Targeting of interleukin-10 is superior to cytotoxic T-lymphocyte associated antigen 4 with human immunoglobulin G(1) for the prevention of chronic allograft deterioration in organ transplantation.
BACKGROUND
Genetic manipulation of the allograft is an attractive approach to prevent the graft against chronic deterioration through stable expression of immunomodulatory or protective genes. However, the best strategy for prevention of chronic allograft deterioration remains unclear.


METHODS
The efficacies of adeno-associated viral vector-mediated stable expression of indoleamine 2,3-dioxygenase (IDO), cytotoxic T-lymphocyte associated antigen 4 with human immunoglobulin G(1) (CTLA4Ig) or interleukin-10 (IL-10) in the prevention of chronic allograft deterioration were compared in a rat heart transplantation model.


RESULTS
Transduction of grafts with IL-10 significantly prolonged allograft survival, whereas transduction of grafts with IDO did not improve graft survival compared to controls. Analysis of long-term survived heart allografts showed that both CTLA4Ig and IL-10 could significantly reduced the T cells and macrophage infiltration. However, stable expression of CTLA4Ig failed to prevent the development of transplant arteriosclerosis. By contrast, IL-10 suppressed the development of transplant arteriosclerosis effectively. The suppressive effects of IL-10 in preventing the development of chronic allograft deterioration were associated with lower transcript levels of transforming tumor growth factor beta 1 and macrophage migration inhibitory factor in the graft. In addition, higher transcript levels of heme oxygenase-1 were found in IL-10-transduced allograft.


CONCLUSIONS
Targeting on IL-10 is superior to CTLA4Ig or IDO for the treatment of chronic allograft deterioration.
Xu
Tao
T
Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.
Haering
Cristina
C
Lau
Chi-Keung
CK
Obed
Aiman
A
Ma
Jian
J
Doenecke
Axel
A
Scherer
Marcus N
MN
Schnitzbauer
Andreas A
AA
Fan
Sheung-Tat
ST
Schlitt
Hans J
HJ
Tsui
Tung-Yu
TY
D000069594:Abatacept; D000818:Animals; D002478:Cells, Cultured; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics* / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D019076:Transgenes; D014184:Transplantation, Homologous
D018796:Immunoconjugates; D016753:Interleukin-10; D000069594:Abatacept