Influence of an Interferon Inducer on Bone Marrow Transplant Reconstitution in Irradiated, Leukemic Mice: Elevated Natural Killer Cell Numbers and Improved Life Span

Abstract

Interferon-γ and interferon inducers such as polyinosinic-polycytidylic acid (poly I:C) promote natural-killer (NK)-cell-mediated killing of a wide range of tumor cells both in vitro and in vivo. The aim of the present work was to administer poly I:C to irradiated, leukemic mice, both before and after syngeneic bone marrow transplant with the intent of boosting the host’s natural immunity in the critical peritransplant period. Briefly, DBA/2 mice were injected with Friend-virus-induced erythroleukemia cells. After 5 days of tumor growth, some mice received daily injections of poly I:C for the next 4 days while control, leukemic mice received the saline vehicle only. All mice were then irradiated (450 R × 2 at 4-hour intervals) and transplanted 1 day following irradiation with bone marrow from age- and sex-matched, normal DBA/2 donor mice. After transplant, daily injections of poly I:C (or vehicle) continued for 8 more days. On day 9 after transplant, treated and control mice were killed, and the total cellularity, total numbers of lymphoid cells, the total numbers of NK cells (identified by the presence of an immuno-labelled, specific cell surface marker) were obtained from both the spleen and the bone marrow. Other identically treated mice subjected, however, to several additional rounds of poly I:C treatment were sampled 3 and 6 months after irradiation and bone marrow transplant. The results indicated that (a) poly I:C administered in the peritransplant period (before and after transplant) significantly increases the absolute numbers of NK cells in both the bone marrow and spleen of the transplanted host at all time intervals studied, (b) no erythroleukemic tumor cells were found, even as late as 6 months after transplant in the poly-I:C-treated hosts in spite of the fact that poly I:C treatment in this group had been terminated more than 2 months prior to tissue sampling, and (c) survival was significantly improved by pre- and posttransplant treatment with poly I:C.

The Effect of Immunization with Killed Tumor Cells, with/Without Feeding ofEchinacea purpureain an Erythroleukemic Mouse Model

“…Finally, even though splenic erythroid cells in E. purpurea-fed, immunized mice were higher than those in mice not receiving E. purpurea by 3 months, all hemopoietic and immune cell lineages in both organs had returned, by 3 months after tumor onset, to within the normal ranges (absolute numbers) for adult male mice, as previously demonstrated by us (Christopher et al, 1991;Currier and Miller, 1998;Miller, 1992;Sun et al, 1999;Whyte and Miller, 1998). This was the case for immunized mice fed either untreated or E. purpurea-containing chow.…”

Type I interferon differential therapy for erythroleukemia: specificity of STAT activation

“…95 Mice with Friend virus-induced leukemia and treated with poly I:C, a strong inducer of type I IFNs, were shown to have higher numbers of NK cells, no evidence of erythroleukemic tumor cells, and prolonged survival. 96 Furthermore, athymic nude mice treated with neutralizing antibodies to IFN-␣/␤ have marked enhancement in growth of 6 different subcutaneous tumors. 13,97 In this study, J2E cell-induced erythroleukemia responded differentially to type I IFN gene therapy, with IFN-A6 and IFN-A9 most effective in prolonging animal survival (P Յ .1) despite similar low levels of all IFN DNA transgenes expressed in vivo (10-40 IU/mL).…”

Reversible Blockade of Thymic Output: An Inherent Part of TLR Ligand-Mediated Immune Response

“…This model was chosen to dissociate the impact of type I IFN production from known deleterious consequences of viral replication on the homeostasis of the immune system (28 -32). Our experimental protocol involved repeated daily injections of poly(I:C) over several days (33)(34)(35), since the impact of poly(I:C) impact is dependent on the dose and timing of its administration (36,37) and its short half-life in vivo (38). First, C57BL/6 mice were injected i.p.…”