Favorable effect of cotransfection with TGF-beta and CTLA4Ig of the donor kidney on allograft survival.
OBJECTIVE
Gene transfer of viral interleukin 10 (vIL-10) or transforming growth factor beta (TGF-beta) successfully prolonged liver and heart graft survival. Here we assessed whether injection of adenovirus (Ad) coding vIL-10 (AdvIL-10) or TGF-beta3 (AdTGF-beta3) prolonged kidney allograft survival. Since we previously demonstrated that transfection of the donor kidney with CTLA4Ig significantly prolonged allograft survival, we also evaluated the effect of a combined injection of AdvIL-10 or AdTGF-beta3 with the AdCTLA4Ig.


METHODS
Adenoviral vectors or saline were ex vivo injected into the renal artery of Brown Norway (RT.1n) donor kidneys subsequently grafted into Lewis (RT.1(l)) rats. Graft survival, transgene expression, graft cell infiltration, and histological changes were assessed.


RESULTS
Allografts of saline or Ad-beta-galactosidase controls were promptly rejected (mean survival time +/- SE 7.6 +/- 0.2 and 7.8 +/- 0.3 days, respectively). AdvIL-10 significantly prolonged survival only in 2 out of 9 animals (23.2 +/- 9.9 days), with vIL-10 expression detected on day 4. Survival was prolonged in 1 out of 5 animals by AdTGF-beta3 (14.4 +/- 5.3 days) despite the fact that the transgene was still observed after 14 days. While the combined injection of AdvIL-10 with AdCTLA4Ig did not protect the kidney from rejection (17.4 +/- 4.6 days), AdTGF-beta3 added to AdCTLA4Ig consistently prolonged the allograft lifespan in all animals (70.6 +/- 39.6 days), inducing indefinite survival in 1 animal which showed long-term gene expression and T cells hyporesponsive to alloantigens.


CONCLUSIONS
Overexpression of AdTGF-beta3 concomitant with the blockade of the CD28/B7 pathway by AdCTLA4Ig induces strong immunosuppression that occasionally allows the acceptance of a fully major histocompatibility complex mismatched renal graft.
Tomasoni
Susanna
S
Mario Negri Institute for Pharmacological Research, Institute for Pharmacological Research, Bergamo, Italy.
Longaretti
Lorena
L
Azzollini
Nadia
N
Gagliardini
Elena
E
Mister
Marilena
M
Buehler
Thomas
T
Remuzzi
Giuseppe
G
Benigni
Ariela
A
D000069594:Abatacept; D000256:Adenoviridae; D000818:Animals; D015870:Gene Expression; D006085:Graft Survival; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics*; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics*
D018796:Immunoconjugates; D016212:Transforming Growth Factor beta; D000069594:Abatacept