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Biomedical subjects

L Romani

Publications and source records attributed to L Romani.

At least 109 records · Page 6Linked to original sources
PubMed1988

Cell-mediated immunity to chemically xenogenized tumors. II. Evidence for accessory function and self-antigen presentation by a highly immunogenic tumor variant.

To determine whether antigen-presenting ability might be involved in the superior immunogenicity of chemically xenogenized tumors over that of parental cells, we tested a murine lymphoma line xenogenized by a triazene derivative for expression of Ia antigens, ability to present soluble antigen in vitro, and production of factor(s) active in a mouse thymocyte assay. Results showed that Ia antigens, absent on nonimmunogenic parental L5178Y cells, were expressed on a xenogenized, highly immunogenic tumor variant (clone D), as detected by immunofluorescence. While the ability of parental cells to stimulate lymphocyte proliferation in vitro was lost on removal of Ia+ cells from the responder population, considerable augmentation of reactivity was observed upon depletion of Ia+ cells from the population of splenocytes responding to the xenogenized cells. Under these conditions, stimulation was blocked by anti-Ia antibodies, or an anti-L3T4 reagent or antibodies to the novel antigenic determinants induced by xenogenization. In addition, no stimulating activity was observed following exposure of clone D cells to glutaraldehyde or lysosomotropic agents such as chloroquine and ammonia. When the ability of clone D cells to present ovalbumin in vitro was assayed, it was found that the xenogenized cells could present the soluble antigen to specifically primed lymphocytes. Moreover, clone D cells could substitute for splenic adherent cells in the proliferative reaction of splenocytes to concanavalin A. Finally, when the supernate from clone D-cell culture pulsed with phorbol myristic acetate was tested in a mouse thymocyte assay, considerable IL-1-like activity was disclosed.

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PubMed1988

Cell-mediated immunity to chemically xenogenized tumors--III. Generation of monoclonal antibodies interfering with reactivity to novel antigens.

To develop monoclonal antibodies (MAbs) recognizing drug-mediated tumor antigens on a chemically xenogenized murine lymphoma, hybridomas were constructed with splenocytes from histocompatible mice hyperimmunized with L5178Y cells antigenically altered by triazene treatment in vivo (clone D, derived from a polyclonal L5178Y/DTIC subline). Screening of supernatants with parental and xenogenized cells showed that nine MAbs displayed exclusive or preferential reactivity with clone D cells as detected by immunofluorescence, and failed, as a rule, to bind normal or unrelated malignant cells of the same or different haplotype. Moreover, no reactivity was displayed to the triazene-xenogenized variants of antigenically unrelated tumors. All nine MAbs, however, were capable of binding a panel of L5178Y/DTIC clones in addition to clone D. When the ability of these antibodies to interfere with the development of cell-mediated immunity to clone D cells in vitro was tested, it was found that the proliferative reaction and generation of cytolytic activity by syngeneic lymphocytes were inhibited by addition of several MAbs to the tumor--lymphocyte co-cultures.

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PubMed1988

Increase of natural killer activity of mouse lymphocytes following in vitro and in vivo treatment with lithium.

The in vivo and in vitro influence of lithium lactate on mouse natural killer activity was investigated. In vitro exposure of effector-target mixture to graded concentrations of lithium did not substantially modify the natural killer activity of mouse splenocytes, untreated or pretreated with cyclophosphamide. However in vitro treatment of effector splenocytes increased the frequency of NK-percursor cells. The in vivo treatment with lithium lactate greatly increased the natural killer activity in intact mice, whereas it did not improve this cytotoxic function in host immunodepressed by cyclophosphamide. These data suggest that lithium salts produce a modulation of natural killer activity of mouse spleen cells, probably through a mechanism involving the increase of the number of NK-precursors in hosts not subjected to cytotoxic chemotherapy.

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PubMed1987

Inhibition of murine lymphoma growth by adoptive transfer of lymphocytes sensitized to a xenogenized tumor variant.

