A Preliminary Investigation towards the Risk Stratification of Allogeneic Stem Cell Recipients with Respect to the Potential for Development of GVHD via Their Pre-Transplant Plasma Lipid and Metabolic Signature

Abstract

The clinical outcome of allogeneic hematopoietic stem cell transplantation (SCT) may be influenced by the metabolic status of the recipient following conditioning, which in turn may enable risk stratification with respect to the development of transplant-associated complications such as graft vs. host disease (GVHD). To better understand the impact of the metabolic profile of transplant recipients on post-transplant alloreactivity, we investigated the metabolic signature of 14 patients undergoing myeloablative conditioning followed by either human leukocyte antigen (HLA)-matched related or unrelated donor SCT, or autologous SCT. Blood samples were taken following conditioning and prior to transplant on day 0 and the plasma was comprehensively characterized with respect to its lipidome and metabolome via liquid chromatography/mass spectrometry (LCMS) and gas chromatography/mass spectrometry (GCMS). A pro-inflammatory metabolic profile was observed in patients who eventually developed GVHD. Five potential pre-transplant biomarkers, 2-aminobutyric acid, 1-monopalmitin, diacylglycerols (DG 38:5, DG 38:6), and fatty acid FA 20:1 demonstrated high sensitivity and specificity towards predicting post-transplant GVHD. The resulting predictive model demonstrated an estimated predictive accuracy of risk stratification of 100%, with area under the curve of the ROC of 0.995. The likelihood ratio of 1-monopalmitin (infinity), DG 38:5 (6.0), and DG 38:6 (6.0) also demonstrated that a patient with a positive test result for these biomarkers following conditioning and prior to transplant will be at risk of developing GVHD. Collectively, the data suggest the possibility that pre-transplant metabolic signature may be used for risk stratification of SCT recipients with respect to development of alloreactivity.

A Systematic Review of the Literature and Perspectives on the Role of Biomarkers in the Management of Malnutrition After Allogeneic Hematopoietic Stem Cell Transplantation

“…Contaifer et al. ( 32 ) studied a lipidomic and metabolomic profile with LCMS and GCMS before transplantation in 14 patients who underwent allogeneic or autologous transplantation after myeloablative conditioning. The time of sampling was at the end of conditioning before transplantation.…”

“…A single but important study by Contafier ( 32 ) brought interesting results in metabolomic and lipidomic patterns of 14 allo-transplanted patients. Five metabolic biomarkers seem to be predictive for GVHD and this approach should be validated on larger numbers.…”

“…Ten studies identified biomarkers of nutritional interest for transplant related outcomes (GVHD, gastrointestinal function, mucositis, SOS, overall survival, and transplant related mortality). Identified biomarkers were those of proteomic origin such as citrulline (25)(26)(27)(28)(29), albumin (25,26,30,31), prealbumin, and total urinary nitrogen (22) and some of metabolomic origin such as 25-OH-D Vitamin (30), 2aminobutirric acid, 1-monopalmitin dyacilglycerol, and short chain fatty acids (32).…”

IFN-γ and PPARδ Influence the Efficacy and Retention of Multipotent Adult Progenitor Cells in Graft vs Host Disease

“…PPARδ is a ligand‐activated transcription factor that regulates key cellular metabolic functions 23 . Natural ligands for PPARδ include free fatty acids, eicosanoids, and oxysterols, 24 which have been shown to increase in plasma of GvHD patients in addition to being predictive of GvHD development 25,26 . Notably, there are important differences in mechanisms of action mediated by mouse and human MSC.…”

“… 23 Natural ligands for PPARδ include free fatty acids, eicosanoids, and oxysterols, 24 which have been shown to increase in plasma of GvHD patients in addition to being predictive of GvHD development. 25 , 26 Notably, there are important differences in mechanisms of action mediated by mouse and human MSC. Although mouse MSC function has been associated with NO production, human MSC do not produce NO and their immunomodulatory functions are more closely associated with factors like IDO and PGE‐2.…”