Immunotherapy using NK cells to promote engraftment

Project: Research project

Description

DESCRIPTION (provided by applicant): Bone marrow transplantation (BMT) is used
for the treatment of a variety of disorders, however, the acute toxicities
associated with the conditioning procedure in BMT has led to the emergence of
non-myeloablative conditioning therapies. Rejection of the BMC graft by host effector cells remains a significant concern. Natural killer (NK) cells are
cells that spontaneously mediate the killing of transformed or virally infected
cells in a MHC-unrestricted manner. We have previously shown that activated NK
cells of donor-type can improve donor engraftment after allogeneic BMT in mice.
We now propose to assess the effects of NK cell transfer using a
non-myeloablative model to ascertain if activated NK cells, either as whole
populations or through the use of purified subsets, can promote donor BMC
engraftment. We hypothesize that activated NK cells of donor-type, particularly
when either purified or those who have their inhibitory receptors (Ly-49 in the
mouse) blocked, can eliminate or suppress host alloreactive cells that come
into contact with them resulting in greater engraftment capability of
subsequent donor BMC. Toward this goal we have developed 4 Specific Aims:
Specific Aim 1 will assess the effects of donor NK cell transfer on promoting
donor chimerism using allogeneic strain combinations and models involving
decreasing amounts of total body irradiation (TBI) as a conditioning regimen.
The effect on both host NK and T cell-mediated rejection pathways will be
assessed using both in vitro and in vivo assays. Extent of donor chimerism,
evidence for GVHD, and specificity of tolerance induction will be assessed.
Specific Aim 2 will determine if transfer of specific Ly-49 NK cell subsets
will enhance the ability of the donor NK cells to prevent subsequent marrow
rejection. NK cell subsets bearing Ly-49 inhibitory receptors specific for the
host MHC will be removed allowing for greater reactivity of the transferred
population for the host effector cells and thus improve engraftment. Specific
Aim 3 will use F(ab?)2 fragments of various antibodies specific for Ly-49 members to block the interaction with the inhibitory receptors with MHC.
Specific Aim 4 will decipher the mechanism by which NK cells inhibit host
resistance. Neutralizing antibodies to various immunosuppressive cytokines
(i.e. TGF-beta) and the use of knockout mice (i.e. perforin) as a source of NK
cells will be used to determine the role of cytokines versus lytic pathways in
the immunosuppressive effect of NK cells. These studies should result in
improving the efficacy of non-myeloablative therapies and to develop a means to
induce tolerance.
StatusFinished
Effective start/end date9/1/028/31/07

Funding

  • National Institutes of Health: $258,100.00
  • National Institutes of Health: $258,100.00
  • National Institutes of Health: $252,035.00
  • National Institutes of Health: $258,100.00
  • National Institutes of Health: $258,100.00

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Natural Killer Cells
Immunotherapy
Bone Marrow Transplantation
Chimerism
Immunosuppressive Agents
Cytokines
Immunoglobulin Fragments
Natural Killer T-Cells
Aptitude
Behavior Therapy
Whole-Body Irradiation
Homologous Transplantation
Graft Rejection
Neutralizing Antibodies
Knockout Mice
Transforming Growth Factor beta
Therapeutics

ASJC

  • Medicine(all)