Abstract
Graft failure is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). The mechanisms involved in this phenomenon are still not completely understood; data available suggest that recipient T lymphocytes surviving the conditioning regimen are the main mediators of immune-mediated graft failure. So far, no predictive marker or early detection method is available. In order to identify a non-invasive and efficient strategy to diagnose this complication, as well as to find possible targets to prevent/treat it, we performed a detailed analysis of serum of eight patients experiencing graft failure after T-cell depleted HLA-haploidentical HSCT. In this study, we confirm data describing graft failure to be a complex phenomenon involving different components of the immune system, mainly driven by the IFNγ pathway. We observed a significant modulation of IL7, IL8, IL18, IL27, CCL2, CCL5 (Rantes), CCL7, CCL20 (MIP3a), CCL24 (Eotaxin2), and CXCL11 in patients experiencing graft failure, as compared to matched patients not developing this complication. For some of these factors, the difference was already present at the time of infusion of the graft, thus allowing early risk stratification. Moreover, these cytokines/chemokines could represent possible targets, providing the rationale for exploring new therapeutic/preventive strategies.
Highlights
One of the main complications occurring after allogeneic hematopoietic stem cell transplantation (HSCT) is represented by graft failure (GF)
Interactome analysis on identified cytokines and chemokines modulated during GF was performed using STRING software with a high interaction score (0.7)
Main transplant characteristics were comparable between the two groups
Summary
One of the main complications occurring after allogeneic hematopoietic stem cell transplantation (HSCT) is represented by graft failure (GF). Our group has recently focused on a deep characterization of this phenomenon, analyzing a cytokine/chemokine asset in PB, (i.e., IFNg, sIL2Ra, CXCL9, CXCL10, TNFa, IL6, IL10, and sCD163), as well as the cellular features in BM biopsies of patients experiencing GF. From this analysis, we confirmed i) the in vivo role of the IFNg-pathway in the development of immune-mediated GF; ii) that the sole inhibition of this pathway by an anti-IFNg monoclonal antibody (mAb) was able to prevent GF. We tested other 44 cytokines/chemokines in the PB of the previously reported patients experiencing GF [5] with the aim of: i) further characterizing the GF signature; ii) identifying new possible targets to prevent/treat GF; iii) developing strategies capable to target a single pathway/ molecule or a combination of them in order to prevent the occurrence of GF in patients at high-risk of developing this complication
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