Interleukin-3: Promises and Perspectives

Interleukin-3 (IL-3) is a multipotent hematopoietic growth factor produced by activated T-cells, monocytes/macrophages and stroma cells. Human IL-3 gene is located on chromosome 5 near segment 5q31. The high affinity receptor for human IL-3 is composed of alpha and beta subunits. IL-3 shares common beta subunit with GM-CSF and IL-5 which has been mapped to chromosome 22q13.1. The biological effects of IL-3 have been studied in human and murine hematopoietic cell lines and normal human bone marrow cells. Addition of IL-3 to the culture medium induces proliferation, maturation and probably self renewal of pluripotent hematopoietic stem cells and cells of myeloid, erythroid and megakaryocytic lineages. Various clinical trials have assessed the in vivo potential of recombinant human interleukin 3 (rhIL-3). Initial results of phase I/II studies of IL-3 at a dose of 5-10 ug/kg subcutaneous (s/c) daily for 5-10 days in patients with relapsed lymphomas, small cell lung cancer, breast cancer and ovarian cancer have shown that post-chemotherapy application of IL-3 reduces chemotherapy delays and induces faster regeneration of granulocytes and platelets. However, these results were not confirmed in phase III studies. The role of IL-3 alone in the treatment of myelodysplastic syndromes (MDS), aplastic anemia (AA) and other bone marrow failure disorders have also been disappointing. However, preliminary studies of IL-3 in combination with chemotherapeutic agents and immunosuppression have demonstrated encouraging results in patients with MDS and aplastic anemia respectively. The therapeutic potential of IL-3 in peripheral blood stem cell harvesting and priming of stem cells before harvest is beginning to be identified. Initial results of IL-3 in combination with granulocyte macrophage colony stimulating factor (GM-CSF) or later acting growth factor like granulocyte colony stimulating factor (G-CSF) have yielded larger amounts of peripheral blood stem cells during PBSC harvesting. This approach and application of IL-3 with cocktail of other cytokines for ex-vivo expansion of stem cells, dendritic cell development and gene transfer requires further evaluation. The role of IL-3 in murine models of antiphospholipid syndrome (APLS) for prevention of recurrent abortion remains experimental and warrants careful assessment of adverse effects of IL-3 therapy on pregnant woman and fetus. The exact therapeutic role of IL-3 in oncology and nononcology patients is beginning to be identified. It appears that future application of IL-3 in combination with other cytokines is an attractive way forward in the prevention of treatment related mortality and morbidity in oncology patients. It also holds prospects for development of new therapeutic strategies for dose escalation and immune modulation for relapsed cancer patients.