Liposomal amphotericin B inhibits in vitro T-lymphocyte response to antigen

Abstract

The effects of free amphotericin B (as Fungizone) and amphotericin B (AMB) incorporated into liposomes on the proliferation of lymphocytes were determined. Freshly obtained guinea pig and rat antigen-specific lymphocytes were compared with rat T-lymphocyte cell lines cultured for a long period of time. Incorporation of AMB into multilayered vesicles significantly reduced its effect relative to that of Fungizone on cultured T-cell lines, as reported by others for mammalian cells. In contrast, the effects on freshly obtained antigen-specific lymphocytes were different. Fungizone inhibited proliferation of antigen-specific lymph node cells freshly obtained from immunized guinea pigs at fungicidal concentrations, and incorporation into multilayered lipid vesicles did not have much of a protective effect. Higher concentrations of Fungizone were required to inhibit proliferation of fresh rat lymph node cells, but incorporation into multilayered lipid vesicles still did not have much of a protective effect. Some T lymphocytes in the peripheral circulation of guinea pigs and in the lymph nodes of rats were more resistant to liposomal AMB than another more sensitive T-lymphocyte population was. Proliferation of lymphocytes in response to mitogens was inhibited less than that in response to specific antigen was. Thus, sensitivity to AMB depended on the species, the strength of the stimulus used to activate the lymphocytes, and on some other property of the lymphocytes, possibly their state of differentiation. Regardless of the reason for the difference in effects on freshly obtained lymph node lymphocytes and cultured line cells, the former may be more relevant to effects in vivo and should be considered in a complete evaluation of the in vivo toxicity of these forms of the drug. Incorporation into sonicated unilamellar vesicles had more of a protective effect, while equimolar drug-lipid complexes had even more of a protective effect. These forms of AMB might have less of an immunosuppressive potential than multilayered vesicles containing low amounts of AMB do.

Influence of Liposomal Amphotericin B on CD8 T-Cell Function

“…Amphotericin B is a polyene macrolide which binds to ergosterol and other sterol components of the fungal cell membrane (2). Apart from other detrimental effects which limit the maximum dosage applicable in humans to 1 mg/kg of body weight/day, amphotericin B inhibits cellular functions of the immune system, including mitogen and antigen-induced proliferation of T and B cells in vitro (1,7,10,13) as well as the cytolytic function of cytotoxic T cells (4). When higher dosages must be used the reduction of undesirable side effects is indispensable.…”

“…In spite of the alterations in the pharmakokinetic properties incorporation in liposomes has been shown to ameliorate most of the side effects of the substance so that higher dosages, usually 3 to 5 mg/kg/day may be used for the treatment of critically ill patients. Similar dosages of 1 mg/kg/day for liposomal amphotericin and standard amphotericin B may be used in special situations including prophylaxis (1,2,15).…”

Hemophagocytic Lymphohistiocytosis Associated with Visceral Leishmaniasis in Late Adulthood

“…On the other hand, amphotericin B may inhibit several cellular functions of the immune system, including macrophage function, cytokine expression, mitogen, and antigen-induced proliferation of T and B cells in vitro, as well as the cytolytic function of cytotoxic T cells. [11][12][13][14] Accordingly, it is reasonable to conceive that, in the present case, amphotericin may have exerted a dual effect on both HLH and leishmaniasis outcomes.…”

Difficulties in antifungal therapy with amphotericin B and the continuous search for new formulations: A literature review

“…In vitro studies showed that low levels of AmB increase the permeability of biological membranes while high levels cause cell lysis (Huang et al, 2002;Cybulska et al, 1984). Other authors have also shown the interaction between AmB and the membrane of polymorphonuclear leukocytes (Marzzullo et al, 1997;Boggs et al, 1991) and described the important modulatory effects, such as inhibition of chemotaxis and decreased the production of antibodies, of this drug on these cells (Lewis et al, 2005;Burgess et al, 2000). AmB presents low therapeutic index.…”