Strategies to Improve Immune Reconstitution After Haematopoietic Stem Cell Transplantation

Immunologic reconstitution is a critical component for successful outcome of haematopoietic stem cell transplantation. Chemotherapy and pre-transplant conditioning impairs thymic function leading to delayed T-cell regeneration and the increased risk of opportunistic infections and leukaemia relapse. Immune reconstitution can be promoted through administration of common γ-chain cytokines such as IL-2, IL-7 and IL-15. Prevention of thymic involution achieved by administration of keratinocyte growth factor, growth hormone and sex hormone inhibition has also been shown to improve immune reconstitution. Additionally, cell therapy that includes adoptive transfer of ex vivo generated T-cells or T-cell precursors, T-cells specific for viral or tumour antigens and, natural killer (NK) cells appears to be a promising therapeutic approach to improve immune reconstitution after transplantation. Pharmacological modulation of signalling pathways, such as Wnt and Notch, play an important role during different stages of Tcell development. Activation of Wnt signalling using small molecule inhibition of GSK3β was shown to promote post-transplant T-cell regeneration in pre-clinical models. The use of pharmaceutical agents to accelerate T-cell reconstitution and boost T-cell-mediated immunity in recipients of haematopoietic stem cell grafts warrants further investigation.

Keywords: Haematopoeitic stem cell transplantation, immune reconstitution, Tcell, thymus, Wnt signaling.