Research Group
- Dr. Ginny Bumgardner, Principal Investigator
- Ms. Anna Marie Hummel, Research Associate
- Mr. Thomas Pham, Research Associate
Location
- Ohio State University, Columbus, USA
Title
- Analysis of a Novel Strategy which Suppresses Aggressive (CD4-Independent) CD8+ T-Cell-Initiated Hepatocyte Rejection
Most
current immunotherapeutic agents interfere with CD4+ T-cell-dependent rejection. Work from our laboratory and
others has identified an aggressive CD8-dependent
rejection response which is CD4 independent and not susceptible to a variety of
immunotherapeutic strategies that readily control CD4-dependent rejection
responses. We have used a unique functional model of hepatocyte
transplantation to separately assess the effect of various interventions on
CD8- and CD4-dependent rejection processes. Recently, we have demonstrated that
a novel immunosuppressive strategy, which targets lymphocyte function
associated antigen 1 (LFA-1) and CD40/CD40L costimulation,
suppresses both aggressive CD8-dependent and CD4-dependent rejection responses.
This proposal will investigate how this strategy influences T cell recruitment
and activation. In addition, we will determine whether this short-term
immunosuppressive strategy results in the development of regulatory T cells,
which permit long-term hepatocellular allograft
survival. These studies involve the transplantation of purified hepatocytes into host mice, which are treated with
monoclonal antibodies directed at LFA-1 and CD40L. Host tissue will be analysed
by immunohistochemical means to determine the
influence of the treatment strategy upon recruitment of host inflammatory cells
to lymph nodes, spleen and liver tissue. Host inflammatory cells at these sites
will also be isolated and analysed by flow cytometry
for expression of various phenotypic and activation markers to determine the
influence of the therapy upon cell subset recruitment, activation and function.
Mice with long-term hepatocellular allograft survival
induced by treatment with anti-LFA-1 and anti-CD40L mAbs
will be assessed for the presence of regulatory T cells. In addition, host
cells will be tested for evidence of immunoregulation
in in vitro assays.
The successful regulation of immune damage of allogeneic
hepatocytes will advance the therapeutic modality in
patients with liver disease who could be cured or supported by successful hepatocyte transplantation.