The pretransplant systemic metabolic profile reflects a risk of acute graft versus host disease after allogeneic stem cell transplantation

Abstract

Allogeneic stem cell transplantation is used in the treatment of younger patients with severe hematological diseases, especially hematological malignancies, and acute graft versus host disease (GVHD) is then an important immune-mediated posttransplant complication. Several risk factors for acute GVHD have been identified, including pretransplant factors that possibly influence the posttranspant course through their effects on host immunocompetent cells. Metabolic regulation is important for immunoregulation, and we therefore investigated whether the pretransplant metabolic status of allotransplant recipients was associated with later acute GVHD. In our population-based study we investigated the systemic (serum) metabolic profile for 86 consecutive allotransplant recipients. The samples were collected before start of the pretransplant conditioning therapy. Patients who developed later acute GVHD especially showed altered pretransplant amino acid metabolism, including (1) altered metabolism of immunoregulatory branched chain amino acids (leucine, isoleucine and valine); and (2) altered levels of potentially proinflammatory tyrosine metabolites (p-cresol sulphate, 3-phenylpropionate) formed by the gastrointestinal microbial flora. However, isobutyrylcarnitine and propyonylcarnitine levels were also altered; the carnitines are important for the transport of fatty acids and may also be important for the release of immunoregulatory cytokines in allotransplant recipients. These metabolic alterations were associated with an ongoing pretransplant acute phase reaction or early hematopoietic/immune reconstitution. Thus, allotransplant recipients developing acute GVHD showed altered preconditioning/pretransplant levels of several immunoregulatory metabolites. Our hypothesis is that these metabolites alter or activate recipient immunocompetent cells and thereby enhance or initiate anti-recipient immune reactivity.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-015-0880-x) contains supplementary material, which is available to authorized users.

Metabolic Serum Profiles for Patients Receiving Allogeneic Stem Cell Transplantation: The Pretransplant Profile Differs for Patients with and without Posttransplant Capillary Leak Syndrome

“…Several metabolites that show different levels are known to induce endothelial dysfunction or altered vascular and renal functions. We have previously described that pretransplant factors reflect the risk of acute GVHD after allotransplantation [ 8 , 65 ], and our present observations suggest that pretransplant metabolic factors are important also for the risk of posttransplant fluid retention.…”

Metabolic Reprogramming—A New Era How to Prevent and Treat Graft Versus Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation Has Begun

“…GVHD target organs show differential kinetic and often discordant progression and vary in cytokine profiles among themselves, despite an allogeneic T cell response being considered the driving cause (Kumar et al, 2017). Figure 2 shows the phases of GVHD pathophysiology with immunoregulatory aspects -modified from Ferrara et al, 2009. Metabolic regulation is important for immunoregulation and GVHD, and pretransplant cytokine profiles and metabolic status of allotransplant recipients are shown to be associated with a risk of later a GVHD development (Reikvam et al, 2016). Previous studies suggest differences in immune cells metabolism and may FIGURE 2 | Schematic overview of graft vs. host disease (GVHD) pathophysiology with immunoregulatory aspects: Conditioning regimen at the time of transplant causes damage to the host tissues.…”

Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers

“…Serum levels of multiple markers of inflammation and oxidative stress were increased in our cGVHD patients ( 36 ), possibly reflecting an increased risk of inflammatory complications after allo-HSCT. Uremic toxicity, metabolic acidosis, and pro-inflammatory soluble mediators may activate protein degradation in cGVHD ( 25 , 32 , 49 ), and cGVHD may thereby be associated with altered metabolic and endocrine functions of several organs ( 8 , 31 , 36 ). An altered balance between protein synthesis and catabolism may then be the final result.…”

“…Graft versus host disease can be considered an exaggerated manifestation of normal inflammatory mechanisms in which donor lymphocytes encounter foreign antigens in a pro-inflammatory milieu, and this inflammation involves several donor immunocompetent cell subsets ( 8 , 9 , 20 – 22 ). Metabolic regulation is important for immunoregulation, and we have previously demonstrated that pretransplant cytokine profiles as well as the pretransplant metabolic status of allotransplant recipients is associated with a risk of later aGVHD ( 23 – 25 ).…”