Biomedical subjects

E M Hadden

Publications and source records attributed to E M Hadden.

At least 19 recordsLinked to original sources

PubMed1992

Thymic involution in aging. Prospects for correction.

The thymus produces several putative thymic hormones: thymosin alpha 1, thymulin, and thymopoietin, which have been reported to circulate and to act on both prothymocytes and mature T cells in the periphery, thus maintaining their commitment to the T cell system. These endocrine influences decline with age and are associated with "thymic menopause" and cellular immune senescence, which contribute to the development of diseases in the aged. Thymus endocrinology is characterized by the action of many hormones and hormone-like substances on the cellular components of the thymus, including thymocytes, thymic epithelial cells, and thymic stromal cells. The intrathymic environment is characterized by a complex network of paracrine, autocrine, and endocrine signals involving both interleukins and thymic peptides, which can be envisioned to operate in a synergistic network to carry the evolving T cell through its stepwise development to a mature T cell. Extrathymic influences regulating the secretory function of thymic epithelial cells and the stepwise evolution of T cells can be ascribed to circulating interleukins, mainly IL1 and IL2, derived from activation and secretion of leukocytes in the periphery. These interleukins act in a synergistic fashion at all levels of T cell development by the induction of high-affinity IL2 receptors and the resultant IL2-dependent proliferative responses. To determine whether exogenous administration of interleukins would induce T lymphocyte development in aged mice, we chemically thymectomized aged mice with a steroid hormone and treated them with mixed interleukins or thymic hormones such as thymosin. We found that mixed interleukins, but not thymosin, restored thymic weight and cellularity and enhanced thymocyte responses to interleukins and mitogen. Thymosin potentiated the effect.

Aging↗

PubMed1992

Mixed interleukins and thymosin fraction V synergistically induce T lymphocyte development in hydrocortisone-treated aged mice.

Analysis of the role of interleukins in T cell ontogeny in vitro indicates that the regulation of T cell development involves interleukins (ILs) as well as thymic hormones (THs). In order to assess their respective roles in T lymphocyte development in vivo, chemically thymectomized mice were treated with ILs and THs. After 2 days of hydrocortisone treatment, aged mice showed acute thymic involution (weight was less than 30% of control) and reduced spleen size (less than 80% of control) with progressive recovery to 8 days. After 2 days of hydrocortisone treatment, adult mice were injected for 5 days with mixed buffy coat interleukins (BC-IL; 50 units IL2 equivalence), purified IL2 (50 units), rIL1 beta (4 ng), and thymosin fraction V (TF5; 100 micrograms). The animals were sacrificed and spleens and thymuses were analyzed for weight, cellularity, T cell number, subsets, and function as determined by proliferative responses to concanavalin A and ILs. BC-IL treatment increased the recovery of spleen and thymus weights and cellularity with corresponding augmentation of number and function of T lymphocytes; neither IL1 or IL2 or their combination had this effect. TF5 had no effect alone but strongly potentiated the effect of BC-IL on T lymphocyte function. These data indicate that BC-IL in combination with thymic peptides potently promotes T lymphocyte development. The combination may be therapeutically relevant for immunorestoration.

Aging↗

PubMed1992

Interleukin 1 regulates secretion of zinc-thymulin by human thymic epithelial cells and its action on T-lymphocyte proliferation and nuclear protein kinase C.

Thymic epithelial cells (TEC) are known to secrete thymic hormones that influence maturation of T lymphocytes. One of these peptides, thymulin, requires zinc in an equimolar ratio for biological activity. A previous study [Cousins, R. J. & Leinart, A. S. (1988) FASEB J. 2, 2884-2890] showed that interleukin 1 (IL-1) in vivo stimulates zinc uptake by the thymus. Both the alpha and beta forms of IL-1, which stimulate proliferation of human TEC, also stimulate their uptake of zinc in vitro, and this latter stimulation is both dependent and independent of proliferation. Zinc induces zinc accumulation without proliferation. Two other stimulants of proliferation, bovine pituitary extract and epidermal growth factor, stimulate zinc uptake by TEC, but only in a manner dependent on proliferation. Utilizing in situ hybridization, we show that the IL-1 alpha and beta forms and zinc induce metallothionein mRNA expression TEC. Metallothionein is thought to be involved in the transfer of zinc to thymulin. IL-1 was shown to stimulate the secretion of thymulin as measured both by its ability to stimulate induction of IL-2 receptor-positive lymphocytes from human peripheral blood lymphocytes and by the azathioprine-sensitive rosette assay. In addition, the zinc-thymulin complex in the presence, but not absence, of IL-1 stimulates nuclear protein kinase C in isolated lymphocyte nuclei. IL-1 apparently regulates the synthesis or secretion and delivery of zinc-thymulin complex to the T-lymphocyte system.

Cell Nucleus↗

PubMed1992

Potentiation of immune responses in mice by a new inosine derivative--methyl inosine monophosphate (MIMP).

