Complement Activation, Immunogenicity, and Immune Suppression as Potential Side Eff ects of Liposomes - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 320

of H1 receptors leads to vasoconstriction and vascular leakage and
is responsible for the cardiovascular and cutaneous symptoms of
anaphylaxis. H2 receptors, in turn, increase cellular cAMP levels and
cause vasodilation, increased heart rate and pulse pressure. Another
potentially important factor in individual variation of HSR symptoms
is the relative abundance of reactive cells in diff erent organs of
response, i.e., in the skin, lung, heart, bowel, etc. [57, 60, 61, 84].
Table 11.5 Observations on C activation-related pseudoallergy caused by
liposomes
• All types of liposomes can cause CARPA in animals and man, with neutral
SUV being the least reactogenic (see Table 11.4).
• The sensitivity of diff erent animals to diff erent liposomes shows
substantial variation.
• The sensitivity of diff erent species to liposomal CARPA decreases
roughly in the following order: pig> dog> human (hypersensitive) >
rabbit> sheep > rat> mouse.
• The minimum eff ective reactogenic dose of liposomes in rats is 10-100
times higher than that in pigs or dogs.
• The individual variation of the cardiopulmonary changes associated
with porcine liposome-induced CARPA is lower than that of dogs.
• In pigs, pulmonary hypertension, while in dogs, systemic hypotension
are the dominant cardiopulmonary symptoms of CARPA.
• Both in pigs and dogs, the cardiopulmonary changes can decrease
or entirely disappear after the second or third dosing, a reflection of
tachyphylaxis (tolerance induction, unpublished observations).
• The latter phenomenon allows the development of desensitization
protocols using empty (placebo) liposomes (unpublished observations).
• Both in pigs and dogs, leukopenia followed by leukocytosis and
thrombocytopenia are varying hematological abnormalities associated
with CARPA.
• The rise of plasma thromboxane A2 (measured as TXB2) closely parallels
the hemodynamic changes in pigs, indicating that TXA2 is a rate limiting
mediator. TXB2 also rises in other species during CARPA.
• CARPA can be inhibited in pigs with C inhibitors (e.g., sCR1, anti-porcine
C5 antibody and indomethacin).
• Based on the minimal eff ective reactogenic dose, porcine and canine
CARPA may represent a model of human CARPA in hypersensitive
individuals