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Abstract: Freund’s adjuvants are irreplaceable adjuvants for experimental work. Nevertheless, their mode of
components of induction protocols of many exper- action is still not completely understood. More so in the face of
imental animal models of autoimmune disease. enormous progress in the knowledge of the molecular and
Apart from the early studies done in the 1950s and cellular basis of the immune system, immunologists have con-
1960s, no further direct investigation on the mode tinued to use CFA without really caring about its mode of
of action of these adjuvants has been undertaken. action. Invariably, the use of CFA in experimental protocols is
It is generally assumed that incomplete (IFA) and hidden in the Materials and Methods sections of experimental
complete Freund’s adjuvant (CFA) act by prolong- studies without further consideration of the implications in the
ing the lifetime of injected autoantigen, by stimu- Discussion sections. The use of CFA is mandatory in the
lating its effective delivery to the immune system induction protocols of many experimental models of autoim-
and by providing a complex set of signals to the mune disease, such as experimental autoimmune encephalo-
innate compartment of the immune system, result- myelitis (EAE), neuritis (EAN), uveitis (EAU), thyroiditis
ing in altered leukocyte proliferation and differen- (EAT), and orchitis. Here, we review older and more recent
tiation. Here, we review evidence collected from studies pertaining to the molecular and cellular basis of the
various types of studies that provide more insight in mode of action of CFA in these models. Autoimmune diseases
the specific alterations of the immune response in animal models involve components of innate and acquired,
caused by IFA and CFA. Early events include rapid as well as cellular and humoral, immunity, and a central
uptake of adjuvant components by dendritic cells, question in considering the role of CFA is whether it merely
enhanced phagocytosis, secretion of cytokines by boosts the autoantigen-specific response or whether its effect as
mononuclear phagocytes, and transient activation a stimulant of innate immunity is in itself also important.
and proliferation of CD4ⴙ lymphocytes. The my-
cobacterial components within CFA signal T lym-
phocytes to assume a Th1 profile so that strong BRIEF HISTORY
delayed-type hypersensitivity against autoantigens
develops. In the absence of mycobacteria, T-lym-
IFA is essentially paraffin oil containing mannide mono-oleate
phocyte differentiation tends to assume a Th2 pro-
as a surfactant (for a detailed description, see ref. [1]). When
file with strong antibody production only. The myco-
mixed with aqueous solutions or suspensions of antigens, the
bacterial component also accounts for a morphologic
adjuvant forms a viscous water-in-oil emulsion, with the anti-
and functional remodeling of the haemopoietic system
gens in the water phase. In addition, CFA contains heat-killed
that develops over a period of several weeks and that
mycobacteria (Mycobacterium tuberculosis or other) and is more
is characterized by a drastic expansion of Mac-1ⴙ
potent and more adequate for certain purposes. Two lines of
immature myeloid cells. These cells have been
investigation are at the basis of the decades-long success of
found to be associated with enhanced disease in
CFA as an instrument in the hands of immunologists. Injec-
some models but with reduced disease in others.
tions of mycobacteria in a fatty excipient were first used by
Thus, in experimental autoimmune diseases, CFA-
Rabinovitch in Koch’s laboratory in an attempt to understand
mediated activation of the innate immune compart-
why pathogenic mycobacterium species did, and nonpatho-
ment is important not only by regulating the early
genic ones did not, induce formation of tubercle lesions. In a
induction phase but also by providing a surplus of
historical account of 1956 [1], Freund recounts Rabinovich’s
effector and regulator cells in the late phase.
finding: “. . . that Mycobacterium butyricum injected in exper-
J. Leukoc. Biol. 70: 849 – 860; 2001.
imental animals caused lesions at the sites of injection some-
what resembling tubercles, but when the bacteria were incor-
Key Words: Freund 䡠 adjuvant 䡠 dendritic cells