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Biomedical subjects

M Giovarelli

Publications and source records attributed to M Giovarelli.

At least 73 records · Page 4Linked to original sources
PubMed1987

In vitro and in vivo immunomodulatory activity of an N-9 arginyl hypoxanthine derivative (PCF-39).

A new synthetic derivative, N-alpha-5 (1,6-dihydro-6-oxo-9-purinyl) pentyloxy-carbonyl-L-arginine (PCF-39) has been evaluated in vitro and in vivo in order to clarify its immunopharmacologic profile. In vitro, PCF-39 did not modify spleen cell functions, whereas parenteral administration in mice of 2.5 and 25 mg/kg (50 and 500 micrograms/mouse) induced an increase in spleen and lymph node cellularity that resulted in a significant resistance to the growth of two distinct syngeneic transplanted tumors. These in vivo findings show that PCF-39 is a potent immunotherapeutic agent with an antitumor effect.

Adenocarcinoma↗
PubMed1987

Immunoregulatory T-cell defects in B-cell chronic lymphocytic leukemia: cause or consequence of the disease? The contributory role of decreased availability of interleukin 2 (IL-2).

Several phenotypic and functional defects have been described within the residual T-lymphocyte population of patients with B-cell chronic lymphocytic leukemia (B-CLL), particularly in those in the more advanced stages of the disease. In this study, we review these abnormalities and discuss their possible effects on the course of the illness. Particular emphasis is devoted to the role of interleukin 2 (IL-2) in B-CLL. Evidence is provided that the IL-2 released by B-CLL T-lymphocytes may be utilized by the neoplastic B-cell clone that expresses the IL-2 receptor and that decreased availability of IL-2 may play a contributory role in some of the T-cell defects encountered in B-CLL.

B-Lymphocytes↗
PubMed1986

Tumour inhibition by interleukin-2 at the tumour/host interface.

Until recently, lymphokines were regarded suspiciously as 'ill-defined factors'. Today, however, some of them have been clearly defined in both structural and functional terms. The interleukin-2 (IL-2) molecule and its specific membrane receptors have been the subject of particular attention. Endogenous IL-2 has proved to be an important signal for the activation and expansion of various cell-mediated immunity functions, while exogenous IL-2 has been used to activate numerous cell functions, both in vitro and in vivo, as well as in tumour immunotherapy, both alone or combined with lymphocytes previously activated in vitro (lymphokine-activated killer cells). Adoptive transfer of these cells together with high doses of IL-2 is particularly promising from the clinical standpoint, though by no means free from problems. IL-2 can also be employed in small doses locally in the presence of non-activated lymphocytes from tumour bearing mice to induce a local reaction that subsequently becomes systemic and can lead to the rejection of incipient tumours. Various host immune cells, primarily eosinophils and lymphocytes are involved in this reaction, which can also give rise to tumour-specific immune memory. In this way, the host immune system, despite its inevitable defeat in the first battle against a tumour, may acquire an important role in the long war that lies ahead.

Animals↗
PubMed1986

Interferon-activated tumor inhibition in vivo. Small amounts of interferon-gamma inhibit tumor growth by eliciting host systemic immunoreactivity.

Ten international units (IU) of recombinant (r) or natural (n) murine interferon (MuIFN)-gamma were used for the in vivo immunotherapy of a chemically induced fibrosarcoma (CE-2) of BALB/c mice. In vitro, doses of r-IFN-gamma below 100 units have a marginal antiproliferative effect on CE-2 cells and do not induce expression of H-2d class-II antigens, whereas they do increase that of class-I antigens. In vivo, 10 daily injections of 10 IU of r- or n-MuIFN-gamma at the challenge site provide significant protection against increasing doses of CE-2 tumor cells. This protection was enhanced when non-reactive T-lymphocytes from CE-2 tumor-bearing mice were admixed at a 10:1 ratio with the CE-2 tumor cells. Combined lymphocyte and r-MuIFN-gamma treatment also inhibited the growth of already established tumors when it was started before these reached a mean diameter of 5 mm. Tumor inhibition depends upon activation of the host immune system. The antitumor activity of r-MuIFN-gamma and T-lymphocytes was null when mice were first irradiated with 450 rads. Moreover, host leukocytes massively infiltrated the area of tumor growth and the small r-MuIFN-gamma doses injected daily activated various host immunoreactivity mechanisms.

Animals↗
PubMed1986

Effect of prolonged administration of low doses of dietary retinoids on cell-mediated immunity and the growth of transplantable tumors in mice.

