Selective Depletion of Liver and Splenic Macrophages Using Liposomes Encapsulating the Drug Dichloromethylene Diphosphonate: Effects on Antimicrobial Resistance

Abstract

The current results provide direct evidence for a role of tissue macrophages (M phi) in natural immunity and support the use of immunomodulators to enhance antiviral resistance in immunocompromised individuals. In this study, macrophages (M phi) in the spleen and liver were eliminated by intravenous (i.v.) injection of the drug dichloromethylene diphosphonate (DMDP) encapsulated in liposomes. The effect of this depletion system on peritoneal M phi, peripheral blood leukocytes, splenic natural killer (NK) activity, and natural and immunomodulator-induced host resistance was then assessed. Barrier-maintained CD-1 female mice were inoculated i.v. either with DMDP liposomes, free liposomes (containing no DMDP), or saline on day -2 or on days -3 and -1 before cell population analysis or infection. Single or double treatment with DMDP liposomes had no effect on peritoneal M phi as indicated by no changes in total number, differential counts, or ectoenzyme patterns. Double treatment with DMDP liposomes caused a marked leukocytosis in blood, primarily of lymphocytes and polymorphonuclear leukocytes (PMN), and a transient depression of spontaneous and interferon-inducible splenic NK activity. The effects on host resistance to i.v. infection with Listeria monocytogenes or herpes simplex virus type 2 (HSV-2) indicated that i.v. treatment with DMDP liposomes significantly reduced natural resistance to these microorganisms as evidenced by increased mortality and decreased median survival time. When DMDP liposomes-treated mice were given the immunomodulator maleic anhydride divinyl ether copolymer (MVE-2) intraperitoneally the day before infection with HSV-2, the immunosuppressive effect of DMDP liposomes treatment was significantly reversed.

Oncolytic viral therapies

“…Some measures suggest activity, including those that modulate neutralizing antibodies such as plasma apheresis, B-cell function inhibitors, immune suppressive therapy, and/or desensitization. [118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134] Combination therapy with other anticancer agents that may also affect the activity of conditional replicating adenoviruses is also being explored. For instance, it has been demonstrated that adenoviral binding is optimal during the M phase of the cell cycle.…”

Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity

“…27 Thus, the delivery of adenovirus to metastatic tumor deposits, and the resulting antitumoral activity, should be improved if hepatic uptake is inhibited. [28][29][30] Furthermore, approaches which decrease hepatocyte and Kupffer cell uptake such as infusion of silica and/or multi-lamellar lyposomes (Cl 2 MBP lyposomes), [31][32][33][34][35][36][37][38][39][40][41][42][43][44] have been shown to delay elimination of adenoviral vectors significantly. A second important factor influencing internalization of adenovirus and induction of actin cytoskeleton reorganization for endocytosis of the viral particle to take place is the expression of coxsackie-adenovirus receptor (CAR) on target cells which serves as a primary receptor for adenovirus.…”

Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients

“…13 One method of inhibition of normal cell uptake, particularly hepatic uptake, includes agents that disrupt macrophage function. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Infusion of silica and/or multilaminar liposomes delays elimination of adenoviral particles following infection in animal models. 14-28 A second factor influencing adenovirus uptake is the expression of coxsackie adenovirus receptor (CAR) on tumor cells.…”