Alterations in dendritic cell phenotype and function associated with immunoenhancing effects of a subcutaneously administered cyclophosphamide derivative.
A single systemic dose of cyclophosphamide (CY) has been shown to enhance cellular immunity in a variety of antigen models. The immunoenhancing effects of CY have been attributed to its ability to selectively abrogate suppressor cell function. Previous studies from our group have demonstrated that local administration of distinct cytostatic drugs at the sensitization site can induce a similar enhancement of delayed-type hypersensitivity as systemic CY, with the obvious advantage of avoiding systemic side-effects. In the present study we investigated the effects of local administration of an optimally immunopotentiating dose of the active CY-derivative Z 7557 and, in selected experiments, of etoposide (VP-16) and systemic CY on mononuclear cells in draining lymph nodes. Whereas CY caused a long-lasting and marked depletion of B-cell areas, locally administered Z 7557 and VP-16 relatively spared B cells and even induced an increase in B- and T-cell numbers in (keyhole limpet haemocyanin-) sensitized mice. At Day 4 the CD4/CD8 ratio was slightly reduced in drug-treated mice. Interestingly, drug treatment reduced the proportion of interdigitating cells staining with the monoclonal antibodies NLDC-145 and MIDC-8. Upon isolation, dendritic cells (DC) from sensitized, Z 7557-treated mice showed longer dendritic protrusions and an enhanced accessory cell function compared to DC from saline-treated controls. These findings suggest that immunoenhancing effects of cytostatic drugs may occur via an effect on DC.
Limpens
J
J
Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
Van Meijer
M
M
Van Santen
H M
HM
Germeraad
W T
WT
Hoeben-Schornagel
K
K
Breel
M
M
Scheper
R J
RJ
Kraal
G
G
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007279:Injections, Subcutaneous; D008198:Lymph Nodes / Q000187:drug effects* / Q000276:immunology; D016131:Lymphocyte Subsets / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
D000276:Adjuvants, Immunologic; C048341:mafosfamide; D003520:Cyclophosphamide