A study was conducted on the activity exerted by prolonged dietary supplementation with progressive amounts of retinoids on cell-mediated immune responses and the growth of transplantable tumors in mice. A few groups of BALB/c mice received 0 (group C), 50 (group A 50), 200 (group A 200), 500 (group A 500), and 1,000 (group A 1000) IU retinol palmitate/mouse/day in drinking water for 150 days. At progressive intervals mice from each group were tested for proliferative responses to concanavalin A (Con A), Escherichia coli lipopolysaccharide, interleukin-2, and interferon-gamma release to Con A. Ten mice from each group were also challenged with the 90-100% tumor-inducing dose of 3 distinct transplantable tumors. At the end of the experiment the principal organs were histologically examined, and the accumulation of vitamin A was evaluated. In groups A 200, A 500, and A 1000, an increase in the proliferative responses and production of lymphokines as compared to those in group C occurred after 60-90 days, but vanished after 150 days. The takes of the 3 tumors were impaired when the challenges were performed on days 75 and 150. This enhancement of distinct functions of cellular reactivity and resistance to transplantable tumors showed a linear relationship with the amount of supplemental retinol palmitate for the first 60-90 days. After 150 days, however, these enhancement effects vanished or tended to decrease.

Animals↗
PubMed1986

Modulation of natural killer activity in mice by prolonged administration of various doses of dietary retinoids.

Groups of BALB/C mice received a diet supplement of 0 (group C), 200 (group A 200), 500 (group A 500), and 1,000 (group A 1,000) IU retinol palmitate (RP)/mouse/day in drinking water for 450 days. At progressive time intervals, mice from each group were tested for natural killer (NK) activity and for the percentage of large granular lymphocytes (LGL) in the spleen. In groups A 200, A 500 and A 1,000, a dose-dependent increase in NK activity was evident 50 days after the beginning of RP supplementation and was accompanied by a parallel increase of LGL number in the spleen. In group A 1,000, the increase of spontaneous or Poly I:C-induced cytotoxicity persisted until day 160. By contrast, inhibition of Poly I:C-induced NK cytotoxicity was found in this group at day 450.

Age Factors↗
PubMed1985

Inhibition of interferon-gamma may suppress allograft reactivity by T lymphocytes in vitro and in vivo.

The addition to mixed-leukocyte reactions of monoclonal antibodies to interferon-gamma abrogated alloantigen recognition and induction of cytotoxic T lymphocytes by inducing early and highly effective suppressor T lymphocytes. This inhibitory activity was not confined to in vitro models, since daily injection of the antibodies into CBA/J mice blocked the usual rejection of allogenic tumor cells.

Animals↗
PubMed1985

A novel leukemia T-cell line (PF-382) with phenotypic and functional features of suppressor lymphocytes.

A human leukemia T-cell line (PF-382) spontaneously derived from the pleural effusion of a child with T-cell acute lymphoblastic leukemia is described. The cell line, which has been maintained in culture for over 10 months, has a modal number of 46 chromosomes and is characterized by a chromosomal abnormality, present in most of the cells, consisting of a translocation between chromosome X and chromosome 15 (46X,Xq-,15p+). The cells are not recognized by the OKT3 and OKT11 monoclonal antibodies (MoAb), nor do they form rosettes with sheep erythrocytes. By contrast, they react with the OKT6, Leu-1, and Leu-9 MoAb, which detect early T-lymphocytes, and express the more mature OKT8 antigen. The presence of the OKT8 marker is associated with suppressor activity on the pokeweed mitogen-induced proliferation and differentiation of normal B-cells, both by the PF-382 cells and by their supernatant. However, no cytotoxic activity against natural killer (NK)-sensitive target cells (K562) was found, indicating that the proliferating cells do not correspond to the subset of NK cells expressing the OKT8 antigen. Furthermore, the cells are incapable of both spontaneous and mitogen-induced interleukin-2 and interferon production. The ability of the PF-382 cell line to release a soluble factor(s) capable of modulating the differentiation of the B-cell compartment suggests that this new cell line represents a valuable model for the investigation of the interrelationships between T-cell subsets and other hematopoietic cell lineages.

Antigens, Viral↗
PubMed1985

Interleukin 2 (IL 2) and interferon-gamma production by T lymphocytes from patients with B-chronic lymphocytic leukemia: evidence that normally released IL 2 is absorbed by the neoplastic B cell population.