Lymphocytes immune to a highly immunogenic ("xenogenized") variant of a murine lymphoma--which were shown to exert anti-xenogenized tumor activity in a previously described model of tumor immunotherapy--were tested in the present study for possible suppressive effects on the growth of an i.c. graft of the original lymphoma. Remarkable tumor-inhibitory effects followed the i.v. infusion of splenic lymphocytes sensitized or restimulated in vitro, or derived from animals immunized in vivo with the xenogenized tumor cells. The pattern of inhibition of the parental cells was apparently similar to that previously described for the xenogenized variant, but preliminary evidence suggests that the underlying mechanisms may be different.

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PubMed1987

DNA methylating activity in murine lymphoma cells xenogenized by triazene derivatives.

We investigated whether epigenetic rather than mutational events may be involved in the induction of novel immunogenicity ("xenogenization") in murine lymphoma treated with triazene derivatives. To this end, we assessed the DNA methylation pattern of tumor cells during the course of in vivo or in vitro xenogenization by 2 triazenes, and compared it with the changes induced by the DNA hypomethylating agent 5-azacytidine (5-aza). While all of the tested agents were able to increase tumor cell immunogenicity, their effects on DNA methylating activity were opposite. In particular, the novel immunogenicity conferred by 5-aza treatment correlated well with the extent of hypomethylation induced, whereas xenogenization by triazenes was accompanied by a limited increase in DNA methylating activity. Interestingly, the antimutagenic compound quinacrine, which is known to block the xenogenizing activity of triazenes, was incapable of hypermethylating effects, whereas the hypermethylating agent cytosine arabinoside (ara-C) was apparently unable to interfere with the induction of novel immunogenicity by triazenes.

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PubMed1987

Chemical xenogenization of experimental tumors.

Chemical xenogenization occurs when experimental tumors, treated in vivo or in vitro with selected chemicals, become immunogenic, i.e., able to induce a strong rejection response, immunological in nature, in the histocompatible hosts. Unlike modifications induced by haptens, changes in tumor cell immunogenicity associated with chemical xenogenization are heritable as a result of drug interference with the genetic code. Drugs endowed with potent mutagenic activity are known to be powerful xenogenizing agents, and their mechanism of action is traditionally regarded as involving changes in DNA nucleotide sequence. Triazene and nitrosoguanidine derivatives are among the best known examples of this type of compound, and a large body of information has been accumulated over the years regarding the immunogenic properties of the tumor variants obtained following treatment with those xenogenizing agents. The present paper reviews this information, and also discusses the therapeutic implications of xenogenization in experimental systems of tumor immunotherapy. Xenogenization of murine tumors has also been obtained by means of chemicals devoid of mutagenic activity but capable of affecting gene transcriptional activity. The characteristics of this 'new' type of xenogenization are also reviewed and compared to those of triazene xenogenization.

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PubMed1987

Immunopharmacological studies of PTT.119, a new synthetic bis-(2-chloroethyl)amino-L-phenylalanine derivative.

The new synthetic tripeptide p-F-Phe-m-bis-(2-chloro-ethyl)amino-Phe-Met-etoxy HCl, PTT.119, was studied for its effects on the host immune system. Doses of PTT.119 ranging from 3 to 18 mg/kg were administered i.p. to recipient mice which, at different times after drug treatment, were tested for allograft response, competence in producing lymphocytes active in lethal graft-versus-host disease, delayed-type hypersensitivity, mitogen responsiveness, humoral antibody production and natural resistance against microbial infections. At therapeutically active dosages, PTT.119 appeared to selectively inhibit functions mediated by B lymphocytes, leaving the majority of those involving T-cell subsets largely unaffected, even at the highest doses employed. Moreover, drug treatment had also a limited impact on the in vivo resistance of mice to microbial infection, which was only affected by a drug injection of 18 mg/kg, a dose well within the confidence limits of the mean lethal dose of the drug.

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PubMed1987

DNA methylating activity in murine lymphoma cells treated with xenogenizing chemicals.

