (blood) stem cell transplantation from a donor to a recipient (or allogeneic transplantation). GVHD happens when the transplanted donor cells recognize the cells of the recipient as foreign and attempt to eliminate them. Among the 50-60% of patients who ultimately develop chronic GVHD, approximately 20% will suffer from sclerosis (or sclerotic GVHD) during the three years after initiating treatment for chronic GVHD 1. Sclerotic GVHD displays as dermatological lesions including thickening of the skin or as fascial lesions such as limited ranges of motion in joints, resulting in wall chest compression and impairment of wound healing. Even though sclerosis may not be life-threatening, it significantly affects the patient’s quality of life. The factors that influence the development of sclerosis in transplanted patients remain largely unknown.
In a recent publication, which also made the cover page of the journal Blood, Drs. John Hansen, Yoshihiro Inamoto and Paul Martin (Clinical Research Division) along with other colleagues from the Fred Hutch and University of Washington, demonstrated an association between gene variants and the risk for developing sclerotic GVHD. The authors initially noticed that the clinical manifestations of sclerotic GVHD and systemic sclerosis were similar. However, while the risk factors of sclerotic GVHD were unknown, association between variations in specific genes with the systemic sclerosis had been identified. “Certain genetic variants that are associated with the development of systemic sclerosis, an autoimmune disorder of unknown etiology, are shared with patients who develop sclerotic chronic graft-versus-host disease”, commented Dr. Hansen. Each individual inherits identical set of genes, but encoded by slightly different DNA sequences (gene polymorphisms). These variations can be associated with minor to major manifestations such as the eye colors or disease development for instance. The authors selected thirteen polymorphisms whose links to the systemic sclerosis had been established and evaluated whether they were also associated with the development of sclerotic GVHD.
To this end, the authors used DNA samples from a cohort of 847 individuals who had undergone allogeneic stem cell transplantation at the Fred Hutch/Seattle Cancer Care Alliance between 2000 and 2009. Among these patients, 23% developed sclerotic GVHD. DNA samples from all these individuals were tested using genome-wide polymorphism arrays to determine genotypes in the 13 regions of interest.
The team focused on three genetic polymorphisms characterized by the most statistically significant associations with the risk of developing sclerotic GVHD. The proteins encoded by these three genes are all involved in immune functions. “The identification of functional genetic variants within the T cell receptor (CD247, encodes a T-cell receptor subunit) and B cell signaling pathway (BANK1, encodes a B-cell scaffold protein), together with a variant in strong linkage disequilibrium with the HLA-DPA1 locus strongly implicates the presentation of pathogenic peptides and a genetically modified adaptive immune response as a mediator of disease pathogenesis”, stated Dr. Hansen. Indeed, BANK1 and CD247 modulate the activation of the B and T-cells at the surface of which they are expressed, respectively. HLA-DPA1 protein participates in presenting processed protein fragments from pathogens or from self origin, in the case of autoimmune disorders, to other cells that will determine if an immune response will be mounted. A comparative analysis of the HLA-DP variants predicted that their structure would remain unchanged, but the type of fragment bound and presented at the cell surface would be different, leading to variations in the immune response activation.
These analyses highlight the importance of understanding the underlying mechanisms by which one variation ultimately affects the protein function, in addition to identifying these genetic variations. Selecting already existing therapies targeting these functions could be tested to alleviate sclerotic GVHD as well. Additionally, Dr. Inamoto explained that to account for the contribution of donor versus recipient cells, “the donor and recipient genotypes could be analyzed in a single model, but a much larger cohort would be required to determine whether their associations are independent or not”. This study is the first demonstrating a link between the three genetic polymorphisms and the risk to develop sclerotic GVHD. “Future research aimed at elucidating primary etiology should focus on identifying peptides preferentially expressed by the sclerotic GVHD-associated HLA-DP genes, and by the development of immune suppression approaches that more specifically target the signaling pathways affected by the variants identified”, concluded Dr. Hansen.
Inamoto Y, Martin PJ, Flowers MED, Lee SJ, Carpenter PA, Warren EH, Geraghty DE, Lee N, Boeckh MJ, Storer BE, Levine DM, Fan W, Zhao LP, Hansen JA. 2016. Genetic risk factors for sclerotic graft-versus-host disease. Blood. 128(11):1516-24.
1- Inamoto Y, Storer BE, Petersdorf EW, Nelson JL, Lee SJ, Carpenter PA, Sandmaier BM, Hansen JA, Martin PJ, Flowers MED. Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. Blood. 121(25):5098-103.
This research was supported by the NIH National Heart, Lung, and Blood Institute, National Cancer Institute and the Japan Society for the Promotion of Science.