We aim to develop a novel immunotherapy based on donor-derived exosomes that specifically suppress the anti-donor T-cell response after organ transplantation, while leaving overall immunity intact. The therapy targets both the direct and the…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
induction of apoptosis in donor-specific T-cells that response directly to
allo-antigen, and induction of anergy (= unresponsiveness to antigenic
stimulation) in donor specific T-cells that respond to indirectly presented
allo-antigens.
Secondary outcome
n.a.
Background summary
Organ transplant recipients need life-long treatment with immunosuppressive
drugs to prevent rejection of their graft. These immunosuppressive drugs have
serious adverse effects. Since not only immunity against the graft is
suppressed, but immunity in general, patients become highly susceptible for
infections and cancer. Induction of specific transplant tolerance is therefore
a major goal in transplantation research. In this proposal, we want to develop
a new therapy, based on donor exosomes that specifically suppress the part of
the immune system directed to donor antigens and leave the rest of the immune
system untouched, thereby allowing proper immune responses to pathogens and
cancer. We aim to treat organ graft recipients with exosomes produced by donor
B-cells that are transfected with Fas-ligand and miR-146. These exosomes
express donor MHC class I and II and co-stimulatory molecules, and are
therefore able to activate recipient T-cells expressing a T-cell receptor that
recognizes donor MHC molecules. When these T-cells are activated they will
upregulate Fas and are forced into apoptosis by ligation to Fas-ligand
expressed on the exosomes. In addition, part of the exosomes will be taken up
by immature antigen presenting cells (APC), and the donor antigens present in
the exosomes will be processed and presented by their MHC molecules to T cells.
However, miR-146 prevents maturation of the APC, and as a result donor-specific
T cells will be rendered anergic.
Study objective
We aim to develop a novel immunotherapy based on donor-derived exosomes that
specifically suppress the anti-donor T-cell response after organ
transplantation, while leaving overall immunity intact. The therapy targets
both the direct and the indirect pathway of allogeneic antigen recognition,
which both contribute to graft rejection.
Study design
Case-control study in which exosomes derived from donor splenic B-cells that
are transfected with FASL and miR-146, are compared with exsosomes derived from
untransfected donor splenic B-cells for their ability to induce donor-specific
apoptosis and anergy in recipient T-cells in vitro.
Study burden and risks
There is no extra risk for the patient.
's Gravendijkwal 230
Rotterdam 3015 CA
NL
's Gravendijkwal 230
Rotterdam 3015 CA
NL
Listed location countries
Age
Inclusion criteria
The experimental group of patients that undergo liver transplantation in Erasmus MC
Exclusion criteria
Liver transplant recipients who recieve a donor liver of which we do not obtain donor spleen tissue
Liver transplant recipients with a low white blood cell count (<4x10E6 cells/ml) at 1 week after transplantation
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL49325.078.14 |