Differences in the Phenotype, Cytokine Gene Expression Profiles, and In Vivo Alloreactivity of T Cells Mobilized with Plerixafor Compared with G-CSF

Abstract

Plerixafor (Mozobil®) is a CXCR4 antagonist that rapidly mobilizes CD34+ cells into circulation. Recently, plerixafor has been used as a single agent to mobilize peripheral blood stem cells (PBSC) for allogeneic hematopoietic cell transplantation. Although G-CSF mobilization is known to alter the phenotype and cytokine polarization of transplanted T-cells, the effects of plerixafor mobilization on T-cells have not been well characterized. In this study, we show that alterations in the T-cell phenotype and cytokine gene expression profiles characteristic of G-CSF mobilization do not occur following mobilization with plerixafor. Compared to non-mobilized T-cells, plerixafor-mobilized T-cells had similar phenotype, mixed lymphocyte reactivity, FoxP3 gene expression levels in CD4+ T-cells, and did not undergo a change in expression levels of 84 genes associated with Th1/Th2/Th3 pathways. In contrast to plerixafor, G-CSF mobilization decreased CD62L expression on both CD4 and CD8+ T-cells and altered expression levels of 16 cytokine-associated genes in CD3+ T-cells. To assess the clinical relevance of these findings, we explored a murine model of GVHD in which transplant recipients received plerixafor or G-CSF mobilized allograft from MHC-matched, minor histocompatibility mismatched donors; recipients of plerixafor mobilized PBSC had a significantly higher incidence of skin GVHD compared to mice receiving G-CSF mobilized transplants (100% vs. 50% respectively, p=0.02). These preclinical data show plerixafor, in contrast to G-CSF, does not alter the phenotype and cytokine polarization of T-cells, which raises the possibility that T-cell mediated immune sequelae of allogeneic transplantation in humans may differ when donor allografts are mobilized with plerixafor compared to G-CSF.

Generation of memory T cells for adoptive transfer using clinical-grade anti-CD62L magnetic beads

“…A disadvantage of the CD62L-depletion method is that both G-CSF mobilisation and cryopreservation induce shedding of CD62L, 20,21 thus increasing the risk that removal of T N will be incomplete. In both cases, CD62L expression returns to baseline following incubation of cells for 18 h at 37°C (data not shown); however, the additional culture step constitutes a significant manipulation and thus, the product would be subject to regulation as an ATMP.…”

“…However, recent data indicates that grafts mobilized with Plerixafor alone do not downregulate CD62L and in this case, CD62L depletion could theoretically be used. 20 In addition, unlike G-CSF, Plerixafor does not alter the cytokine or effector profile of T cells toward a Th2 phenotype and there may therefore be some advantages for this approach especially where rapid restoration of immunity to intracellular pathogens via memory-type Th1 responses is required.…”

Plasmacytoid dendritic cells in allogeneic hematopoietic cell transplantation: benefit or burden?

“…32,41,59,60 Similarly, P induces Treg cells, 43 but without altering T-cell phenotype and cytokine gene expression like G-CSF. 61 …”

“…32,41 In contrast to G-CSF, P induces Treg cells, 43 but without altering T-cell phenotype and cytokine gene expression. 61 Based upon general DC expansion, FL would seemingly have a complex influence on aGvHD risk. In this regard, Blazar et al 51 found that FL therapy expanded splenocyte myeloid and plasmacytoid DCs and reduced T cells in donors, but did not modify subsequent aGvHD induction when donor splenocytes were administered to transplant recipients.…”

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

“…Two recent studies in mice compared the effect of G-CSF and plerixafor on T-cell alloreactivity, showing that alterations in the T-cell phenotype and cytokine gene expression profile characteristic of G-CSF mobilization do not occur with plerixafor. 51,61 Interestingly, in the study by Lungvist et al, 61 mice which received plerixafor-mobilized PBSC had a significantly higher incidence of skin GVHD compared to the ones tranplanted with G-CSF mobilized graft.…”