Effect of administration of CTLA4-Ig as protein or cDNA on corneal allograft survival.
OBJECTIVE
To examine the role of the CD28-CD80-CD86 pathway of T-lymphocyte costimulation in corneal allograft rejection and the effect of blockade of that pathway on graft survival.


METHODS
Kinetics of CD80 and CD86 expression in the cornea and draining lymph nodes were examined by RT-PCR and immunohistochemistry in untreated allograft recipients in a high-responder rat model. The effect of blockade of CD28-mediated costimulation was first examined by ex vivo incubation of excised Brown Norway rat donor cornea with the inhibitory protein CTLA4-Ig or an adenovirus vector (AdCTLA) expressing CTLA4-Ig, before grafting into Lewis rat recipients. A second group of graft recipients received systemic posttransplantation treatment with either CTLA4-Ig or AdCTLA.


RESULTS
Expression of CD80 mRNA was increased in both donor and recipient cornea 16 hours after transplantation, whereas CD86 was detected constitutively, with no significant early increase. Immunohistochemistry on day 5 after transplantation demonstrated major histocompatibility complex (MHC) class II expression, no CD80, and only a trace of CD86 in corneal allografts. In lymph nodes strong MHC class II, weak CD80, and moderate CD86 expression was noted. Both donor cornea and recipient treatment with CTLA4-Ig resulted in prolonged allograft survival. AdCTLA was found to induce sustained secretion of bioactive CTLA4-Ig from corneas infected ex vivo. Survival of corneal allografts incubated with AdCTLA was marginally prolonged, and systemic treatment with AdCTLA significantly prolonged survival.


CONCLUSIONS
Protein- or gene-based administration of CTLA4-Ig prolongs allograft survival by treatment of either the recipient or the donor tissue ex vivo before grafting.
Comer
Richard M
RM
Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom.
King
William J
WJ
Ardjomand
Navid
N
Theoharis
Stefanos
S
George
Andrew J T
AJ
Larkin
D Frank P
DF
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000943:Antigens, Differentiation / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D060908:CTLA-4 Antigen; D003315:Cornea / Q000378:metabolism*; D016039:Corneal Transplantation; D018076:DNA, Complementary / Q000008:administration & dosage*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006085:Graft Survival / Q000187:drug effects*; D018796:Immunoconjugates; D007124:Immunoenzyme Techniques; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008198:Lymph Nodes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497966:Cd86 protein, rat; C556708:Ctla4 protein, rat; D018076:DNA, Complementary; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D000069594:Abatacept