asialo-gm1-ganglioside and Leukemia--Erythroblastic--Acute

We have previously shown that an intact immune system was essential to the increase in survival time of IFN-alpha/beta-treated mice injected i.v. with an IFN-alpha/beta-resistant line of Friend erythroleukemia cells (FLC) highly metastatic to the liver and spleen. Here, we have investigated the early interactions of IFN alpha/beta with host cells prior to the development of the immune response. IFN alpha/beta treatment resulted in 50- to 100-fold inhibition of FLC multiplication in the liver and spleen of normal DBA/2 mice shortly after tumor inoculation, as evaluated by colony formation in agarose. IFN treatment was far less effective in inhibiting the multiplication of FLC in the livers of NK-cell-deficient DBA/2 beige mice, or in immunocompetent DBA/2 mice treated with antibody to asialo GMI, or silica, or in mice subjected to sub-lethal irradiation. Injection of antibody to CD4 or CD8 did not affect the early inhibitory action of IFN alpha/beta on FLC multiplication but did decrease survival time. Light- and electron-microscope examination of the livers of IFN-treated, FLC-injected mice confirmed the early inhibition of FLC multiplication in the liver and spleen. Our results indicate that IFN alpha/beta inhibits the development of FLC visceral metastases by acting first on host cells, such as NK cells and macrophages, and then continues to act in consort with the developing immune response.

Topics: Animals; Antibodies; Antineoplastic Combined Chemotherapy Protocols; Arginine; CD4 Antigens; CD8 Antigens; Cell Division; Friend murine leukemia virus; G(M1) Ganglioside; Interferon Type I; Leukemia, Erythroblastic, Acute; Liver Neoplasms, Experimental; Mice; Mice, Inbred DBA; Neoplasm Transplantation; Nitroarginine; Silicon Dioxide; Splenic Neoplasms

We investigated the effects of the systemic administration of thymosin alpha 1 plus relatively low doses of human recombinant interleukin-2 or very low doses of interferon alpha,beta in untreated and cyclophosphamide (CY)-treated DBA/2 mice challenged either subcutaneously or intravenously (i.v.) with Friend erythroleukemia cells (FLC). Both treatments resulted in the complete regression of subcutaneous tumor and cured a significative percentage of mice. They also increased the survival time of mice i.v. injected with large numbers of FLC. Neither immunotherapy alone nor CY, alone or in combination with single cytokines, produced similar effects. The antitumor action of these combined chemoimmunotherapy protocols seems to involve activation of the immune response since (a) a synergistic increase of the cytotoxicity of spleen cells was demonstrated in treated mice; (b) selective in vivo depletion of asialo-GM1, CD4, or CD8-positive cells abrogated this antitumor activity; and (c) a high lymphoid cell infiltration was found at the tumor site and in the livers of treated mice.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; CD4 Antigens; CD8 Antigens; Cyclophosphamide; Cytotoxicity, Immunologic; Disease Models, Animal; Friend murine leukemia virus; G(M1) Ganglioside; Interferon-alpha; Interferon-beta; Interleukin-2; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Male; Mice; Mice, Inbred DBA; Thymalfasin; Thymosin; Tumor Virus Infections

Mice were irradiated and infused with BALB/c Friend virus-induced FLD-3 erythroleukemia cells. Growth of the cells was estimated by measuring splenic incorporation of 5-iodo-2'-deoxyuridine-125I 5 days after cell transfer. BALB/cJ and C3H mice were 'poor responders' in that FLD-3 cells grew well in their spleens, while mice of other strains were 'good responders', resisting the growth of FLD-3 cells. No H-2 or Fv genetic locus was associated with resistance. Athymic nude mice and mice depleted of marrow tissue by 89Sr or estradiol resisted FLD-3 cells, indicating that the effectors were thymus- and marrow-independent. Silica, carrageenan and Propionibacterium acnes organisms all altered resistance, suggesting a function of macrophages. Neither interferon nor anti-interferon serum treatment altered resistance. Anti-asialo GM1 serum inhibited resistance to FLD-3 cells in vivo and inhibited natural cytotoxic (NC) activity against FLD-3 cells in vitro. NC (FLD-3) activity was greatly decreased in spleens 3 days after irradiation, in contrast with NK (YAC-1) and NC(WEHI-164.1) activities. Moreover, a 3-day delay in infusion of FLD-3 cells 'synergized' with silica in weakening genetic resistance in vivo. Thus, natural immunity to FLD-3 cells in vivo differs from that of genetic resistance to normal bone marrow cell allografts, and the lysis of FLD-3 cells in vitro seems to be mediated by cells which do not easily fit into the definition of natural killer (NK) or natural cytotoxic (NC) cells.

Topics: Animals; Antibodies; Asialoglycoproteins; Bone Marrow; Bone Marrow Cells; Carrageenan; Cell Line; Cytotoxicity, Immunologic; Friend murine leukemia virus; G(M1) Ganglioside; Glycosphingolipids; Immunity, Innate; Immunization, Passive; Interferons; Killer Cells, Natural; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Lung; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Silicon Dioxide; Spleen; T-Lymphocytes, Cytotoxic; Thymus Gland