The effects of CTLA-4Ig on acute lung allograft rejection: a comparison of intrabronchial gene therapy with systemic administration of protein.
BACKGROUND
Blockade of T-cell costimulation by local delivery of an adenoviral vector encoding for CTLA-4Ig and systemic administration of the protein are compared in a rat lung allograft model.


METHODS
Left lungs of Brown Norway rats (RT1n) were transplanted into Lewis (RT11) recipients in four groups of six animals each: 1) no treatment; 2) intrabronchial transduction of donor lung with adenovirus encoding mCTLA-4Ig (adeno-mCTLA-4Ig); 3) intrabronchial transduction with empty adenovirus; and 4) intraperitoneal injection of mCTLA-4Ig. Grading of rejection, mCTLA-4Ig measurement in serum and bronchial washings, RT-PCR for virally encoded transcripts, and immunohistochemistry for mCTLA-4Ig were carried out 4 days later.


RESULTS
Intrabronchial transduction with adeno-mCTLA-4Ig resulted in detectable transgene expression in graft tissue and bronchial fluid but not in serum. Significant reduction in rejection grade (from grade 3 to 2) occurred after systemic mCTLA-4Ig but not adeno-mCTLA-4Ig transduction.


CONCLUSIONS
Local expression of immunomodulatory proteins can be achieved within lung allografts by intrabronchial delivery of adenoviral vector but may not significantly modify acute rejection.
Ugurlu
M M
MM
Department of Surgery, Mayo Transplant Center, Mayo Clinic, Rochester, MN 55905.
Griffin
M D
MD
O'Brien
T
T
Tazelaar
H D
HD
Miller
V M
VM
McGregor
C G
CG
D000069594:Abatacept; D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D060908:CTLA-4 Antigen; D015316:Genetic Therapy; D006084:Graft Rejection / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D018796:Immunoconjugates; D007274:Injections, Intraperitoneal; D008168:Lung / Q000473:pathology; D016040:Lung Transplantation; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D000069594:Abatacept