STEM CELLS FOR TOLERANCE INDUCTION

  • Kenyon, Norma S (PI)
  • McIntosh, Kevin (PI)
  • Chong, Anita S. (PI)
  • Bartholomew, Amelia M. (PI)

Project: Research project

Description

DESCRIPTION (provided by applicant): With the continued introduction
of new agents capable of intervening at different stages in the generation of
an immune response, significant progress has been made in the field of
transplantation over the past decade. One of the major challenges facing the
field today concerns definition of protocols that result in the establishment
of a state of donor specific tolerance, thus obviating the need for life-long
immunosuppression of the recipient. Several strategies proven successful for
tolerance induction in rodent models have not translated-well to pre-clinical
models or man. Bone marrow transplantation and the establishment of mixed
hematopoietic chimerism can lead to tolerance to allogeneic organs and ceils,
as well as prevention or amelioration of autoimmune disease in rodents.
Clinical application of this strategy has been hampered by the requirement for
intensive conditioning of the recipient in order to attain donor HSC
engraftment across MHC barriers. Variables associated with the ability to
overcome this challenge are being defined in a rapid manner in basic research
models. In this program project, we aim to bring together and test, in a
rigorous pre-clinical model, several approaches that have been demonstrated to
facilitate donor HSC engraftment in rodents. In Project I, the following
concepts will be tested: I) can intraportal infusion of donor hematopoietic
cells and/or MSCs lead to recruitment of peripheral regulatory mechanisms that
predispose the host to become tolerant to islet allografts, 2) does
intraportal transplantation of stromal cells result in the establishment of a
microenvironment within the liver that facilitates donor HSC engraftment
(augmented by i.v. HSC infusion), and 3) do HSC repopulate host tissues, thus
leading to recruitment of central deletional mechanisms that, combined with
peripheral regulatory processes, will lead to a state of robust tolerance. In
Project 2, we propose to: I) manipulate donor stem cells to engineer a graft
that exerts immunoregulatory effects on the host, 2) determine whether stem
cells of the bone marrow microenvironment can be manipulated to further
enhance graft survival, and 3) address issues related to residual host T and B
cells in relation to late graft loss. Overlapping both projects 1 and 2 are
newly emerging concepts regarding the role of regulatory cells in the
induction and maintenance of tolerance (project 3). Animals transplanted in
Projects 1 (islet) and 2 (kidney) will be studied in Project 3 to identify and
analyze putative regulatory cells in monkeys with stable allografts, and we
will then utilize this information to refine our transplant strategies. Core A
will provide MSCs for transplantation in Projects 1 and 2.
StatusFinished
Effective start/end date9/15/026/30/08

Funding

  • National Institutes of Health: $1,014,469.00
  • National Institutes of Health
  • National Institutes of Health: $99,554.00
  • National Institutes of Health: $883,394.00
  • National Institutes of Health: $922,666.00
  • National Institutes of Health: $807,723.00
  • National Institutes of Health: $849,008.00

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Stem Cells
Tissue Donors
Rodentia
Transplantation
Chimerism
Transplants
Allografts
Islets of Langerhans Transplantation
Aptitude
Graft Survival
Stromal Cells
Bone Marrow Transplantation
Mesenchymal Stromal Cells
Autoimmune Diseases
Haplorhini
Bone Marrow
Liver
Maintenance
Islets of Langerhans
Kidney

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)