Gene therapy in allergic encephalomyelitis using myelin basic protein-specific T cells engineered to express latent transforming growth factor-beta1.
A myelin basic protein (MBP)-specific BALB/c T helper 1 (Th1) clone was transduced with cDNA for murine latent transforming growth factor-beta1 (TGF-beta1) by coculture with fibroblasts producing a genetically engineered retrovirus. When SJL x BALB/c F1 mice, immunized 12-15 days earlier with proteolipid protein in complete Freund's adjuvant, were injected with 3 x 10(6) cells from MBP-activated untransduced cloned Th1 cells, the severity of experimental allergic encephalomyelitis (EAE) was slightly increased. In contrast, MBP-activated (but not resting) latent TGF-beta1-transduced T cells significantly delayed and ameliorated EAE development. This protective effect was negated by simultaneously injected anti-TGF-beta1. The transduced cells secreted 2-4 ng/ml of latent TGF-beta1 into their culture medium, whereas control cells secreted barely detectable amounts. mRNA profiles for tumor necrosis factor, lymphotoxin, and interferon-gamma were similar before and after transduction; interleukin-4 and -10 were absent. TGF-beta1-transduced and antigen-activated BALB/c Th1 clones, specific for hemocyanin or ovalbumin, did not ameliorate EAE. Spinal cords from mice, taken 12 days after receiving TGF-beta1-transduced, antigen-activated cells, contained detectable amounts of TGF-beta1 cDNA. We conclude that latent TGF-beta1-transduced, self-reactive T cell clones may be useful in the therapy of autoimmune diseases.
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
L Z
LZ
Chen
G M
GM
Hochwald
C
C
Huang
G
G
Dakin
H
H
Tao
C
C
Cheng
W J
WJ
Simmons
G
G
Dranoff
G J
GJ
Thorbecke
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000937:Antigen-Antibody Reactions; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology; D002999:Clone Cells; D003433:Crosses, Genetic; D017931:DNA Primers; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D004676:Myelin Basic Protein / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D004676:Myelin Basic Protein