Achievement of a synergistic adjuvant effect on arthritis induction by activation of innate immunity and forcing the immune response toward the Th1 phenotype

• Published in: Arthritis and rheumatism Vol. 50; no. 5; pp. 1665 - 1676
• Main Authors: Hanyecz, Anita, Berlo, Suzanne E., Szántó, Sándor, Broeren, Chris P. M., Mikecz, Katalin, Glant, Tibor T.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-05-2004; Wiley
• Subjects: Adjuvants, Immunologic - pharmacology; Adult; Animals; Arthritis, Experimental - chemically induced; Arthritis, Experimental - epidemiology; Arthritis, Experimental - immunology; Biological and medical sciences; Cartilage; Cattle; Disease Models, Animal; Diseases of the osteoarticular system; Drug Synergism; Female; Genetic Predisposition to Disease; Humans; Immunophenotyping; Incidence; Inflammatory joint diseases; Joints - pathology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, SCID; Quaternary Ammonium Compounds - pharmacology; Severity of Illness Index; Sheep; Species Specificity; Swine; Th1 Cells - immunology; Immunopathology; Immune response; Induction; Diseases of the osteoarticular system; Rheumatology; Th1 lymphocyte; Autoimmune disease; Inflammatory joint disease; Activation; Immunity; Synergism; Phenotype; T-Lymphocyte; Achievement
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.20180

Objective
To apply and analyze the mechanisms of action of dimethyldioctadecylammonium bromide (DDA), a powerful adjuvant that does not have the side effects of the conventionally used Freund's adjuvants, in proteoglycan‐induced arthritis (PGIA) and collagen‐induced arthritis (CIA).
Methods
PGIA and CIA were generated using standard immunization protocols with cartilage proteoglycan aggrecan (PG) or human type II collagen (CII) emulsified with Freund's complete adjuvant (CFA), and compared with PGIA and CIA generated using immunization protocols in which the same antigens were used in combination with the adjuvant DDA. Immune responses to immunizing and self PGs and CII, and the incidence, severity, and onset of arthritis were monitored throughout the experiments. In addition, a new, inexpensive, and powerful method of inducing arthritis using crude cartilage extracts is described.
Results
A significantly reduced onset period and a more severe arthritis were achieved in BALB/c mice immunized with cartilage PGs in DDA. PGs from bovine, ovine, and porcine cartilage, which otherwise have no effect or have only a subarthritogenic effect, and crude extracts of human osteoarthritic cartilage induced a 100% incidence with a very high arthritis score in BALB/c mice. The overall immune responses to either CII or PG were similar in antigen/CFA‐immunized and antigen/DDA‐immunized animals, but the Th1/Th2 balance shifted significantly toward a Th1 bias in DDA‐injected animals with either PGIA or CIA.
Conclusion
DDA, which was first used in autoimmune models, is a potent nonirritant adjuvant, which eliminates all undesired side effects of the Freund's adjuvants. DDA exerts a strong stimulatory effect via the activation of nonspecific (innate) immunity and forces the immune regulation toward Th1 dominance. These lines of evidence also suggest the possibility that seemingly innocuous compounds may exert an adjuvant effect in humans and may create the pathophysiologic basis of autoimmunity in susceptible individuals via the activation/stimulation of innate immunity.