We investigated whether epigenetic rather than mutational events might be involved in the induction of immunogenicity by the triazene derivative 1-(p-chlorophenyl)-3,3-dimethyltriazene (DM-Cl). To this purpose, we assessed the DNA methylation pattern of murine lymphoma cells xenogenized by DM-Cl and compared it with the changes induced by the DNA hypomethylating agent 5-azacytidine (5-Aza), which is also capable of affecting tumor cell immunogenicity. Both agents were found to increase the immunogenic potential of the treated tumor but according to different modalities. In particular, the novel immunogenicity conferred by 5-Aza treatment correlated well with the extent of hypomethylation induced, as opposed to what was observed for tumor xenogenization by DM-Cl.

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PubMed1987

Combined effects of immunity and antitumor drugs against cancer. I. In vivo studies with cis-diamminedichloroplatinum and cyclophosphamide in mouse models.

Cis-diamminedichloroplatinum (DDP) or cyclophosphamide (Cy) were given to mice bearing L1210 or LSTRA leukemia in H-2 compatible tumor-host combinations. Little anti-tumor activity was afforded by DDP against both leukemias inoculated in entirely histocompatible recipients. However, when the drug was given to mice incompatible for minor histocompatibility loci (MMHL) with the tumor, the efficacy of the treatment was markedly augmented and a substantial number of long-term survivors was found among BALB/c mice inoculated with L1210 cells. On the other hand, no difference in survival times was found between histocompatible or allogeneic mice inoculated with both leukemias, not subjected to chemotherapy. The LSTRA model was much less susceptible to this type of DDP-mediated antineoplastic immuno-chemotherapy synergism. Moreover no synergistic effects with allograft reaction were detected with Cy in both L1210 and LSTRA models, although Cy was markedly more active than DDP against leukemic cells in histocompatible recipients.

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PubMed1985

Humoral response against murine lymphoma cells xenogenized by drug treatment in vivo.

Treatment of murine lymphomas with triazene derivatives may lead to the appearance of novel drug-mediated tumor antigens, a phenomenon known as chemical xenogenization. Such antigens, which are capable of eliciting specific transplantation resistance in histocompatible mice, have been previously detected by in vivo and in vitro cell-mediated immune responses. In the present report we address the question of the humoral antibody response to a chemically xenogenized lymphoma. Histocompatible mice were given several injections of live cells of the xenogenized tumor. Ten days after each immunization, pooled sera from different animals were analyzed for Ab content by means of flow microfluorometry analysis and CEL-ISA assay. The results reveal that antibodies of both IgG and IgM classes capable of binding the xenogenized tumor can already be detected after one single sensitization. However, the Ab titer gradually increases through subsequent immunizations, reaching a peak level after 3-4 injections at a time when most of the humoral response is made up of antibodies of IgG class. The specificity of the anti-xenogenized tumor hyperimmune sera was subsequently investigated by its reaction with the parental, non-xenogenized line and with normal tissue cells of the same or allogeneic haplotypes. The data obtained point out that cross-reactivity with the parental line could be completely removed by absorption of the hyperimmune sera on parental cells, which removed most of the IgM antibodies. Moreover, the presence of an excess of anti-parental antibodies on the xenogenized tumor cells does not prevent the subsequent binding of the hyperimmune absorbed serum, thus indicating that the novel determinant(s) recognized on xenogenized cells are not spatially related to those shared with the original parental tumor. In addition, the hyperimmune absorbed serum does not cross-react with normal hemopoietic or lymphoid cells of the same (H-2d) or allogeneic H-2b and H-2k haplotypes. Furthermore, no alien histocompatibility antigens of H-2b or H-2k haplotypes could be detected on the xenogenized tumor cell surface. Taken together, these data provide evidence that chemical xenogenization of a murine lymphoma leads to the appearance of novel determinant(s) detectable by specific antibodies.

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PubMed1985

Adoptive immunotherapy of intracerebral murine lymphomas: role of different lymphoid populations.

In an attempt to elucidate the cellular mechanisms responsible for the therapeutic activity of systemic immunotherapy in an adoptive transfer system, lymphoma cells were implanted i.c. It was found that, upon peripheral injection of cytotoxic T-lymphocytes with specificity for the tumor, the cells reached and infiltrated the diseased brain but did not accumulate selectively in the malignant graft. In order to accomplish significant tumor inhibition, the infused lymphocytes, largely expressing the Lyt-1+2+ phenotype, apparently cooperated with radioresistant phagocytic cells present in histocompatible hosts and athymic mice.

