In vivo administration of a novel synthetic GMCSF and IL7 fusion cytokine (GIFT7) leads to transient thymic hyperplasia by driving double-negative (DN), single-positive CD8 (SPCD8) and gamma-delta (γδ) thymocyte proliferation (165.7)

Abstract

Abstract T-cell deficiency secondary to cytotoxic agents, viral assaults or ageing predisposes to defective adaptive immunity. Therefore, therapeutic approaches to enhance thymic output leading to T cell reconstitution are of clinical importance. We develop a novel synthetic fusion cytokine between Granulocyte-macrophage colony stimulating factor (GM-CSF) and Interleukin 7 Fusion Transgene (GIFT7). In vitro, GIFT7 acts as a hyperagonist for the IL7 receptor (IL7R) leading to hyperphosphorylation of STAT5. To test the effect of GIFT7 on IL7R-expressing primary thymocytes, we dissociated normal thymii from C57BL/6 mice and exposed unfractionated thymic cells in vitro to GIFT7 for 5 days. We observed a marked anti-apoptotic and proliferative response in CD3+CD4-CD8+ single-positive CD8 (SPCD8) and CD4-CD8-CD44+CD25- double negative 1 (DN1) T cell precursors in both αβ and γδ T cell lineage. In vivo, intravenous administration of recombinant GIFT7 at 5 µg/kg daily for 2 days into non-irradiated mice leads to a significant 2 fold increase in thymic DN1 population after 7 days. After 14 days, there was a subsequent 100% increase in total thymocyte number which returned to baseline at day 35. We propose the use of GIFT7 as a novel IL7R targeted thymopoietic growth factor for the treatment of catastrophic human immune deficient ailments characterized by thymic involution such as congenital or HIV-mediated acquired immunodeficiency, post-chemotherapy/radiation therapy and ageing.