Feasibility of immunosuppression in composite tissue allografts by systemic administration of CTLA4Ig.
BACKGROUND
Although recent experimental studies have demonstrated CTLA4Ig to be a potent immunosuppressant in vascularized solid organ allografts, little attention has been given to the effect of this soluble recombinant fusion protein on immunosuppression in composite tissue allografts (CTAs). Using a rat hind limb allograft model, we examined the efficacy of CTLA4Ig against the allograft rejection of composite tissue.


METHODS
The hind limbs of ACI rats (RT1a) were heterotopically transplanted to Lewis rats (RT11). Controls received no immunotherapy. Experimental recipients were treated with a single i.p. injection of either human immunoglobulin (Ig)G (0.5 mg/body) or CTLA4Ig (0.5 mg/body) according to different time schedules. Graft survival time and histopathological changes for each experimental group were evaluated and statistically compared.


RESULTS
Graft survival times were prolonged significantly in rats treated with CTLA4Ig on day 1 and day 2 after transplantation, compared with survival times of controls. In particular, the most significant prolongation was found in rats treated on day 2. At 7 days after transplantation, moderate-to-severe histological rejection occurred in all tissues in control rats. On the other hand, in rats treated with CTLA4Ig, all tissues showed significantly better preservation. Among these treated rats, the rats treated on day 2 showed excellent histopathological conditions in each tissue.


CONCLUSIONS
This study supports the feasibility of using CTLA4Ig for preventing acute rejection in CTA. On the basis of the current results, the administration of CTLA4Ig for CTA is more effective at 24-48 hr after transplantation, after the initial immune response has been allowed to begin.
Iwasaki
Norimasa
N
Department of Orthopaedic Surgery, Hokkaido University School of Medicine, Hokkaido University, Sapporo 060-8638, Japan. niwasaki@med.hokudai.ac.jp.
Gohda
Taketoshi
T
Yoshioka
Chika
C
Murakami
Masaaki
M
Inobe
Manabu
M
Minami
Akio
A
Uede
Toshimitsu
T
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D060908:CTLA-4 Antigen; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology; D006614:Hindlimb / Q000637:transplantation; D007108:Immune Tolerance; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept