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) is strongly influenced from the complications arising during the post-transplant immune restoration and has been well studied and described. However, the metabolic status of the recipient pre-transplant also has the potential to influence this outcome and has never been studied before and has the potential to enable risk stratification with respect to the development of transplant associated complications such as graft vs. host disease (GVHD). In order to better understand this aspect of transplant related complications we investigated the pre-transplantation metabolic signature to assess the possibility of pre-transplant risk stratification. This pilot study was composed of 14 patients undergoing myeloablative conditioning followed by either HLA matched related, unrelated donor, or autologous stem cell transplantation. Blood samples were taken prior to transplant and the plasma was comprehensively characterized with respect to its lipidome and metabolome via LCMS and GCMS. The results indicated a significantly pro-inflammatory metabolic profile in patients who eventually developed Graft vs. Host Disease (GVHD). The data revealed 5 potential pre-transplant biomarkers (1-monopalmitin, diacylglycerol (DG) 38:5, DG 38:6, 2-aminobutyric acid, and fatty acid (FA) 20:1) that demonstrated high sensitivity and specificity towards predicting post-transplant GVHD development. The predictive model developed demonstrated an estimated predictive accuracy of risk stratification of 100%, with an Area under the Curve of the ROC of 0.995 with 100%. 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 pre-transplant will likely have very high odds of developing GVHD post-transplant. Collectively the data demonstrates the possibility of using pre-transplant metabolic signature for risk stratification of SCT recipients with respect to development of GVHD.Recent studies have demonstrated that a dynamical systems model of T cell reconstitution may allow understanding alloreactivity in terms of antigenic differences between donors and recipients and ensuing T cell responses [27][28][29] . This model incorporates the idea that when T cells become activated and undergo metabolic changes upon antigen encounter, they may increase mass, and this appears to be the case when T cell masses are measured following allogeneic SCT 30 . This change in mass is likely driven by the cytokine and chemokine milieu in these patients, which is likely to be altered because of conditioning chemotherapy and radiation induced tissue damage. Further chemokine release is mediated by the effects of inflammation due to infections and endothelial injury. These changes in the post-transplant milieu may be investigated through the study of the metabolomic and lipidomic profile. In this paper we describe the lipidomic and metabolomic profiles of patients undergoing myeloablativ...

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

“…Analysis of lipidome and metabolome in blood samples taken prior to transplant suggested a crucial pro-inflammatory metabolic profile in patients who later developed GVHD (Contaifer et al, 2018a). Lipids containing polyunsaturated fatty acid (known as modulators of inflammation) -such as arachidonic (20:4) eicosapentaenoic (20:5) and docosahexaenoic acid (22:6) containing lipids are predictors of GVHD (Contaifer et al, 2018b).…”