ARC Australian Postdoctoral (Industry) Fellow
Anatomy and Developmental Biology
Overcoming immune senescence to establish transplantation tolerance
Jessica Morison1, Cara Anticevic1, Maree Hammett1, Richard Boyd1, Tracy Heng1.
1Anatomy and Developmental Biology, Monash University, Melbourne, Australia
Organ transplantation traditionally depends on the lifelong use of immunosuppressive drugs to combat graft rejection. A logical solution to avoiding prolonged global immunosuppression is to induce graft-specific tolerance, which allows for long-term graft acceptance whilst maintaining immune competence. This can be achieved via graft-matched haematopoietic stem cell transplantation to produce a chimeric immune system that is tolerant to both host cells and donor graft. Aged recipients, however, exhibit reduced engraftment of transplanted haematopoietic stem cells, which is further compounded by poor T cell recovery due to age-related involution of the thymus. Thus, minimal conditioning regimes that do not fully ablate the immune system would mitigate the damage to the thymus and improve immune recovery.
To this end, we recently were the first to achieve chimerism-based long-term tolerance across major histocompatibility barriers in aged mice using a radiation-free, low-dose conditioning regime. We found that low-dose busulfan, in combination with host T cell depletion and short-term sirolimus-based immunosuppression, facilitated efficient engraftment of donor haematopoietic stem cells and led to durable mixed chimerism. Chimeric mice were tolerant to full MHC-mismatched donor skin grafts and rejected third-party grafts, indicating immune competence. Tolerance induction was associated with an expansion in Foxp3-expressing regulatory T cells and, surprisingly, was not abrogated in the absence of a thymus. Instead, partial depletion of regulatory T cells at the time of donor skin grafting affected the integrity of the graft and reduced the overall graft size.
Thus, in this minimal conditioning model, peripheral regulation operates in the absence of a thymus and donor-specific tolerance induction is not impeded by age-related thymic involution and immune senescence. Our findings are especially relevant in the clinic as the majority of transplant recipients are older patients who would benefit from minimal conditioning regimes that allow efficient donor engraftment without fully ablating the immune system.
 Morison J, et al., and Heng T, Am J Transplant, 2014. 14(11): p. 2478-90.
15:30 - 17:00
|Immunology||Overcoming immune senescence to establish transplantation tolerance||Room 111-112|