Harnessing the biology of IL-7 for therapeutic application

Abstract

Interleukin-7 (IL-7) is required for T cell development in mice and humans and is produced by stromal tissues rather than activated lymphocytes. Under normal conditions, IL-7 is a limiting resource for T cells, but it accumulates during lymphopenic conditions. IL-7 signals through a heterodimeric receptor consisting of the IL-7 receptor α-chain (IL-7Rα) and the common cytokine receptor γ-chain (γc). IL-7 is not required for human B cell development in fetal life, but it affects early B cell progenitors and contributes to B cell development under normal conditions. IL-7 has also been recently demonstrated to regulate lymphoid tissue inducer (LTi) cells, which induce the development of secondary lymphoid organs and can induce tertiary lymphoid tissue postnatally in settings of chronic inflammation. In animals, IL-7 therapy enhances the effectiveness of adoptive immunotherapy for cancer, enhances vaccine responses and enhances viral clearance in the setting of acute and chronic infections. In mature T cells, IL-7Rα is most highly expressed on recent thymic emigrants, maintained on naive T cells, downregulated upon T cell activation, and re-expressed on memory T cell subsets. As a result, treatment with recombinant human IL-7 (rhIL-7) preferentially expands recent thymic emigrants and naive T cells, as well as central memory T cells, but largely spares senescent T cells and regulatory T cells. This results in increased repertoire diversity following rhIL-7 therapy in humans. Clinical results with rhIL-7 thus far have shown it to be well tolerated with dose-dependent increases in T cell numbers that persist long after the cytokine is cleared. Based on the pharmacological and biological properties demonstrated thus far, IL-7 is particularly well-suited as a therapy for conditions associated with lymphocyte immunodeficiency. Multiple trials are ongoing or planned in HIV infection, other chronic infections (including hepatitis B and C), cancer (including as an adjuvant to immune-based therapies), post-haematopoietic stem cell transplantation and ageing.