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Biomedical subjects

D Frasca

Publications and source records attributed to D Frasca.

At least 55 records · Page 3Linked to original sources
PubMed1992

Effect of synthetic thymic humoral factor (THF-gamma 2) on T cell activities in immunodeficient ageing mice.

Immunodeficient ageing (C57BL/10 x DBA/2)F1 mice were treated by a single injection of synthetic thymic hormones and 4 days later their thymus and spleen cells were assayed in vitro for T cell activities. A few nanograms of THF-gamma 2 were found to raise the frequency of mitogen-responsive T cells in thymus and spleen cell populations as well as the frequency of cytokine-producing splenic T cells, up to the levels observed in young mice. Moreover, injection of THF-gamma 2 was found to restore T cell growth factor (TCGF) production by mitogen-stimulated spleen cells. Also, the helper activity of spleen cells was enhanced by this treatment and increased with increasing the THF-gamma 2 dose over a wide range. Similarly, the effects of thymopentin and thymosin-alpha 1 on T helper cell activity increased with increasing the injected dose, but the efficiencies of THF-gamma 2 and thymopentin were, respectively, 400-fold and eight-fold greater than that of thymosin-alpha 1.

Aging↗
PubMed1991

Immune parameters in a population of institutionalized elderly subjects: influence of depressive disorders and endocrinological correlations.

Twenty-six institutionalized elderly subjects, selected as healthy according to the SENIEUR protocol, were compared to adult controls to establish correlations between affective disorders and immune abnormalities and to investigate underlying neuroendocrine mechanisms. After an extensive psychodiagnostic examination, 35% of the aged subjects were classified as depressed. Cutaneous delayed hypersensitivity tests showed reduced responses in the aged, but no correlation was found with the psychological status. Examination of the peripheral blood lymphocyte subsets revealed no imbalance in the percentages of CD3+, CD4+, CD8+ cells in the aged. A slight reduction in the CD4+/CD8+ cell ratio could however be detected in the non-depressed aged, as compared to adult controls. The CD4+/CD45R+ cell subset was reduced in non-depressed aged. The percentage of B lymphocytes was reduced in the aged, mostly in the non-depressed subjects. No changes were detected in the percent of OKDR+ cells. The percentage of CD16+ cells was found unchanged, while that of Leu7+ cells was significantly higher in the aged than in the adults and in the non-depressed than in the depressed aged. Leu7+ cell levels were negatively correlated with the depression score. On double labelling, the percent of CD16+/Leu7+ cells appears increased in the subgroup of depressed aged and positively correlated with age. Plasmatic and urinary cortisol levels were both positively correlated with depression score. Urinary cortisol level was higher in the depressed aged. These parameters, as well as plasmatic ACTH, beta-endorphin and urinary catecholamines, were not correlated with immune responses. Based on these findings, we recommend that the neuroendocrinological conditions should be taken into account when healthy subjects are examined in studies of immune senescence.

Aged↗
PubMed1991

Impairment of lymphocyte activities in depressed aged subjects.

Lymphocyte activities were determined in a population of 26 institutionalized aged subjects, selected as healthy according to the SENIEUR protocol and previously reported to display immunological and endocrinological abnormalities correlated with depressive disorders. The lymphocyte mitotic response to PHA, which was reduced in aged as compared to adult subjects, was found to be significantly lower and negatively correlated with the depression score in the elderly subjects. In supernatants of PHA-stimulated lymphocyte culture from aged subjects, IL-2, IL-4 and gamma-IFN levels were very low and more severely affected in the depressed aged group. Each cytokine production was negatively correlated with age and depression score. NK activity was lower in the aged and it could be augmented by the addition of IL-2 or alpha-IFN, even though to a lesser extent than in the adult subjects. The nondepressed aged displayed higher levels of IL-2 inducible NK activity than the depressed aged subjects. IL-2 and alpha-IFN stimulated NK activities were negatively correlated with depression score. The present work indicates that the psychological status could affect lymphocyte reactivity in the aged. Given the relatively high frequency of affective disorders in these subjects, the psychological status should be considered in studies of immune senescence.

