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Gene Transfer of Noncleavable Cell Surface Mutants of Human CD154 Induces the Immune Response and Diminishes Systemic Inflammatory Reactions
- Source :
- Journal of Immunotherapy. 30:694-704
- Publication Year :
- 2007
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2007.
-
Abstract
- CD154 (CD40-ligand) is a critical transmembrane molecule with potent immune-stimulatory properties that is used in clinical applications of gene therapy for leukemia and lymphoma. However, CD154 is cleaved into a soluble form, and high levels of sCD154 contribute to systemic inflammatory and cardiovascular diseases, suggesting a deleterious side effect of CD154 gene therapy. In this study, we engineered noncleavable mutants of human CD154 with point mutations to develop a potentially less toxic molecule in vivo. In contrast to wild-type CD154 (CD154-WT) subsequently released as sCD154, both mutants CD154-M3 and CD154-M4 were resistant to cleavage in tumor cells. Also, CD40-expressing leukemia B cells transfected with CD154-M3 mutant were highly effective stimulators in a mixed lymphocyte-leukemia reaction, indicating that CD154-M3 mutant did not lose biologic activity. In mice transplanted with tumors expressing CD154-WT, we found increased plasma levels of human sCD154 followed by various systemic inflammatory reactions such as glomerulonephritis and an increased number of infiltrating mononuclear cells in the liver. However, CD154-M3 mutant did not induce any systemic inflammatory effects in vivo. As such, the noncleavable mutant of CD154 is fully capable of inducing the immune response with less toxic properties and is a useful tool for CD154 immune gene therapy.
- Subjects :
- Cancer Research
medicine.medical_treatment
Genetic enhancement
CD40 Ligand
Immunology
Mutant
Mice, Nude
chemical and pharmacologic phenomena
Inflammation
Transfection
Mice
Immune system
immune system diseases
parasitic diseases
medicine
Animals
Humans
Immunology and Allergy
CD154
Pharmacology
CD40
biology
hemic and immune systems
Genetic Therapy
Neoplasms, Experimental
Immunotherapy
Leukemia, Lymphocytic, Chronic, B-Cell
surgical procedures, operative
biology.protein
Cancer research
Mutant Proteins
Lymphocyte Culture Test, Mixed
medicine.symptom
Neoplasm Transplantation
Subjects
Details
- ISSN :
- 15249557
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Journal of Immunotherapy
- Accession number :
- edsair.doi.dedup.....486b47d0dd2097876d410d773bb373c7