Abstract: Lymphocytes are central to the progression of autoimmune disease, transplant
rejection, leukemia, lymphoma and lymphocyte-resident viral diseases such as HIV/AIDs.
Strategies to target drug treatments to lymphocytes, therefore, represent an opportunity to
enhance therapeutic outcomes in disease states where many current treatment regimes are
incompletely effective and promote significant toxicities. Here we demonstrate that highly lipophilic
drug candidates that preferentially access the intestinal lymphatics after oral administration show
significantly enhanced access to lymphocytes leading to improved immunomodulatory activity.
When coadministered with such drugs, lipids enhance lymphocyte targeting via a three tiered
action: promotion of drug absorption from the gastrointestinal tract, enhancement of lymphatic
drug transport and stimulation of lymphocyte recruitment into the lymphatics. This strategy has
been exemplified using a highly lipophilic immunosuppressant (JWH015) where coadministration
with selected lipids led to significant increases in lymphatic transport, lymphocyte targeting and
IL-4 and IL-10 expression in CD4+ and CD8+ lymphocytes after ex vivo mitogen stimulation.
In contrast, administration of a 2.5-fold higher dose of JWH015 in a formulation that did not
stimulate lymph transport had no effect on antiinflammatory cytokine levels, in spite of equivalent
drug exposure in the blood. The current data suggest that complementary drug design and
delivery strategies that combine highly lipophilic, lymphotropic drug candidates with lymphdirecting
formulations provide enhanced selectivity, potency and therapeutic potential for drug
candidates with lymphocyte associated targets.