Tokaimura’s experience convinced us that the triage would be delayed if we depended on conventional dosimetry. Based on these experiences, Fliedner TM et al. established practical triage methods according to an organ-oriented symptom-guided grading system, named METREPOL2. Symptoms of acute radiation syndrome (ARS) are evaluated in each radiosensitive organ according to severity. Damage to the neurological system (Ni), hematological system (Hi), cutaneous system (Ci) and gastrointestinal (GI) system (Gi) are graded for each organ. Based on these criteria, on day 7, our victim was N2 H4 C3 G1, RC = 4d7. RC4 patients should be considered for transfer to a highly equipped hospital for supportive care or HSCT. The promotion of METREPOL information among all health-care providers is an urgent task in the current worldwide situations.
Waselenko JK et al. recommended in their clinical guidelines of the Strategic National Stockpile Radiation Working Group that HLA-matched related and unrelated allogeneic stem cell transplantations are lifesaving and potentially curative treatments in patients with certain predominantly hematological malignant conditions3. In the Chernobyl experience, thirteen patients who were exposed to an estimated whole-body dose of 5.6 to 13.4 Gy received bone marrow transplants4. Nine recipients showed hematopoietic recovery; six out of these nine recipients showed transient partial engraftment, and GVHD were diagnosed in four and suspected in two other recipients. Densow D et al. reviewed the cases of 4,500 victims, significantly exposed in 450 radiation accidents worldwide. Among them, twenty-nine recipients received allogeneic bone marrow or fetal liver cells (FLCs), but all patients with burns died, and only three out of 29 lived beyond one year5. Four years later, the US National Marrow Donor Program (NMDP) and American Society for Blood and Marrow Transplantation established the Radiation Injury Treatment Network (RITN)6. Based on the results of thirty-one HSCT recipients, the median survival for these patients was approximately one month, and all four recipients who survived more than one year showed autologous hematopoietic recovery. The RITN also raised the question of whether HSCT provides any benefit; in particular, more than 20% of recipients died from GVHD. These findings indicated that the avoidance of GVHD is the most critical problem in HSCT for ARS. There are several possibilities for donor candidates and stem cell sources for HSCT for ARS (Figure).
Considering the engraftment rate and risk of infection/GVHD, an MSD is the highest donor candidate priority. (1) If the victim lacks an MSD, considering the rapid availability of UCB during the HSCT critical window, UCBT has a significant advantage compared to matched unrelated donor (MUD) and related one-haploidentical donor (Haplo) transplantation. MUD transplantation requires several months for the coordination and confirmation of donor eligibility, and Haplo transplantation requires growth factor administration to donors for mobilization and harvesting. Cryopreserved and pathogen-tested UCB is a ready-to-use stem cell source of HSCs for patients with ARS. (2) MUD transplantation offers the best possibility of engraftment, as there is a limited stem cell dose in UCBT and HLA disparity in the Haplo setting. (3) Considering the risk of infection, UCBT requires a prolonged time for hematopoietic recovery, and Haplo transplantation requires sustained immunosuppressive therapy (IST). As described below, the low risk of GVHD in the UCBT setting permits the early discontinuation of IST, but UCBT has a concomitant risk of graft rejection, as in our patient. However, recent advances in clinical pharmacology have provided us with more effective novel antibiotics, antiviral drugs (e.g., letermovir) and antifungal medication (e.g., posaconazole). The indications for HSCT have been significantly widened compared to our previous experience 20 years ago. (4) The most critical issues in the treatment of ARS are the avoidance of GVHD and the worsening of cutaneous/GI syndromes. The current regimen is one-haploidentical HSCT using post-transplantation cyclophosphamide (CY). ARS causes severe damage to the exposed skin and GI mucosa. Endothelial damage is an ARS worsening factor. MUD