The capacity of T lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) to release interleukin 2 (IL 2) and interferon (IFN)-gamma was assessed following various stimuli. The spontaneous release of IL 2 and IFN-gamma was practically absent both with B-CLL and normal T lymphocytes. By contrast, after stimulation with phytohemagglutinin (PHA) or with PHA plus 12-O-tetradecanoylphorbol-13-acetate, the production of IL 2 and IFN-gamma by B-CLL T lymphocytes was similar to that of normal T lymphocytes, irrespective of the reversed T lymphocyte subset distribution (OKT4/OKT8 ratio) observed in B-CLL. However, the titer of IL 2 was greatly reduced when autologous leukemic B cells were added to the culture system. Unlike IL 2, the presence of leukemic B cells did not affect the titer of IFN-gamma in the culture supernatants. The indication that IL 2 may be adsorbed in vivo by the neoplastic B cells was further confirmed by the demonstration of the IL 2 receptor (revealed by anti-Tac monoclonal antibody) on the leukemic B cells, particularly following mitogenic stimulation, and by the evidence that exogenous IL 2 can be directly absorbed by untreated B-CLL T lymphocytes to release IFN-gamma and IL 2 is preserved, but that IL 2 may be rapidly removed by the neoplastic B-CLL cells, thus contributing to the well-documented T lymphocyte abnormalities present in this disease.

Absorption↗
PubMed1985

Lymphokine-activated tumor inhibition in vivo. I. The local administration of interleukin 2 triggers nonreactive lymphocytes from tumor-bearing mice to inhibit tumor growth.

CE-2 is a chemically induced tumor of low immunogenicity in syngeneic BALB/c mice. Nylon wool columns eluting lymphocytes from the spleen of mice bearing clinically evident (5-mm mean diameter) CE-2 tumors (CE-2 TB lymphocytes) do not react with CE-2 cells in vitro, nor are they able to affect their growth in vivo in a Winn-type neutralization assay at 5:1 lymphocyte:tumor cell ratio. However, they become able to inhibit CE-2 tumor growth when 20 U of interleukin 2 (IL 2) in 0.4 ml are injected daily for 10 days at the challenge site. In contrast, mice injected with CE-2 cells and IL 2 only display tumor takes and growth that are not significantly different from those in controls challenged with CE-2 cells alone. This lymphokine-activated tumor inhibition (LATI) is not a peculiarity of the CE-2 tumor-host combination, because different tumors can be inhibited in this way and various TB lymphocytes can initiate it. In these experiments, IL 2-rich 25,000 to 30,000 m.w. fractions were obtained routinely from the culture supernatants of a clone of EL-4 thymoma stimulated with phorbol myristic acetate. Equally active IL 2-rich preparations were obtained from rat spleen cells stimulated with concanavalin A, or from MLA 144 gibbon lymphosarcoma spontaneously releasing IL 2. Treatment of CE-2 TB lymphocytes with various antibody and C, with 2000 rad gamma-irradiation, or fractionation on Percoll density gradients suggested that radioresistant functions of Thy-1.2+, Lyt-1.2+, Lyt-2.2- and of asialo GM1+ cells are independently involved in LATI induction. These lymphocytes inhibit tumor growth by recruiting the radiosensitive effector mechanisms of the recipient mice required for ultimate tumor destruction. CE-2 tumor inhibition by LATI leaves a specific delayed-type hypersensitivity and an immunologic memory, resulting in rejection of a second lethal CE-2 challenge in a significant number of mice.

Adenocarcinoma↗
PubMed1985

The roles of vitamin A in the prevention of neoplastic diseases: a critical assessment.

The role of vitamin A and its analogs (retinoids) in the prevention and therapy of neoplastic diseases is discussed. Epidemiological data showing a relationship between vitamin A deficiency and increased frequency of tumors in man and animals are examined and the experimental models demonstrating the protective action of retinoids in the respect of both spontaneous and induced neoplasias of animals are reviewed. Among the possible mechanisms responsible of the antineoplastic activity, the immunopotentiating effect is underlined. Some toxicological aspects of retinoids administration and the consequent application of the experimental results in human medicine are finally discussed.

Animals↗
PubMed1985

Alloantigen-activated lymphocytes from mice bearing a spontaneous "nonimmunogenic" adenocarcinoma inhibit its growth in vivo by recruiting host immunoreactivity.

