Primary Investigators: Dr. Jane Miha O, MD
Institution: Massachusetts General Hospital at Harvard Medical School
Funding began in 2017.
Please read below to learn more about this co-funded research project with ISHLT.
Although kidney allograft tolerance has been achieved in nonhuman primates (NHPs) 1-3 and in humans, 4-7, protocols that achieve tolerance of kidney allografts in NHPs fail to induce tolerance of heart allografts 8. Kidney transplants are more tolerance-prone than heart transplants across species, including humans. Dr. Madsen’s group has taken advantage of the intrinsic tolerogenicity of kidney allografts and, through donor kidney cotransplantation, has achieved, for the first time, stable tolerance of heart allografts in NHPs which, if transplanted alone, are rejected acutely. The consistency with which kidney allografts confer long-term tolerance to recipients of cotransplanted heart allografts across different species (mouse, swine, NHP), across different histocompatibility barriers, and across different tolerance protocols is extraordinary (reviewed in 9). Interestingly, registry studies suggest that human recipients of kidney and heart allografts from the same donor experience less acute rejection and less cardiac allograft vasculopathy (CAV) compared to those receiving heart transplants alone. Although the effects of kidney cotransplantation on cardiac allograft tolerance are remarkable, transplanting a kidney simply to achieve tolerance in human recipients is untenable.
The goal of this study is to determine if a vascularized donor thymus will substitute for the donor kidney and confer tolerance upon a cotransplanted heart allograft. Dr. Madsen’s preliminary results in murine, swine, and NHP models strongly suggest that the tolerogenic properties of kidney allografts relate to organ-specific mechanisms intrinsic to a kidney but not a heart that expand/activate regulatory T cells (Tregs) in the host. Not only does the thymus contain the largest numbers of Tregs but thymic-derived Tregs (tTregs) possess greater stability/less plasticity than peripherally-induced Tregs (pTregs).
We hypothesize that a donor thymus will promote a similar type of regulatory tolerance as a donor kidney and induce robust tolerance of a cotransplanted heart. We will test the hypothesis by transplanting heart en bloc thymus allografts into NHP recipients undergoing a mixed chimerism conditioning regimen.
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