Differences in Kinetics of Donor Lymphoid Cells in Response to G-CSF Administration May Affect the Incidence and Severity of Acute GvHD in Respective HLA-Identical Sibling Recipients

Abstract

Granulocyte-colony stimulating factor (G-CSF), in addition to myeloid and stem cells, mobilizes a large number of lymphoid cells. We examined which lymphoid populations were mobilized in 21 consecutive donors of peripheral blood stem cells (PBSC) and whether the differences in mobilization could affect the incidence of acute and chronic GvHD in respective HLA-identical recipients. G-CSF administration induced significant increases of donor B (CD3-CD19+) lymphocytes and slight increases of T (CD3+) and cytotoxic (CD16+CD56+) NK cells. The number of extrathymic cells (CD3+ cells with NK markers, or CD7+) remained unchanged except for an increase of CD3+CD57+CD8+ cells. Donors of patients without subsequent grade II-IV acute GvHD compared to donors of patients who developed significant acute GvHD were found to have in peripheral blood stable numbers of CD3+CD4+ cells producing IL2, with a concomitant increased number of CD3+CD4low+CD25+ T regulatory cells and decreased NK-mediated cytotoxicity, together with a higher number of suppressive extrathymic CD57+CD3+ cells in the blood and G-PBMC grafts. Increasing numbers of activated T and NK cells in the blood were associated with the development of chronic GvHD. We suggest that differences in steady-state levels and kinetics of G-CSF induced mobilization of donor lymphoid cells may in addition to other well-known factors affect the incidence of GvHD in HLA-identical recipients. However, owing to the small number of donor-recipient pairs studied, our results must be verified in a larger group of patients.

rhG-CSF does not affect the phenotype of adult donor peripheral blood NK cells

“…20,22,23 There are contradictory reports on changes in the absolute numbers of NK cells and their proportion within total lymphocytes, following rhG-CSF administration. 20,22,23,[29][30][31][32][33] Functional assays produced equally contradictory results, 31,[33][34][35][36][37][38] although in most instances impaired natural cytotoxic activity against NK-sensitive cell lines was evidenced after rhG-CSF treatment. Two studies reported a decreased expression of proinflammatory cytokines such as IFN-g, IL-2 and TNF-a 31,39 after rhG-CSF mobilization; interestingly, they observed no change in perforin, Fas and Fasligand expression on allogeneic NK cells, a result consistent with our observations.…”

“…Several groups 17,33,35,39 already demonstrated that rhG-CSF administration in vivo had no effect on the expression of CD2, CD7, CD8, CD16, CD25, CD94, CD161 and NKB1 receptors on PB NK cells. There is only one report that suggest a downmodulation of CD56 cell surface density, on both CD56 bright /CD3 À cells and CD56 dim / CD3 À cells.…”

Regulatory T-cell therapy in Crohn’s disease: challenges and advances

“…The risk of developing GvHD following haematopoetic stem cell transplantation (HSCT) is associated with low numbers of Tregs in the periphery,100 and in vivo expansion of Tregs post-HSCT using low-dose IL-2 has demonstrated efficacy against GvHD 101 102. Studies in mice involving infusion of cultured CD4 + CD25 + T cells resulted in a significantly reduced GvHD phenotype,103 and in humans it was found that infusion of freshly isolated donor Tregs given at the same time as haplotype mismatched HSCT prevented the development of GvHD 104…”

T cell regulation of natural killer cells

“…For example, the induction of NK cell effector function in response to the c-Kit tyrosine kinase inhibitor Gleevec (STI571) in patients with gastrointestinal stromal tumors, or in response to exosomes in patients with melanoma, correlated with decreased T reg cell numbers, increased antitumoral responses, and delayed cancer progression (Ghiringhelli et al, 2005, 2006). In patients undergoing HLA-identical blood stem cell transplantation, increased donor T reg cell numbers were associated with reduced NK cell cytotoxic activity (Trzonkowski et al, 2004b). Acute depletion of T reg cells in mice also lead to a significant increase in NK cell numbers, in line with the phenotype of Foxp3-deficient Scurfy mice, which harbor abnormally activated and proliferating NK cells (Ghiringhelli et al, 2005; Kim et al, 2007).…”