Nylon wool columns eluting lymphocytes from the spleen of mice bearing a clinically evident spontaneous, nonimmunogenic adenocarcinoma of recent origin (TS/A) do not display cytotoxic response, release of lymphokines, and proliferation in vitro against TS/A cells, nor do they inhibit TS/A tumor growth in a Winn-type neutralization assay in vivo. After 5-day co-culture with allogeneic spleen cells from mice differing at multiple minor histocompatibility antigens only, these lymphocytes are still noncytolytic against TS/A cells, whereas they release interferon-gamma, mediate delayed-type hypersensitivity (DTH) reactions, and inhibit TS/A tumor growth in the Winn assay. In the Winn test, alloactivated lymphocytes from TS/A tumor-bearing mice are more effective than those from normal mice on a per cell basis. The induction of this TS/A tumor inhibition ability depends on the presence in the cultures of Thy-1+ lymphocytes. The presence of Lyt-2+ lymphocytes is also important, whereas that of asialo GM1+ is not. The TS/A inhibition in vivo by alloactivated lymphocytes mostly depends on Thy-1+, Lyt-2- and asialo GM- lymphocytes, even though a few Thy- cells are also very efficient tumor inhibitors. The alloactivated lymphocytes inhibit TS/A tumor growth by recruiting the radiosensitive effector mechanisms of the recipient mice required for ultimate tumor rejection. TS/A tumor rejection leaves a specific DTH and an immunologic memory resulting in rejection of a second lethal TS/A challenge in a significant number of mice.

Adenocarcinoma↗
PubMed1984

Physiological and pathological influences of central nervous system on the immune system: a critical appraisal.

There is considerable evidence of intricate links between central nervous and immune systems. This paper makes a critical assessment of these relationships. Recent experimental data on hypothalamic influences on Natural Killer activity in mice have been presented and the problems met with in defining causal nexuses discussed. Some information on immune reactivity in patients with mental disorders has briefly been reviewed.

Animals↗
PubMed1984

In vitro reeducated T helper cells from sarcoma-bearing mice inhibit sarcoma growth in vivo.

Spleen cells from BALB/c mice bearing a small, but already clinically evident transplantable methylcholanthrene-induced sarcoma (CE-2) are not able to release interferons, proliferate and perform a cytotoxic response against CE-2 cells, nor able to inhibit their growth in vivo in a Winn-type neutralization assay. They can, however, be reeducated to be efficiently active against the tumor. Spleen cells (25 X 10(6) ) and 10(6) mitomycin C-treated CE-2 cells were cultured in 20 ml of medium for 6 days. The surviving spleen cells were then cultured for another 5 days under the same conditions plus 10% interleukin 2-rich supernatant from a clone of EL-4 thymoma cells stimulated with phorbol-12-myristate-13-acetate. Reeducated spleen cells were then able to inhibit the growth of a 100% lethal dose of CE-2 tumor cells in a Winn-type assay, even when the lymphocyte to tumor cell ratio was 5:1. In vitro, they released interferon-gamma when restimulated by CE-2 cells, and displayed a marked cytotoxicity in an 18-hr assay. Their in vivo tumor-neutralizing activity was not affected by the removal of Lyt-2.2+ lymphocytes, nor by the absorption of cytolytic cells on CE-2 monolayers. The absorbed cell population no longer contained cytotoxic cells nor cytotoxic cell precursors, but still contained CE-2-specific helper cells, which assist the in vitro induction of cytotoxic cells by normal thymocytes. Lyt-2.2-, noncytotoxic, reeducated spleen cells from tumor-bearing mice thus play an important role in tumor neutralization in vivo.

Animals↗
PubMed1983

In vivo requirements for the immune recognition of L1210 leukemia cells by allogeneic T-lymphocytes.

The resistance of normal BALB/c mice (H-2d) against the L1210 Ha leukemia of DBA/2 mouse (H-2d) origin is due to the T-lymphocyte-dependent reaction towards DBA/2 multiple minor histocompatibility antigens (Mhas). These Mhas are displayed by the leukemic cells, though in a poorly immunogenic manner. The simultaneous presence of mitomycin C-inactivated DBA/2 leukocytes induces a significantly stronger T-lymphocyte-dependent reaction. This efficient presentation of target Mhas is restricted to Ia+ leukocytes. Their presence significantly increases BALB/c resistance, even when they are injected 3 days after the L1210 Ha challenge.

Animals↗
PubMed1983

H-Y antigen entrance into the immune system: relationship between lymphokine release, proliferation, cytotoxicity and delayed hypersensitivity.

In this paper we tested in parallel lymphokine release, proliferation, cytotoxicity and delayed hypersensitivity (DTH) reactions to H-7 antigen in high responder C57Bl/6 female mice. In vivo priming and in vitro restimulation are required in order to activate all the in vitro T-lymphocyte functions, and the ability to locally transfer DTH reactions. By contrast, a discrepancy is found between in vitro and in vivo tests of T-lymphocyte reactivity. In primed mice DTH reactions are evident, whereas no in vitro reactivity to H-Y is detectable.

Animals↗