Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 297

of glomerulonephritis in experimental models. Furthermore, the delivery of IL-10
[271] ; 15-Lipoxygenase [272] ; Smad-7 , which inhibit signals to TGF- [273] ; and
hepatocyte growth factor (HGF) [274] resulted in improvement of glomerulonephritis
in experimental models. The protein overload models of glomerulonephritis and inter-
stitial fibrosis were also attenuated using experimental gene therapy [275] .
6.6.3 Renal Transplantation
The immune response of a host's body to renal graft is the major problem in kidney
transplantation. Further, the immunogenicity of the graft is augmented by the initial
ischemia-reperfusion injury, which negatively influences both acute and chronic graft
failure. Gene therapy can provide an alternative therapy to reduce immune response
in renal transplantation.
6.6.3.1 Gene Therapy for Acute Rejection
Acute rejection is primarily a cell-mediated immune response of the recipient against
the alloantigens present on the renal graft. In a study, local expression of cytotoxic
T-lymphocyte antigen4 immunoglobulin (CTLA4Ig) in the renal graft resulted in pro-
longed graft survival by inhibiting T-cells activation [276] . Moreover, the delivery of
CTLA4Ig along with TGF-3 (antifibrotic) further improved the graft survival [277] .
The delivery of cytokines also improved the survival of graft in experimental mod-
els because of their anti-inflammatory activity [278] . Targeting transcription factors
relevant for acute rejection decoy ODN is one of the strategies used in acute graft
rejection [279] . A strategy of limiting T cell expansion using Fas ligand-mediated
apoptosis has been implicated for acute graft rejection [280] . Induction of tolerance
is one of the way to prevent acute rejection of transplant. The transduction of autolo-
gous BM cells with genes coding for donor MHC class II, using retrovirus in a swine
model, exhibited tolerance and significant survival of the transplants [281] .
6.6.3.2 Gene Therapy for Ischemia-Reperfusion Injury
During the process of transplantation, donor kidneys undergo ischemia followed by
reperfusion. This process of ischemia and reperfusion causes injuries and increases
the expression of MHC class II molecules on the kidney, resulting in cell death and
acute rejection, which leads to chronic graft dysfunction. A gene therapy strategy
has been designed to deliver antiapoptotic gene, Bcl-2 resulted in prolongation of
preservation time compared to control [282] . The cryoprotection of heat shock pro-
tein (HSP) has been utilized as a strategy for ischemia-reperfusion injury. The gene
transfers of HSP70 and HSP32 resulted in prolonged animal survival and improved
renal function and histology [282,283] . Anti-inflammatory genes have also been tried
for ischemia-reperfusion injury. Delivery of AS-ODN to ICAM-1, using liposomes,
resulted in immediate graft function and histology and limitation of inflammatory
cell infiltration [284] . The use of antioxidant gene therapy (overexpression of Cu/Zn
superoxide dismutase) has been utilized for ischemic-reperfusion injury [285] . Small
interfering (Si)-RNA has also been used for mouse models of ischemia reperfusion.