Complement Activation, Immunogenicity, and Immune Suppression as Potential Side Eff ects of Liposomes - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 322

additional adjuvant), the “array theory” [91] provides a likely
explanation. Adapting this theory to the special case of immunogenic
non-vaccine liposomes, it can be proposed that because of their
similarity to viruses, liposomes may present their surface conjugates
or protruding repetitive surface elements to APC and other immune
cells (monocyte/macrophages, dendritic cells, B lypmphocytes and
mast cells) in the form of an array, which resembles the regular
and symmetric spatial arrangement of viral capsid glycolipids
and glycoproteins, for which the so-called “pattern recognition
receptors” (e.g., LPS and Toll-like receptors (TLRs) on the above cells
readily react, generating innate and subsequent specific immune
responses.
Originally TLRs recognize molecule arrays that are broadly
shared by pathogens (called pathogen-associated molecular
patterns, PAMPs, such as LPS, lipoproteins, lipopeptides, flagellin,
double-stranded RNA or the unmethylated CpG islands of bacterial
and viral DNA). However, “liposomal arrays” may also trigger
“danger” signaling by pattern recognition receptors on the above
immune cells despite the absence of PAMPs, which ultimately leads
to antibody production against the “pseudo-PAMPs” on liposomes
and their phospholipid support. The resultant immune response
may or may not diff er from a standard immune response to vaccines,
depending on the pathway of immune activation.
An example of non-standard, partial immunogenicity is the
so-called “ABC phenomenon”, i.e., accelerated blood clearance of
PEGylated liposomes, a phenomenon that has great clinical relevance.
As shown by Ishida and colleagues [49-55, 58, 59], repeated injection
of PEGylated liposomes in mice and rats causes rapid clearance of
liposomes from the bloodstream, due to the formation of anti-PEG
IgM in the spleen. Importantly, the phenomenon is absent with
PEGylated liposomes encapsulating doxorubicin, which is consistent
with the lack of ABC in cancer patients treated with Doxil. On the other
hand, free doxorubicin given in doses that correspond to the amount
given in Doxil, restores ABC. These data indicate that immune cells
responsible for the ABC phenomenon might be selectively aff ected
by doxorubicin encapsulated in PEGylated liposomes, as detailed in
the section on liposome-induced immune suppression below. Since
the ABC phenomenon was also observed in BALB/c nu/nu mice, but
not in BALB/c SCID mice, it was suggested that antibody production
represents a T cell-independent, B cell response, and that PEGylated