Aged↗
PubMed1991

Radiation protection and restoration by the synthetic 163-171 nonapeptide of human interleukin 1 beta.

We have previously reported that the synthetic nonapeptide VQGEESNDK, position 163-171 of human interleukin 1 (IL-1 beta), when injected in immunodepressed mice, shows immunorestorative activity similar to that of the whole protein, but with no IL-1-like inflammatory effects [Frasca et al., J. Immunol. 141, 2651-2655 (1988)]. In the present study we have compared the protective and restorative activities of the nonapeptide and human recombinant (hur) IL-1 beta on the survival of lethally irradiated mice. When mice were given a single injection of different doses of the nonapeptide or hurIL-1 beta 20 h before total-body irradiation, both molecules increased the percentage survival of mice exposed to 750 or 850 cGy, but not to 950 cGy. The nonapeptide, however, is less effective than hurIL-1 beta and displays a different dose-response relationship, suggesting that the two molecules act through different radioprotective pathways. When mice were injected with the nonapeptide or hurIL-1 beta immediately after exposure to 850 cGy, the percentage survival was also increased but restoration was lower than protection in both cases. The nonapeptide was also less effective than hurIL-1 beta in restoration, but the two molecules displayed a comparable dose-response relationship as if they shared similar mechanisms. These findings indicate that the 163-171 nonapeptide is able to protect from lethal radiation injury and to restore viability. The nonapeptide appears less effective than hurIL-1 beta but does not exhibit the IL-1-like side effects of the whole molecule.

Adjuvants, Immunologic↗
PubMed1989

Cholinergic agonists selectively induce proliferative responses in the mature subpopulation of murine thymocytes.

The incubation of murine thymocytes for 24 hr in the presence of cholinergic agonists induces selective proliferation of PNA- cells as measured by thymidine incorporation. The response of PNA- cells is mediated by the activation of nicotinic receptors. This conclusion is suggested by the inability of the muscarinic agonist, oxotremorine, to induce cell proliferation and by the inhibition exerted by the nicotinic antagonist, d-tubocurarine. The presence of cholinergic axons in the murine thymus adds biological interest to the selective expression of functional cholinergic receptors on mature thymocytes.

Animals↗
PubMed1989

Age-related changes within a suppressor T cell circuit.

The effects of aging on cellular and molecular components of the 4-hydroxy-3-nitrophenyl acetyl-specific suppressor T (Ts) cell circuit were analyzed in vitro using inducer (Ts1), transducer (Ts2), and effector (Ts3) cells and activating factors (TsF1 and TsF2) derived from young or old mice. The activation of Ts2 cells by TsF1 and of Ts3 cells by TsF2 was found age-restricted, suggesting a loss of Ts2 and Ts3 cell subsets in old mice. However, the activation of Ts3 cells by small amounts of TsF2 is more efficient when both are derived from old rather than from young mice while the same level of maximum suppression is attained. Higher affinity of the interactions involved in Ts cell activation may compensate for loss of Ts cell subsets in old mice. No age restriction was found for antigen presentation to Ts1 cells and for the interaction between Ts3 cells and target B cells. Thus, the effects of aging on immunosuppression result from changes within the Ts cell circuit.

Aging↗
PubMed1988

In vivo restoration of T cell functions by human IL-1 beta or its 163-171 nonapeptide in immunodepressed mice.

The immunorestorative capacities of human (hu) IL-1 beta or its synthetic fragment 163-171 (VQGEESNDK) were assessed in vivo in mice immunodepressed by aging, sublethal irradiation, or both. Subcutaneous administration of hu rIL-1 beta into immunodepressed animals immediately after carrier (horse red blood cells, HRBC) priming could restore to normal levels Th cell activity. This was measured as the ability of spleen cells from HRBC-primed mice to induce a hapten-specific antibody response in spleen cells from nonimmune mice in vitro stimulated with the hapten-carrier conjugate TNP-HRBC. In parallel, the ability of spleen cells from hu rIL-1 beta-treated immunodepressed animals to produce T cell growth factor activity upon in vitro mitogen stimulation was also increased significantly as compared to that of untreated mice and approached that of immunocompetent controls. The immunorestorative activity of hu rIL-1 beta on Th cell activity and T cell growth factor production could be mimicked by the synthetic nonapeptide 163-171 which, at the doses used, produced in most instances even greater effects than the whole protein. Although the optimal immunorestorative doses of the 163-171 peptide were several orders of magnitude higher than those of hu rIL-1 beta, the complete lack of IL-1-like inflammatory and toxic effects suggests that the synthetic hu IL-1 beta fragment may be successfully used as immunomodulating agent in the therapy of T cell immunodeficiencies.

