Abstract
T and B lymphocyte subsets have been not univocally associated to Graft-versus-host disease (GVHD) and relapse of hematological malignancies after stem cell transplantation (SCT). Their sequential assessment together with B and T cell neogenesis indexes has been not thoroughly analysed in relation to these changing and interrelated immunologic/clinic events yet.Lymphocyte subsets in peripheral blood (PB) and B and T cell neogenesis indexes were analysed together at different time points in a prospective study of 50 patients. Principal component analysis (PCA) was used as first step of multivariate analysis to address issues related to a high number of variables versus a relatively low number of patients. Multivariate analysis was completed by Fine-Gray proportional hazard regression model. PCA identified 3 clusters of variables (PC1-3), which correlated with acute GVHD: PC1 (pre-SCT: KRECs≥6608/ml, unswitched memory B <2.4%, CD4+TCM cells <45%; HR 0.5, p = 0.001); PC2 (at aGVHD onset: CD4+>44%, CD8+TCM cells>4%; HR 1.9, p = 0.01), and PC3 (at aGVHD onset: CD4+TEMRA<1, total Treg<4, TregEM <2 cells/μl; HR 0.5, p = 0.002). Chronic GVHD was associated with one PC (TregEM <2 cells/μl at day+28, CD8+TEMRA<43% at day+90, immature B cells<6 cells/μl and KRECs<11710/ml at day+180; HR 0.4, P = 0.001). Two PC correlated with relapse: PC1 (pre-SCT: CD4+ <269, CD4+TCM <120, total Treg <18, TregCM <8 cells/μl; HR 4.0, p = 0.02); PC2 (pre-SCT mature CD19+ >69%, switched memory CD19+ = 0 cells and KRECs<6614/ml at +90; HR 0.1, p = 0.008). All these immunologic parameters were independent indicators of chronic GVHD and relapse, also considering the possible effect of previous steroid-therapy for acute GVHD. Specific time-varying immunologic profiles were associated to GVHD and relapse. Pre-SCT host immune-microenvironment and changes of B cell homeostasis could influence GVH- and Graft-versus-Tumor reactions. The paradoxical increase of EM Treg in PB of patients with GVHD could be explained by their compartmentalization outside lymphoid tissues, which are of critical relevance for regulation of GVH reactions.
Highlights
Long term efficacy of allogeneic stem cell transplantation (SCT) in haematological malignancies relies primarily on graft-versus-tumor (GVT), which partly overlaps with graft-versushost disease (GVHD)[1,2], the most common cause of morbidity and mortality in SCT [3]
GVT and GVHD are probably characterized by different intensity of immune reactions, which can be modulated by different subsets of donor T and B lymphocytes [1,2,3,4]
We prospectively evaluated T and B lymphocyte subsets together with thymic and bone marrow output indexes in 50 patients at different time points before and after SCT in relation to acute GVHD (aGVHD), chronic GVHD (cGVHD), and relapse, as clinical indicator of ineffective GVT
Summary
Long term efficacy of allogeneic stem cell transplantation (SCT) in haematological malignancies relies primarily on graft-versus-tumor (GVT), which partly overlaps with graft-versushost disease (GVHD)[1,2], the most common cause of morbidity and mortality in SCT [3]. Several studies correlated T lymphocyte subtypes in peripheral blood (PB) with GVHD (acute and chronic) and relapse, without univocal results [5,6,7,8,9,10,11,12,13,14,15,16,17,18]. The role of B lymphocytes in chronic GVHD (cGVHD) was evidenced by several authors, whereas their relationship with acute GVHD (aGVHD) and relapse has been poorly investigated [5,19,20,21,22,23,24,25,26]. The importance of B and T cell neogenesis indexes as well
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