P81: Recovery of distinct T cell subsets under severe lymphopenic conditions in hemoblastosis patients

Abstract

Numerous studies have shown that high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT) led to a profound and long-lasting state of immunodeficiency characterized by persisting low levels of T cells in hemoblastosis patients. Well-timed T-cell reconstitution is crucial for early restoration of anti-infectious and anti- tumor immune response. Lymphocyte recovery is mediated through the two main mechanisms – a homeostatic proliferation of T cells and generation of new naive T cells via thymopoiesis. It is known, that homeostatic proliferation is important for the restoration of T cell count in immune competent host during the 1st year following AHSCT. Thymus begins to fill up T cell repertoire approximately from the 6th month following AHSCT. We have investigated dynamics of CD4+FOXP3+ Treg recovery following AHSCT and possible relationship between Tregs and clinical outcomes since the suppressive activity of Tregs under lymphopenic conditions may influence on peripheral expansion of T cells. Thymic activity following AHSCT has been evaluated by measuring amounts of CD4+ CD45RA+CD31+ naive T cells, i.e. “recent thymic emigrants” (RTEs).109 patients with non-Hodgkin’s lymphomas, Hodgkin’s lymphoma and multiple myeloma underwent AHSCT in 2009–2014. The content of circulating CD4+FOXP3+ Tregs and CD4+CD45RA+CD31+ T cells was evaluated using flow cytometry before AHSCT, at the day of engraftment, and following 6 and 12 months. Pre-transplant count of CD4+FOXP3+ Tregs was significantly higher compared to healthy controls (5.4 ± 2.9 vs 3.8 ± 1.9%; pU = 0.011; here and below data presented as Mean ± SD). Percentage of Tregs restored rapidly and reached initially high level at the time of engraftment, and then subsequently decreased within a year until it lowered to healthy donors‘ values. CD4+FOXP3+ Tregs at the time of engraftment were increased in patients with relapse or progression of disease within 6 and 12 months following AHSCT compared to non-relapsed patients (11.0 ± 6.1 vs 6.2 ± 3.0%; pU = 0.016, and 10.1 ± 5.2 vs 6.1 ± 3.8%; pU = 0.008). Pre-transplant count of CD4+CD45RA+CD31+ T cells was significantly lower compared to healthy controls (17.1 ± 11.4 vs 30.3 ± 11.2%, pU = 0.0005) and did not reach donors‘ values following 12 month (23.1 ± 13.5%, pU = 0.032). Relapsed patients had the same quantity of RTEs as the patients with remission within the 1st year following AHSCT. There was no any significant association between RTEs and Tregs counts. Surprisingly, we have found high levels of circulating CD4+CD45RA- T cells co-expressing CD31 molecule in patients before AHSCT, since this molecule is infrequent on memory subsets in healthy controls (20.7 ± 12.0 vs 8.2 ± 2.1%,pU Our data of Tregs reconstitution may confirm the earlier assumption that the presence of Tregs during the period of immune recovery preserves optimal T cell receptors diversity. However, the excess of these cells leads to the inhibition of proliferative activity and immune response and is associated with early relapse. Conversely, relatively slow recovery of RTEs determines theirlack of influence on survival within the 1st post-transplant year. The biological role and the way of appearance of CD31 molecule on T cell memory subset (CD4+CD45RA- and/or CD4+CD45RO+) still remain unclear. Further studies are required to enlighten the role of CD31+ memory T cells on lymphoproliferative disorders pathogenesis.