Immunoregulation by mononuclear phagocytes. Mechanisms and clinical implications

Sammanfattning: The cytotoxic effector lymphocytes of the immune system, the natural killer (NK) cells and the CD8+ T lymphocytes (CTL), have been ascribed a pivotal role in defense against malignancy. However, the function of these cells is frequently compromised, in particular at sites of malignant cell expansion. This phenomenon, which is commonly referred to as cancer-induced immunosuppression, may not only facilitate malignant cell growth, but also explain why immunotherapies, which aim at triggering the tumor cell killing activity of NK cells and CTL, are frequently inefficacious in many forms of cancer. The first two papers in this thesis focus on the role of mononuclear phagocytic cells as potential inhibitors of NK cell and CTL function. Paper I accounts for the effects of mononuclear phagocytes on two activating receptors, NKp46 and NKG2D, which are expressed on the NK cell surface. Phagocytes triggered the disappearance of these receptors, with ensuing inhibition of NK cell-mediated anti-tumor function. The NK cell-inhibitory signal was conveyed by phagocyte-derived reactive oxygen species (ROS) and NK cells hence were protected by inhibitors of ROS formation as well as by scavengers of ROS. The molecular mechanisms of ROS-induced lymphocyte toxicity were addressed in Paper II, which demonstrates that a nuclear DNA-repairing enzyme, poly(ADP-ribose) polymerase and a mitochondrial protein, apoptosis-inducing factor, were essential for ROS-induced NK cell and CTL suppression. The study presented in Paper III applied these regulatory mechanisms clinically by treating patients diagnosed with acute myeloid leukemia (AML) with a ROS formation inhibitor, histamine dihydrochloride (HDC), and an NK cell and CTL-activating cytokine, interleukin-2 (IL-2), in a multi-center phase III trial. Combination immunotherapy with HDC/IL-2 was found to significantly (p=0.0096) protect adult AML patients (n=320) from leukemic relapses with acceptable treatment-related toxicity. Paper IV addressed the putative role of mononuclear cells (MNC), such as NK cells, T cells and mononuclear phagocytes, in hepatitis C virus (HCV) infection. Systemic levels of a hepatocyte-derived MNC chemoattractant, interferon- ¶-inducible protein 10 (IP-10), were found to correlate with the outcome of combined immunostimulatory and antiviral treatment with interferon- ´/ribavirin; thus, a low IP-10 value in the serum of patients with chronic HCV infection (n=270) accurately predicted a favorable response to therapy.