MERIT Award Recipient: Michael Caligiuri, M.D.
IL-15 Characterization Through Experimental Immunology
Natural killer (NK) cells are large granular lymphocytes that constitute ~10% of total peripheral blood lymphocytes in humans. NK cells are part of the body's innate immune system providing the first line of defense against invading pathogens and likely against certain types of cancer. The recent discovery, in both experimental and several clinical studies, of NK cells' ability to recognize and control the relapse of chemo-resistant acute myeloid leukemia (AML) could significantly improve the clinical outcome of patients with this disease, of which only 30% currently achieve long term disease-free survival.
Despite these advances in the clinical utilization of human NK cells, little is known about their normal development, their different functions, and the extent of their protective and pathologic effects in our bodies. Our laboratory has focused on the role of interleukin 15 (IL-15), one key cytokine (secreted protein) in the symphony of cytokines and immune effector cells that orchestrate the human immune response. Based on our experimental evidence, we originally proposed that IL-15 is critical for NK cell development; this prediction was confirmed by others, who engineered mice with a targeted genetic disruption of the IL-15 gene, resulting in the absence of IL-15 protein and the consequent absence of NK cells. We have since discovered that human NK cells can develop within secondary lymphoid tissue (SLT) such as tonsils and lymph nodes, and that NK cells do require IL-15 for this development. Thus far our work would suggest that hematopoietic progenitor cells migrate from the bone marrow into SLT, where they progress through five different stages toward NK cell maturation before exiting into the peripheral blood. Throughout this process, the NK lineage cells appear to require IL-15, which is provided at least in part from encounters with conventional dendritic cells residing within the SLT. We will now further identify and characterize the progenitor and precursor cells that differentiate into mature human NK cells, and study the role of IL-15 in this process. The more we can understand the interplay between IL-15 and human NK cells, the more we can understand how to manipulate the immune system to prevent and treat diseases such as cancer.
Given its ability to activate both NK cells and memory T lymphocytes, IL-15 might be an ideal immune stimulant for cancer therapy or immune adjuvant for use in cancer vaccines. Indeed, the first production of IL-15 for clinical trials has recently been achieved at the National Cancer Institute. We therefore developed a mouse strain with constitutive over-expression of IL-15, to mimic a clinical IL-15 therapy scenario. As expected, mild over-expression of this cytokine resulted in an expansion of NK cells and memory T cells; importantly, immunity against experimental cancers was improved in vivo in instances where another key immune cytokine, IL-2, was not effective. However, in some instances, prolonged over-expression of IL-15 in the mice resulted in an acute and rapidly fatal T- and NK large granular lymphocytic leukemia (LGLL). Interestingly, human LGLL cells often require IL-15 (or IL-2) to grow in vitro, suggesting that IL-15 may play a role in the development of human LGLL. Our laboratory will pursue the mechanism of this IL-15-induced LGLL in our experimental system and look to develop effective means for its treatment, which could then hopefully be translated into the clinic for this otherwise incurable cancer.