Clonal heterogeneity of dendritic cells derived from patients with chronic myeloid leukemia and enhancement of their T-cells stimulatory activity by IFN-α

Abstract

Adoptive immunotherapy in form of donor leukocyte infusions is effective in a significant number of patients with chronic myeloid leukemia (CML) that have relapsed after allogeneic bone marrow transplantation (BMT). However, the therapy is associated with clinically significant side effects such as graft-versus-host disease (GVHD) and bone marrow (BM) hypoplasia that may be avoided through the administration of T cells with specific antileukemic activity. Dendritic cells (DC) functioning as potent antigen presenting cells (APC) may play an important role in the generation of T cells with specificity against CML. We examined a subpopulation of CD1a + /CD14 − DC generated in vitro from BM of normal subjects and patients with CML using granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4). These DC derived from both the BM of normal subjects and of patients with CML, differentiated and matured in culture in a similar way. However, DC derived from patients with CML, displayed decreased activity when tested with allogeneic T cells in a mixed lymphocyte reaction (MLR). Addition of interferon-α (IFN-α) to DC cultures significantly upregulated the expression of major histocompatibility complex (MHC) molecules (class I and class II) and costimulatory molecules (B7.1 and B7.2) on DC from normal donors and CML patients. However, DC grown from CML patients required a higher concentration of IFN-α. IFN-α also significantly improved the capacity of CML DC to stimulate T-lymphocyte responses. Fluorescence in situ hybridization (FISH) showed that only some CD1a + /CD14 − DC derived from BM of patients with CML expressed the bcr/abl fusion gene. Incubation with INF-α decreased the proportion of bcr/abl positive DC.