Guest Editorial: new basic and clinical aspects of graft-versus-host disease: what can we do without “Doc” Brown’s help?

Abstract

When confronting a difficult case of graft-versus-host disease (GVHD), have you ever wished to be able to go back in time? I suppose that only those of you who already have a time machine, like the one operated by Emmett ‘‘Doc’’ Brown and his friend, Martin ‘‘Marty’’ McFly from the 1985 film Back to the Future can honestly say they have not. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative therapy for malignant and nonmalignant hematologic diseases and other disorders. However, GVHD remains a major and lethal complication that limits the wider application of allogeneic HSCT. GVHD develops in recipients of donor grafts that contain T cells responding to genetically distinct proteins on host cells. Human leukocyte antigen (HLA) genes, such as HLA-A, B, C, DRB1, DPB1, and DQB1, which have vast numbers of single nucleotide polymorphisms (SNPs), are the most important factor affecting the risk and severity of GVHD. Polymorphisms of non-HLA genes that mainly impact individual immune response to infections and inflammatory reactions are involved in GVHD as well, as evidenced by the fact that GVHD also sometimes occurs in 12/12 matched transplants. The greatest concern in the treatment of GVHD is that steroids remain the first-line therapy for GVHD and no standard treatment strategy for patients refractory to steroid therapy exists. In other words, once GVHD has begun, it is already too late to effectively intervene. In Back to the Future, Doc Brown constructed a machine that enabled him to travel back in time to alter the course of future events. This allowed Marty McFly to eliminate the causes of unfavorable events before they could take place. We are now faced with a similar situation in the management of GVHD. Without Doc Brown’s help, what can be done? I hope this month’s ‘‘Progress in Hematology’’ will provide readers with some fresh clues. This issue includes three excellent review articles [1–3] in addition to my own [4], which focus on novel developments in the pathophysiology of acute GVHD, and on the prediction of GVHD using HLA and non-HLA polymorphisms and GVHD biomarkers. Dr. Junya Kanda summarizes findings from large cohort studies, including those he directed, to investigate the effect of HLA mismatch in each allele and antigen on the risk and severity of acute GVHD, and reports that the effect of HLA matching should be evaluated cautiously with respect to stem cell source, GVHD prophylaxis, the year of transplant, recipient age, ethnicity, and HLA distribution. This information should be useful in selecting an optimal donor in light of current practice. In my review, I detail non-HLA gene polymorphisms associated with GVHD and their clinical significance, which may be useful in further analyses, including functional investigations and genome-wide association studies. Prior to HSCT, it is important to choose an optimal donor with an eye to achieve a lower risk of GVHD; high-resolution HLA genotyping for recipients and donor candidates is effective, while non-HLA genotyping may also provide useful information. Dr. Yoshinobu Maeda reviews the importance of innate immune response in GVHD. HSCT is associated with cellular and tissue damage due to the use of cytotoxic agents, total body irradiation, infections, and so on, which can result in the release of exogenous and endogenous ‘‘danger signals’’, activating the innate immune response, which then triggers or amplifies acute GVHD. This review A. Takami (&) Department of Hematology and Oncology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa 920-8641, Japan e-mail: takami@staff.kanazawa-u.ac.jp