Adjuvants, Immunologic↗
PubMed1988

In vivo stimulation and restoration of the immune response by the noninflammatory fragment 163-171 of human interleukin 1 beta.

The synthetic nonapeptide VQGEESNDK, corresponding to the fragment 163-171 of human IL-1 beta, showed in vivo immunomodulatory capacities qualitatively and quantitatively comparable to those of the mature human IL-1 beta protein. In fact, both IL-1 beta and the 163-171 fragment stimulated the immune response of normal mice and restored immune reactivities of immunocompromised animals. In addition, the synthetic IL-1 peptide was as efficient as the entire protein in inducing tumor rejection and radioprotection. On the other hand, the 163-171 fragment did not cause any of several inflammation-associated metabolic changes inducible by the whole IL-1 beta molecule in vivo: hypoferremia, hypoglycemia, hyperinsulinemia, increase in circulating corticosterone, SAA and fibrinogen, decrease in hepatic drug-metabolizing enzymes. Furthermore, at variance with IL-1 beta, the 163-171 peptide did not show the toxic effects causing shock and death in adrenalectomized mice. Thus, these results confirm our previous in vitro observations that functional domains are identifiable within the multipotent cytokine IL-1 beta, and demonstrate the biological relevance of this finding in a variety of in vivo systems. The identification of a selectively active fragment of a cytokine may thus represent a significant step towards a better directed and more rational immunotherapeutic approach.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

Enhancement of suppressor T cell activity by injection of anti-IFN-gamma monoclonal antibody.

In the present study, the contribution of IFN-gamma to the generation of helper activity in mice was investigated by use of anti-mouse IFN-gamma rat mAB (AN 18.17.24). This mAb was alum precipitated and injected i.p. before or after carrier priming. Results show that spleen cell helper activity is markedly inhibited by anti-IFN-gamma mAb injection. This inhibition is time and dose dependent, and counteracted by IFN-gamma administration. Thus, the anti-IFN-gamma mAb appears to inhibit helper cell activity by neutralization of the IFN-gamma required for the antibody response. Moreover, AN 18.17.24 mAb injection results in increased activation of Lyt-2+ T cells which markedly suppress Th activity. These findings altogether indicate that besides the activation of macrophages and Th, IFN-gamma seems to exert a negative interference in suppressor T lymphocyte circuits and, as a consequence, to inhibit immunosuppression.

Animals↗
PubMed1988

Heterogeneity of immune responsiveness in healthy elderly subjects.

We studied a group of healthy elderly subjects (satisfying the SENIEUR Protocol admission criteria), chosen as a model of age-associated immune deficiency on the basis of their reduced skin reactivity to recall antigens. Results show that aged subjects, taken as a whole, display impaired T-cell functions: reduced blastogenetic responses to mitogens, IL-2 production, responsiveness to exogenous IL-2, and percentage of Tac positive blasts. However, the age-associated immune defect shows a wide range of impairment, even in a relatively homogeneous group of anergic/hypoergic subjects. In fact, a considerable proportion of our elderly subjects displays responses comparable with those of adult controls. These observations suggest that (a) immune deficiency is not a characteristic of aging per se; (b) cutaneous delayed hypersensitivity is not a criterion sensitive enough to identify people with age-associated immune deficit; and (c) more than one test is required to evaluate T-cell impairment in aging.

Aging↗
PubMed1988

In vivo immunopotentiating activity of thymopentin in aging humans: modulation of IL-2 receptor expression.

