SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R I M M U N O L O G Y P R O G R A M
ROBERT B. LEVY, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
Researchers in Dr. Levy’s laboratory study the
immunological responses following allogeneic
bone marrow transplantation (BMT), which
determine the success or failure of the hematopoietic
graft. The primary objective of these studies
is to define how different effector molecules
produced by transplanted donor T cells and by
barrier cells in the recipient regulate the development
of graft versus host disease (GVHD) and
control hematopoietic engraftment, respectively.
The work concerning GVHD has focused
on elucidating the role of donor-mediated cytotoxicity
against recipient cells following the transplant.
Their findings have demonstrated that
differing pathways of cytotoxicity play different
roles in the GVHD process. Granule dependent
cytotoxicity dependent on perforin function is
important in the development and onset of the
disease. Cytotoxicity mediated by CD95L (FasL)
is an important pathway in the pathogenesis
occurring in the liver during GVHD and also can
contribute to cutaneous GVHD. Most interestingly,
even when both of these molecular pathways
are absent in donor T cells (i.e., when they
are “doubly cytotoxic deficient”), they remain
capable of inducing many GVHD symptoms and
death in recipients. Dr. Levy and his colleagues
have recently found that highly purified populations
of CD8 + or CD4 + T cells lacking these killing
functions also induce lethal GVHD posttransplant.
Researchers in this laboratory also investigate
the process of engraftment following BMT. These
studies examine the presence of defined donor
progenitor cell populations (lineage committed
and more primitive multi-lineage stem cells) and
peripheral chimerism in recipients post-transplant.
They are interested in understanding the
mechanisms used by: 1) donor lymphoid cells for
their facilitation and support of progenitor cells
and engraftment after transplant, and 2) barrier
cells in the host, which inhibit progenitor cells
112
and engraftment. Their recent findings have surprisingly
demonstrated that total body irradiated
BMT recipients lacking both perforin- and
CD95L-dependent mechanisms maintain strong
barrier function. Thus, efforts directed at diminishing
the host’s ability to affect cytotoxicity
through these pathways are unlikely to facilitate
the engraftment process. Transplant of progenitor
cells with defined cytokine receptor deficiencies
will be used to further investigate the molecules
involved. Recent studies also have documented
that during the first month following BMT, there
are two defined stages of engraftment, i.e., an
early period when progenitor cells from the donor
are present in the recipient followed by a later
period during which time such cells may be
eliminated. These findings show that cytotoxic
function via perforin and FasL is not necessary to
establish early progenitor presence but is required
for the establishment of long-term chimerism in
the recipient.
SELECTED PUBLICATIONS
2002
Jiang, Z, Adams, GB, Hanash, AM, Scadden,
DT, and Levy, RB. The contribution of cytotoxic
and noncytotoxic function by donor T-cells that
support engraftment after allogeneic bone marrow
transplantation. Biology of Blood and Marrow
Transplantation 8:588-96, 2002.
Chill, JH, Nivasch, R, Levy, RB, Albeck, S,
Schreiber, G, and Anglister, J. The human interferon
receptor: NMR-based modeling, mapping
of the IFN-alpha 2 binding site, and observed
ligand-induced tightening. Biochemistry
41:3575-85, 2002.
Levy, RB and Aoki, C. Alpha7 nicotinic acetylcholine
receptors occur at postsynaptic densities
of AMPA receptor-positive and -negative excitatory
synapses in rat sensory cortex. The Journal of
Neuroscience 22:5001-15, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004