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PubMed1985

Search for class II major histocompatibility complex molecular involvement in the response of Lyt-2+ cytotoxic T lymphocyte precursors to alloantigen.

A possible requirement for class II major histocompatibility complex (Ia) molecules in the initial activation of cytotoxic T lymphocyte precursors (CTLp) for allocytotoxic responses was investigated. To avoid possible interaction with other alloreactive cell types, a highly purified population of Lyt-2+ splenocytes was used as a source of CTLp. In the light of preliminary results indicating that Lyt-2+ CTLp, even in the presence of interleukin 2 (IL2), could best be triggered into mature CTL in vitro by cells known to be Ia+, we examined whether an interaction of CTLp with Ia antigens (either on syngeneic accessory cells or on allogeneic stimulators) played a role in the development of allocytotoxicity. Results from experiments done with C57BL/6 Lyt-2+ splenocytes co-cultured with P815 stimulator cells and IL 2 showed that the early activation of CTLp was independent of Ia+ syngeneic accessory cells: (a) flow microfluorometry analysis of the responder population at the beginning or after 1 or 3 days of co-culture did not reveal the presence of Ia+ cells; (b) procedures for removal of residual Ia+ cells or of dendritic cells from the responder population before co-culture did not affect the development of cytotoxicity; (c) co-culture with monoclonal antibodies against syngeneic Iab antigens did not inhibit the CTLp activation. By comparing an Ia+ P815 tumor line with its Ia- clone as allogeneic stimulator cells, it was found that the CTLp activation was also independent of Ia alloantigen on the stimulator cells. The response against both the Ia+ and the Ia- stimulator cell types was not inhibited by monoclonal anti-L3T4 present in the co-culture, indicating that these responses were not affected by residual L3T4 helper cells.

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PubMed1984

Immunogenic changes of murine lymphoma cells following in vitro treatment with aryl-triazene derivatives.

A series of dimethyl aryl-triazene derivatives and related monomethyl compounds were studied for their efficacy in mediating a strong increase in immunogenicity (i.e., chemical xenogenization, CX) of murine leukemic cells following in vitro treatment. It was found that all compounds under investigation were able to induce CX. The dimethyl derivatives were able to induce CX only after metabolic activation, whereas related monomethyl compounds were active per se. The antigenicity acquired by triazene-treated leukemic cells was very marked; intact hosts histocompatible with the parental line were able to reject up to 10(7) cells. Antigenic tumor cells retained their immunogenic properties even after a large number of transplant generations in the absence of the drug. This means that marked immunogenicity of triazene-treated cells is a stable and heritable characteristic.

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PubMed1984

Chemical xenogenization of murine lymphoma cells with triazene derivatives: immunotoxicological studies.

Equitoxic doses of 5-(3-3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) and aryl-triazene derivatives (compounds all capable of inducing a marked increase in murine tumor cell immunogenicity) were studied for their effects on the host immune system. At different times after drug exposure the animals were tested for allograft responses, competence in producing lymphocytes active in lethal graft-versus-host disease, delayed-type hypersensitivity, humoral antibody production, and mitogen responsiveness. While some of the aryl-triazenes tested (DM-COOK DM-NO2) showed a pattern of immunodepression similar to that of DTIC, others were less (MIC, MM-COOK, MM-Cl) or far less (DM-Cl, MM-NO2) active than DTIC in impairing host immunocompetence, although all retained or even augmented their ability to induce chemical xenogenization.

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PubMed1983

Antilymphoma graft responses in the mouse brain: a study of T-dependent functions.

The ability of mouse brain to provide T-dependent antilymphoma graft responses was studied in a model in which graded numbers of tumor cells were implanted intracerebrally into recipient hosts. By using survival criteria, it was possible to demonstrate the occurrence of both primary and secondary responses against tumor-associated histocompatibility antigens in allogeneic models as well as tumor-associated transplantation antigens in histocompatible recipients. The patterns of this intracerebral graft resistance did not differ significantly from those of peripheral T-dependent immune reactivity. The findings are discussed with regard to the concept of the brain as an immunologically privileged site.

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