Bases fondamentales et role de l'IL-12 dans l'hematopoiese

IL-12 is a heterodimeric cytokine which has a long half-life and is mainly secreted by dendritic cells, macrophages, EBV-transformed lymphoblastoid B cells and neutrophils. IL-12 subserves a variety of biological functions on activated NK and T cells, such as proliferation, production of IFNγ and differentiation of CD4⁺ T cells towards a Th1 pattern, and links innate and cognate immune responses. Following systemic or paracrine administration, IL-12 has potent antitumor effects and can cure infectious opportunistic diseases in mice. The role of IL-12 in hematopoiesis has been investigated, both in vitro and in vivo, in mouse and man. IL-12, like IL-6 and IL-11, in a synergistic (along with IL-3, FL, SCF) and direct fashion can enhance the growth of hematopoietic progenitor cells in vitro, whereas it can indirectly suppress (through IFNγ and TNFα) hematopoiesis in vitro. IL-12 can potently and synergistically enhance colony formation of primitive bone marrow progenitor cells in combination with other cytokines. The endogenous role of IL-12 in hemtopoiesis remains ill-defined. The role of IL-12 in the development of hematopoiesis has been suggested in mouse models. However, following systemic administration of high doses of IL-12 in rodents and primates, anemia, neutropenia, lymphopenia (adverse effects of enhanced IFNγ production), and splenomegaly (with both progenitor mobilization from bone marrow to extramedullary sites and enhanced proliferation of peripheral progenitors) occurred. In the phase I clinical trial for cancer and AIDS utilizing recombinant daily intravenous injections of hIL-12, patients developed leucopenia. Finally, IL-12 could inhibit graft- versus host disease in murine models.