Evaluating the potential of RANK ligand to restore effective thymic functions after bone marrow transplantation and during aging – RANKLthym

CONTEXT: T lymphocytes are critical cellular actors in the host response to various pathogens i.e. viruses, bacteria and fungi and in the control of malignant cell transformation. Importantly, the thymus ensures a continuous production of naïve T cells with a diverse TCR repertoire capable to mount effective immune responses. However, this organ undergoes severe changes upon aging in its mass and architecture, accompanied by a progressive decrease in T cell production, a process referred to as “thymic involution”. Furthermore, the thymus is highly sensitive to myeloablative treatments used to cure hematological disorders such as genetic disorders or cancer by hematopoietic stem cell transplantation. Both aging and myeloablative treatments have deleterious effects on thymic epithelial cells, leading to a drastic reduction in T cell production and consequently to increased susceptibility to opportunistic infections, autoimmunity and cancer. Nevertheless, the thymus shows a high plasticity and is prone to regenerative therapies. Although in mice, certain growth factors or cytokines protect or regenerate thymic epithelial cells and improve thymopoiesis, their efficacy in humans in preclinical trials either failed or remains to be determined. Identifying effective therapeutic molecules to regenerate thymic functions thus still constitutes an unmet clinical need. In this context, we recently showed in mice that the administration of the epithelial growth and differentiation cytokine, RANK ligand (RANKL), ameliorates the regeneration of the thymus and T-cell reconstitution upon myeloablative treatments and bone marrow transplantation (BMT) (Lopes et al. EMBO Mol Med 2017 et brevet WO/2018/154122).

OBJECTIVES: The objectives of this project are to determine:
(1) whether T-cell production improved by RANKL enhances protection against lethal opportunistic infections in a pre-clinical BMT mouse model,
(2) to what extent RANKL is beneficial to reverse age-related thymic involution,
(3) the impact of RANKL on the prevention of bone loss by bisphosphonates upon BMT and thymic involution,
(4) the translational potential of using RANKL to regenerate human thymic functions.
In summary, the ambition of this project is to bring the proof of concept that RANKL could be clinically pertinent to improve the recovery of T-cell functions without inducing bone loss in pathophysiological conditions in which the thymus has been severely damaged.

CONSORTIUM: This project is a close collaboration between three French research teams. It brings together a fully complementary expertise on the biology of thymic function in mice (Team #1) and humans (Team #2) as well as on bone physiology (Team #3).

BIOMEDICAL RELEVANCE: This project is expected to improve the immune system by acting on the production of T lymphocytes by regenerating the thymic function. We are convinced that the expected results could have a significant impact on public health, given the incidence of 20 to 30% of mortality related to infections after HSC transplantation and the demographic increase in the number of elderly people in our societies, a phenomenon also associated with a high rate of infections. This project has the potential to improve the health of many patients who incur morbidity and mortality due to T cell deficiency and reduce the associated medical costs.