The effect of thymopentin treatment was investigated in immunocompromised elderly subjects. Thymopentin was able to increase IL-2 production and IL-2 receptor expression, as assessed on PHA-activated blasts by percentage of Tac-positive cells and response to exogenous IL-2. After treatment, an increased precursor frequency, estimated by limiting dilution analysis, of PHA-responding lymphocytes was observed in two out of six subjects tested. In vitro experiments with thymopentin show that the drug was able to enhance blastogenesis by PHA of elderly lymphocytes but not of adult cells. These results indicate that (a) the increased IL-2 synthesis/IL-2 receptor expression may be the crucial mechanism of the immunopotentiating activity of the drug in elderly subjects and (b) an increased intrinsic T-cell responsiveness seems to be responsible for this immunopotentiating activity, although an increase in the size of the responsive T-cell pool could not be excluded.

Adjuvants, Immunologic↗
PubMed1987

Age restriction in antigen-specific immunosuppression.

Age-related alterations of antigen-specific T cell-mediated suppression have been examined in the 4-hydroxy-3-nitrophenyl acetyl (NP) system. Inducer suppressor T cells (Tsi) were activated in mice at the age of 3 mo (young) or 18 mo (old) by i.v. injection of NP-conjugated syngeneic spleen cells (SC). Spleen cells from the NP-SC-injected mice were subcultured in vitro with spleen cells from normal young or old mice to generate transducer suppressor T cells (Tst). Four days later subcultured cells were added to responder cell cultures 1 day before the PFC assays to trigger effector suppressor T cells (Tse). Responder cell cultures, containing NP-conjugated horse red blood cells (HRBC) and spleen cells from HRBC-primed young or old mice, were assayed on day 4 for anti-NP and anti-HRBC PFC. Suppression was found to be antigen specific and age restricted. NP-specific suppressor cells are easily induced in subculture if the Tsi and Tst cell populations are both derived from young or old mice. Conversely, if Tsi cells from young or old mice are subcultured with Tst cells from mice of a different age, suppression of the anti-NP PFC response is hardly observed. Age restriction was also found to operate in the interactions between subcultured and responder cell populations, indicating that age-matching is required for effective triggering of Tse cells by Tst cells. These results altogether suggest that aging may affect the recognition repertoire expressed in suppressor T cell subsets. Moreover, the finding that suppression is less efficient when exerted on responder spleen cells from old than from young mice provides an explanation for the increased frequency of autoimmune disorders in aging.

Aging↗
PubMed1987

Enhanced frequency of mitogen-responsive T cell precursors in old mice injected with thymosin alpha 1.

Injection of old mice with thymosin alpha 1, a synthetic peptide consisting of 28 amino acid residues and exhibiting thymic hormone-like activity, increases the splenic frequency of T cell precursors. Young (3-month-old) or old (19-20-month-old) mice received a single i.p. injection of thymosin alpha 1 or of an equimolar amount of the N14 (N-terminal amino acid residues 1-14) or C14 (C-terminal amino acid residues 15-28) synthetic fragment of the thymosin alpha 1 molecule and their spleen cells were assayed 3 days later under limiting dilution conditions to assess the frequency of mitogen-responsive and interleukin 2-producing T cells. Injection of thymosin alpha 1 or of its N14 fragment increases the frequency of responsive T lymphocytes in old, but not in young mice whereas injection of the C14 fragment has no demonstrable effect in either young or old mice. These data are consistent with our previous observation that the biological activity of thymosin alpha 1 is restricted to the N-terminal half of the molecule and suggest that this peptide amplifies the pool of mitogen-responsive and interleukin 2-producing T cells in immunodeficient old mice.

Aging↗
PubMed1987

In vivo immunopotentiating activity of thymopentin in aging humans: increase of IL-2 production.