transplantation involves a potential risk of GVHD that inadvertently worsens ARS. Furthermore, post-transplantation CY inevitably complicates regimen-related toxicities (RRTs) involving the GI mucosa and hematopoiesis. Considering the risk of RRT, CY may be one of the contraindicated drugs for ARS. In our patient who underwent UCBT, we showed that there was no evidence of cutaneous GVHD (on days 24, 40, 94) or gut GVHD (on day 40) by repeated biopsy1. We have previously described that UCB T cells have an impaired response to CD3/CD28 stimulation with decreased cell surface expression of costimulatory CD40L and FasL. These results indicate the bipotent risk and benefit of UCB T cells, as they are associated with a decreased risk of GVHD but an increased risk of infection7. The current understanding of stem cell biology clearly documents that HSCs have a definite fate of aging in a murine model. Aged HSCs exhibit functional alterations, including a loss of immune function and reduced regenerative capacity and myeloid-biased differentiation. Rossi et al. highly purified murine c-kit+lin−Sca-1+flk2−CD34− long-term HSCs (LT-HSCs), and they demonstrated the contribution of these cells to adult impaired lymphopoiesis8. Other mechanisms, including accumulated DNA damage, impaired levels of autophagy, accumulated metabolic stress with DNA mutations in mitochondria, and epigenetic reprogramming with aged clonal hematopoiesis, concurrently affect the self-renewal properties of aged HSCs9. In human patients, Vaziri et al. clearly documented the shortened telomeric DNA of human bone marrow HSCs compared to UCB-derived HSCs10. Shortened telomeric DNA strongly suggests the limited proliferating potential of bone marrow HSCs compared to UCB HSCs. Furthermore, impaired cutaneous re-epithelization and GI mucosa regeneration stem from impaired endothelial regeneration. We have previously described that lineage-negative (Lin−) CD34+ cells in UCB expressed TIE2 (18.8%)11. TIE2 is a marker of HSCs in UCB, and the TIE2 ligand Ang-1 promotes HSC adhesion to fibronectin and the maintenance of HSC stemness. These results indicate that human UCB contains bipotent Lin−CD34+TIE2+ hematopoietic and endothelial progenitors with the potential contribution of HSCs for endothelial regeneration in UCBT in ARS settings.
A severely irradiated cell expresses mutated DNA transcripts and aberrant proteins on its cell surface. These molecules may be candidate epitopes for autologous immune system targets. GVHD is an allogeneic immune reaction initially evoked by a pretransplant conditioning regimen consisting of high-dose chemoradiation ensuing from tissue damage12. GVHD causes the release of pathogen-associated molecular patterns (PAMPs) and various chemokines and cytokines (TNF-a, IL-1b, IL-6, IFN-g, etc.). Finally, host- and donor-derived antigen-presenting cells (APCs) activate donor-acquired immune cells, including type 1 and type 17 CD4+ helper cells (Th1 and Th17 cells, respectively), type 1 CD8+ cytotoxic T lymphocytes (Tc1 cells), natural killer (NK) cells, macrophages and B cells. These reactions markedly resemble the pathophysiology of ARS. Appropriate IST is mandatory to overcome ARS. Recent advances in IST provide several treatment options for GVHD. Not only conventional IST drugs (calcineurin inhibitors, mTOR inhibitors, antimetabolites, and corticosteroids) but also tyrosine kinase inhibitors and several monoclonal antibodies targeting T cells or cytokines lead to clinical responses in patients with a steroid-resistant GVHD.
If there are no suitable donor candidates, cryopreserved UCB is a promising source of HSCs for the treatment of ARS. The rapid availability of UCB and limited risk of GVHD with UCBT are advantages of UCBT compared with MUD or Haplo transplantation, considering the risk of engraftment failure and susceptibility to infection. Supportive care in HSCT has markedly progressed and includes the possible use of growth factors (keratinocyte growth factor, KGF), more feasible and effective antibiotics, and antiviral/antifungal agents with effective IST. A high-quality UCB-banking system is mandatory for preparedness against nuclear events. Further discussion of triage, indication or donors for HSCT and suitable IST for ARS is necessary for future victims.