Allogeneic stem cell transplantation for chronic myeloid leukemia

Cellular mechanisms and key molecules regulating GVL in CML. Induction of donor T-cell responses requires presentation of antigens on leukemia cells to CD4⁺ and CD8⁺ T cells of the donor by CML-derived dendritic cells (DC) (or indirectly via donor DC). Critical molecules required for antigen presentation and T-cell activation are peptide antigens presented by MHC class I and II molecules, costimulation via B7.1 /B7.2 interaction with CD28 on the T cell, and (for professional APC such as DC) CD40 interaction with CD40 ligand on the T cell (not shown). Expansion of the immune response generates CD4⁺ and CD8⁺ antigen-specific T cells. Cytokines IL-2 and IL-12 promote T-cell proliferation, IL-10 and IL-4 control the balance between Th1 and Th2 cells modifying the effector behavior: Th1 cells in favor of cytotoxic responses and Th2 cells in favor of humoral responses (not shown). The GVL effect is mediated by both CD4⁺ and CD8⁺ T cells. CML cells including progenitors are killed directly by perforin and granzyme release inducing cytoplasmic damage and apoptosis and by Fas ligand interaction with Fas on the target surface inducing apoptosis. (Both CD4⁺ and CD8⁺ cells use these pathways). Cytokines such as TNF-α and IFN-γ also suppress CML by inhibiting cell proliferation and inducing apoptosis.