The effect of thymopentin (TP-5) treatment on lymphocyte immune functions has been investigated in immunocompromised aged subjects. TP-5 was able to improve the cutaneous delayed hypersensitivity (CDH) to recall antigens and the proliferative response to phytohemagglutinin (PHA), concanavalin A, and Pokeweed (PWM) as well as the PHA-induced interleukin-2 (Il-2) production. On the other hand, no detectable changes were induced by TP-5 treatment either on PWM-induced immunoglobulin synthesis or on lymphocyte subsets identified by monoclonal antibodies. Our results suggest that the enhancement of Il-2 synthesis might be a crucial mechanism of the immunopharmacological action of TP-5 in aging humans.

Adjuvants, Immunologic↗
PubMed1987

Effect of subcutaneous thymopentin treatment in drug addicts with persistent generalized lymphadenopathy.

The effect of thymopentin treatment on the immune defects in drug addicts with persistent generalized lymphadenopathy and HTLV-III infection was investigated. Thymopentin was administered subcutaneously at two different dose schedules: 50 mg three times a week for 3 weeks (first cycle) and 50 mg/week for 3 months (second cycle). After the first cycle an increased number of OKT4+ lymphocytes and an improvement of PWM-induced blastogenesis and IgG synthesis in vitro was observed. The second cycle was unable to modify the same immune parameters in vitro. The treatment had no effect on the PHA responsiveness and on PHA-induced interleukin 2 production. The significance and the prognostic value of these findings are discussed in terms of the clinical evolution of the syndrome.

AIDS-Related Complex↗
PubMed1986

Reconstitution of T cell functions in aging mice by thymosin alpha 1.

Helper T cell activity of spleen cells from BDF1 mice is impaired by aging but is restored to a large extent by injection of thymosin alpha 1, a synthetic peptide consisting of 28 amino acid residues. Injection of an equimolar amount of the N14 (N-terminal half of thymosin alpha 1) synthetic fragment is at least as effective as the entire alpha 1 molecule in increasing helper T cell activity of spleen cells from old (6-18 months) mice but not from young (3 months) mice. Conversely, injection of the C14 (C-terminal half of thymosin alpha 1) synthetic fragment is devoid of any effect in both young and old mice. Since helper T cell activity of spleen cells from old mice is also increased by injection of interleukin-2, the observed enhancement of interleukin-2 production by mitogen-activated spleen cells from old mice upon injection of thymosin alpha 1 or the N14 fragment suggests that these peptides amplify helper T cell activity by increasing the cell precursor frequency of interleukin-2-producing T cells. This conclusion is further supported by the finding that injection of thymosin alpha 1, or its N14, but not C14, fragment enhances the expression of interleukin-2 receptors on mitogen-activated spleen cells from old but not from young mice.

Aging↗
PubMed1985

Enhancement of helper and suppressor T cell activities by thymosin alpha 1 injection in old mice.

A single injection of immunodeficient old (15-24 month old) BDF1 mice with 1-100 micrograms of synthetic thymosin alpha 1 (T alpha 1), a 28-amino acid residue peptide, shortly before horse erythrocyte (HRBC)-priming, enhances the helper activity of their spleen cells. Helper activity of spleen cells from uninjected or T alpha 1-injected HRBC-primed old mice was titrated by adding graded numbers of these primed cells to cultures containing a constant number of normal spleen cells from unprimed young (3-month-old) mice and the conjugate 2,4,6-trinitrophenyl (TNP)-HRBC. As evaluated from the in vitro anti-TNP antibody response, spleen cells exhibit higher helper activity when derived from T alpha 1-injected, as compared to uninjected, HRBC-primed old mice. No effect is observed when T alpha 1 is injected in young mice before HRBC-priming. Old mice were also injected with the N14 (N-terminal amino acid residues 1-14) or the C14 (C-terminal amino acid residues 15-28) synthetic fragments of the T alpha 1 molecule. Injection of T alpha 1 or the N14 fragment restores the helper activity of old mice to levels comparable to that displayed by helper cells from young mice. Conversely, injection of the C14 fragment in old mice induces only a negligible increase in helper activity of their spleen cells. T cells from HRBC-primed mice were separated by nylon wool filtration into Th1 (non-adherent) and Th2 (adherent) T cells and these cell subpopulations were assayed for helper activity. Helper activity of Th1 and Th2 cells is found to be impaired by aging when they are tested either separately or upon their recombination.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