Composite Tissue Transplantation:
Major soft tissue and skeletal defects,
including limb amputation, represent a deficit of form and function,
as well as diminution of life quality for the affected individuals.
However, any reconstructive measures to improve these non-life
threatening conditions must address a delicate balance of risks
and benefits. As composite tissue transplant experiments are
being conducted, a number of human hand transplants have been
performed worldwide. These allografts have required an intense
maintenance regimen of medications, subjecting the recipients
to the significant morbidities of chronic, systemic immunosuppression.
To address the risk-benefit ratio, therefore, our laboratory
investigates novel techniques in inducing tolerance to composite
tissue allografts without long-term immunosuppression.
Building on years of research at the Massachusetts General Hospital,
we are utilizing a minimally toxic, non-myeloablative regimen
for the creation of mixed chimeric miniature swine, in order
to achieve tolerance to allogenic composite tissue grafts. This
large animal protocol entails use of an anti-CD3 immunotoxin,
in conjuction with high dose hematopoietic donor cell infusion
and short-term cyclosporin administration. Tolerance to the
musculoskeletal portions of grafts has been achieved. Future
research will focus on the tolerance of the epidermal elements
and the mechanisms behind skin allograft rejection.
Dendritic cells have been a highly active area of research in
the fields of cancer immunology and transplantation. Several
groups have investigated the tolerogenic function of these unique
antigen-presenting cells, and postulated mechanisms for their
manipulation. Our laboratory is focusing on the use of host
dendritic cells as carriers of foreign peptide and inducers
of donor specific tolerance. We propose to utilize donor antigen-pulsed
host dendritic cells, in conjuction with antilymphocyte serum,
to induce tolerance to composite tissues allografts in an orthotopic,
rat hindlimb model.
Other future avenues of research include the xenotransplantation
of composite tissues, and the use of thymoglobulin as a tolerance
induction agent.
Key investigators: W. P.
Andrew Lee, M.D., Maryam Hairiri, Ph.D.
