Long-term acceptance of rat cardiac allografts on the basis of adenovirus mediated CD40Ig plus CTLA4Ig gene therapies.
BACKGROUND
We have previously demonstrated that blockade of either CD80/86-CD28 or CD40-CD154 costimulatory pathways by using adenovirus vector coding CTLA4Ig (AdCTLA4Ig) or CD40Ig (AdCD40Ig) genes induced donor-specific tolerance in rat liver transplantation. In this study, we asked whether these gene-therapy-based costimulation blockade would induce tolerance in cardiac transplantation.


METHODS
Heterotopic heart transplantation was performed in a full major histocompatibility complex (MHC) barrier combination of ACI (RT1avl) to Lewis (LEW, RT1l) rats. Vector (1 x 10(9) plaque forming unit [PFU]), AdLacZ, AdCTLA4Ig, or AdCD40Ig, was administered intravenously to recipient animals immediately after grafting, and graft survival, serum CTLA4Ig/CD40Ig levels, and graft histology were assessed. Tolerance was determined by secondary skin-graft challenging.


RESULTS
Allografts of both untreated and AdLacZ controls were promptly rejected within 7 days, whereas a single treatment with AdCTLA4Ig or AdCD40Ig significantly prolonged median graft survival to 55.5 and 28.5 days, respectively. In contrast, the combined AdCTLA4Ig and AdCD40Ig gene therapy maintained high CTLA4Ig and CD40Ig levels through the posttransplant period and allowed long-term cardiac allograft survival for more than 270 days. However, both donor and third-party skin grafts were rejected in the animals who harbored cardiac grafts over 150 days. Also, typical features of chronic rejection were evident in the long-term surviving grafts.


CONCLUSIONS
Simultaneous blockade of CD28 and CD154 pathways by AdCTLA4Ig plus AdCD40Ig induces a strong immunosuppression that allows long-term acceptance of full MHC mismatched cardiac graft in rats. This strategy, however, was not enough to induce tolerance to skin grafts and to avoid chronic rejection, as shown in the liver-transplantation model.
Yamashita
Kenichiro
K
First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
Masunaga
Taro
T
Yanagida
Naoyuki
N
Takehara
Megumi
M
Hashimoto
Taku
T
Kobayashi
Tokushi
T
Echizenya
Hayato
H
Hua
Nan
N
Fujita
Miri
M
Murakami
Masaaki
M
Furukawa
Hiroyuki
H
Uede
Toshimistu
T
Todo
Satoru
S
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006085:Graft Survival; D016027:Heart Transplantation; D018796:Immunoconjugates / Q000097:blood / Q000235:genetics*; D008198:Lymph Nodes / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D011184:Postoperative Period; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016038:Skin Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology; D019076:Transgenes; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D018796:Immunoconjugates; D000069594:Abatacept