IL-2 gene and antisense TGF-beta1 strategies counteract HSV-2 transformed tumor progression.
The H238 tumor cells are Herpes simplex virus type 2-transformed BALB/c mouse fibroblasts that constitutively express transforming growth factor (TGF-beta1). TGF-beta can diminish immune capacity, whereas interleukin 2 (IL-2) is stimulatory to the immune system and can counteract the negative effects of TGF-beta1. The H238-BALB/c system provides a syngeneic model to evaluate new strategies with the potential to ameliorate tumor-induced immune depression. Plasmids expressing either antisense TGF-beta1 or murine Il-2 were constructed and stably transformed cells generated (masH238 and H238-IL2, respectively). In vitro measurements (ELISA and RT-PCR) demonstrated a >70% decrease in TGF-beta1 secretion by the masH238 tumor cells, and significant levels of IL-2 production by the H238-IL2 transfected cells when compared to wild type and control plasmid-transfected H238 cells. BALB/c mice injected subcutaneously with the masH238 cells developed significantly smaller tumors than the controls. Mice injected with H238-IL-2 cells developed tumors that failed to progress relative to control tumor growth. The differences in tumor growth in the mice were associated with enhanced immune reactivity and an increased response to T lymphocyte mitogens. Significant differences were also noted in lymphocyte populations and expression of CD25 and CD71 activation markers in the blood and spleens of mice receiving transfected tumor cells. Collectively, the data demonstrate that strategies employing antisense TGF-beta1 and IL-2 expression by transfected tumor cells can counteract the progression of a TGF-beta1-secreting tumor and enhance immune function involving modulation of T lymphocyte populations.
Kettering
James D
JD
Dept. of Biochemistry & Microbiology, Loma Linda University, Loma Linda, CA 92350, USA. jkettering@som.llu.edu
Mohamedali
Azim M
AM
Green
Lora M
LM
Gridley
Daila S
DS
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D018258:Herpesvirus 2, Human / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics*; D007700:Kinetics; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D020319:Oligodeoxyribonucleotides, Antisense; D016212:Transforming Growth Factor beta