Modes of action of Freund's adjuvants in experimental models of autoimmune diseases

Freund's adjuvants are irreplaceable components of induction protocols of many experimental animal models of autoimmune disease. Apart from the early studies done in the 1950s and 1960s, no further direct investigation on the mode of action of these adjuvants has been undertaken. It is generally assumed that incomplete (IFA) and complete Freund's adjuvant (CFA) act by prolonging the lifetime of injected autoantigen, by stimulating its effective delivery to the immune system and by providing a complex set of signals to the innate compartment of the immune system, resulting in altered leukocyte proliferation and differentiation. Here, we review evidence collected from various types of studies that provide more insight in the specific alterations of the immune response caused by IFA and CFA. Early events include rapid uptake of adjuvant components by dendritic cells, enhanced phagocytosis, secretion of cytokines by mononuclear phagocytes, and transient activation and proliferation of CD4+ lymphocytes. The mycobacterial components within CFA signal T lymphocytes to assume a Th1 profile so that strong delayed-type hypersensitivity against autoantigens develops. In the absence of mycobacteria, T-lymphocyte differentiation tends to assume a Th2 profile with strong antibody production only. The mycobacterial component also accounts for a morphologic and functional remodeling of the haemopoietic system that develops over a period of several weeks and that is characterized by a drastic expansion of Mac-1+ immature myeloid cells. These cells have been found to be associated with enhanced disease in some models but with reduced disease in others. Thus, in experimental autoimmune diseases, CFA-mediated activation of the innate immune compartment is important not only by regulating the early induction phase but also by providing a surplus of effector and regulator cells in the late phase.