We aim at identification of novel genetic and immunological factors that influence susceptibility to graft-versus-host disease (GvHD), a major, life-threating complication of allogeneic hematopoietic stem cell transplantation, which is the only known curative treatment for severe hematological malignancies, such as leukemias.
GvHD results from immunological recognition of patient’s tissues as foreign by the immune cells in the transplanted graft and subsequent immune activation and destruction of patient’s cells and tissues. Severe GvHD can kill the patient.
A better prediction and understanding of GvHD risk and better histocompatibility matching are amongst key components on the road to safer allogeneic hematopoietic stem cell transplantation. The project utilizes the facts that all histocompatibility testing in Finland with about 5 million inhabitants, is centralized as is also the actual transplantation activity.
We can assume three mutually non-exclusive genetic models for GvHD risk:
- Immunogenetic or protein-level compatibility between donor and recipient, for example, matching of HLA alleles, or the role of gene deletions;
- Immunologically high versus low responder genotypes, that is, gene variation that regulates individual’s general tendency to alloimmune response or immunological tolerance, for example, certain cytokine IL-10 gene variants regulate the overall level of immune response and are related to GvHD risk;
- Pharmacogenetic response for immunosuppression or conditioning; that is, GvHD manifests when patient’s pharmacogenetic profile leads to decreased response to immunosuppressive drugs.
Genome-level histocompatibility concept
Basically any protein sequence level difference between donor and recipient can lead to alloimmune response. As an extreme example of protein differences, we have earlier reported that mismatching for common gene deletions predisposed to GvHD in a large collaborative study (McCarroll et al Nature Genetics 2009)
We now are developing bioinformatic algorithms that would estimate the personalised, genomic level histocompatibility by taking into account (i) all amino acid differences in each donor-recipient pair, (ii) binding of the peptides onto patient’s HLA molecules (= immunogenic potential of the difference) and (iii) their expression profiles. We are testing the concept of predicting graft-versus-host disease in HSCT samples from which the exome level sequencing have been done by the McGill Genome Centre [linkki Quebec Genomé Centre = http://gqinnovationcenter.com/index.aspx ], Montreal, Canada. This study is funded by the Academy of Finland (grant #288393 to Jukka Partanen).
Genome-level association analysis
We are using Genome Wide Association Study (GWAS) approach to look for novel gene loci that predisposes to graft-versus-host disease and to other complications of HSCT. We have identified some exciting candidates which we are now verifying in other cohorts and pinpointing the actual polymorphisms.
We have also addressed certain candidate genes for their role in GvHD susceptibility and we participate in the international ‘workshops’ [ http://ihiws.org/ ] in which roles of novel candidate genes in HSCT are tested in large, multinational patient cohorts. For example, we study the effect of NK-cell KIR genotypes in predicting GvHD, the collaboration is lead by Dr Hsu of Memorial Sloan-Kettering Cancer Center, NY, USA [ https://www.mskcc.org ]. This study is partially supported by TEKES-funded Salwe GID program.
Utilisation of genome-data in histocompatibility
As genome analyses are becoming more and more common in the future, we want to understand how much histocompatibility (e.g. HLA alleles, blood groups etc) information we can reveal from standard genome screens. We are testing, for example, how accurately we can impute using different bioinformatics tools the HLA and KIR alleles and blood groups from SNP and NGS sequence data.
This study is partially supported by TEKES-funded Salwe GID program.
Team and key collaborators:
FRC Blood Service
• Jukka Partanen
• Satu Koskela
• Kati Hyvärinen
• Antti Larjo
• Kaarina Lähteenmäki
• Jarmo Ritari
• Päivi Saavalainen
• Tiira Johansson
• Ulla Impola
• Tiina Linjama
• Joni Keto
• Elina Kilpeläinen
• Sisko Lehmonen
• Lotta Andersson
Helsinki University Central Hospital
• Liisa Volin
• Riitta Niittyvuopio
Turku University Hospital
• Maija Itälä-Remes
• Mervi Putkonen
McGill University Canada
• Tomi Pastinen
• Tony Kwan
University of Helsinki
Research Program for Immunobiology
• Päivi Saavalainen [linkki:
• Lotta Koskinen
Finnish Institute of Molecular Medicine
• Janna Saarela
• Kati Donner
McCarroll SA, et al. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nature Genet 2009;41(12):1341-1345. PM: 19935662.
Spierings E, et al. Multi-center analyses demonstrate significant clinical efforts of minor Histocompatibility antigens on GvHD and GvL after HLA matched related and unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013;19(8):1244-53. PM: 23756210.
Impola U et al. Donor haplotype B of NK KIR receptor reduces the relapse risk in HLA-identical sibling hematopoietic stem cell transplantation of AML patients. Front. Immunol 2014;5(article 405):1-5. PM: 25202311.
Turpeinen H, et al. Genetic Similarity of Chromosome 6 between Patients Receiving Hematopoietic Stem Cell Transplantation and HLA Matched Sibling Donors. Hematologica 2009;94(4):528-35. PM: 19278967
Turpeinen H, et al. Minor histocompatibility antigens as determinants for graft-versus-host disease after allogeneic haematopoietic stem cell transplantation. Int J Immunogenet 2013;40(6):495-501. PM: 23480177
Sivula J, et al. Association of IL-10 and IL-10R beta gene polymorphisms with graft-versus-host disease after hematopoietic stem cell transplantation from an HLA-identical sibling donor. BMC Immunol 2009;10(1):24. PM: 19409109
Sivula J, et al. Killer-cell immunoglobulin-like receptor ligand compatibility in the outcome of Finnish unrelated donor hematopoietic stem cell transplantation. Transplant Immunol 2007;18(1): 62-66. PM: 17584604.