Inosine 5'-methyl monophosphate (MIMP) is a new immunomodulator designed to improve upon the activity of other thymomimetic purines. In Balb/c mice, MIMP was assessed for toxicity and activity on immune responses. The lethal dose for half the mice (LD50) exceeded 500 mg/kg of body weight by both the parenteral and oral routes. At doses of 1-100 mg/kg, the mice showed no visible untoward effects. The antibody response of splenocytes to sheep erythrocytes (SRBC) was measured by IgM plaque-forming cells (PFC) in soft agar under optimal conditions of immunization and challenge. MIMP (1-100 mg/kg) was given by both the intraperitoneal and oral routes (gavage) at the time of SRBC injection and 4 days thereafter. The PFC response was found to be significantly augmented. The maximum effect (approximately 2x) was observed at 50 and 100 mg/kg, via intraperitoneal (i.p.) and oral routes, respectively. Increases (maximally 1.5x) in the responses of splenic lymphocytes to mitogen stimulation with phytohemagglutinin (PHA) and concanavalin A (Con A) were observed under similar conditions of MIMP treatment. SRBC-induced delayed-hypersensitivity (DTH) was also measured under optimal conditions. By both i.p. and oral routes, enhancement of DTH response was produced by the lower doses of MIMP (0.01-1 mg/kg). Again, a second peak of optimum stimulation of DTH response was produced by 50 mg/kg of MIMP when administered by both routes. The effect was observed mainly on the sensitization rather than on the expression phase. MIMP qualifies as an effective immunopotentiator in normal mice.

Adjuvants, Immunologic↗

PubMed1992

Methyl inosine monophosphate: a potential immunotherapeutic for early human immunodeficiency virus (HIV) infection.

MIMP is a new thymomimetic purine under development for immunorestorative therapy. Lymphocytes were obtained from eight patients with acquired immunodeficiency disease (AIDS), eight with symptomatic pre-AIDS (ARC), and 22 normal controls and were stimulated in vitro with phytohemagglutinin (PHA). AIDS patients (mean CD4 counts of 40) showed PHA responses less than 10% of control while ARC patients (mean CD4 counts of 544) showed responses approximately 50% of the control responses. MIMP (0.1, 1, 10 and 100 micrograms/ml) progressively augmented the PHA responses in all these groups. The augmentation of the responses of the leukocytes of AIDS patients while statistically significant was minimal. The augmentation of the responses of ARC patients was significant and their maximal responses approached control levels. The effect of 1 micrograms/ml MIMP was comparable with that observed with indomethacin (10(-6) M) and interleukin-2 (IL2 - 4 units/ml) and was additive with each of these stimulants. In a parallel manner, MIMP restored the suppression of control lymphocytes induced by the immunosuppressive 17 amino acid fragment of the P41 peptide of HIV. In vivo experiments showed that MIMP significantly delayed death in a murine FLV AIDS model at a dose of 1 mg/kg by the oral or parenteral route. MIMP is under preclinical development for early HIV disease to forestall progression to AIDS by attenuating virus-induced immunosuppression.

Adjuvants, Immunologic↗

PubMed1991

Methyl inosine monophosphate (MIMP), a new purine immunomodulator for HIV infection.

Prior work has documented the thymomimetic and immunotherapeutic activity of purine molecules related in structure to inosine. Synthesis of a series of new structures has yielded a stable methylated form of IMP resistant to hydrolysis by 5' nucleotidase. With both human peripheral blood lymphocytes and murines splenocytes, Methyl Inosine Monophosphate (MIMP) augments proliferative responses to T-cell mitogens like phytohemagglutinin (PHA), but less so, or not at all, to B-cell mitogens like pokeweed or endotoxin (LPS). MIMP does not directly stimulate lymphocytes alone in the absence of mitogen. The optimal effects of MIMP parallel the optimal effects of PHA. The magnitude of the effect is greater and more consistent than with other purine immunomodulators. MIMP is non-toxic in vitro and in vivo and is orally active in mice. Significant effects are observed as low as 0.1 and 1 micrograms/ml in vitro and 0.1 or 1 mg/kg in vivo. MIMP is a candidate third generation purine under development for immunotherapeutic purposes.

Adjuvants, Immunologic↗

PubMed1990

Prolactin and known modulators of rat splenocytes activate nuclear protein kinase C.

Prolactin (PRL) and other trophic factors rapidly activate a nuclear pool(s) of protein kinase C (nPKC) in purified splenocyte nuclei. The PRL also enhanced [2-3H]glycerol incorporation into nuclear mono- and triacylglycerol. An assay was devised which not only probed the ability of the hormone to activate protein kinase C (PKC) but also demonstrated the presence of nuclear substrates. Using this methodology, a biphasic concentration-response curve to PRL was observed. Heterologous species of PRL and various growth factors also activated nPKC. The PRL-induced nPKC stimulation was antagonized by various immunomodulators, G protein-coupling inhibitors, PKC inhibitors, a calmodulin inhibitor, and a peripheral benzodiazepine agonist and antagonist. A monoclonal antibody to PKC, anti-rat PRL antiserum and a monoclonal anti-rat PRL receptor antibody antagonized PRL-induced PKC-dependent nuclear phosphorylation, further implicating nPKC and a PRL receptor-mediated activation process. Nuclear PKC may be a major target for trophic regulation in response to both positive and negative growth signals.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1989

Therapy of secondary T-cell immunodeficiencies with biological substances and drugs.

Thymus-dependent (T) lymphocyte defects are common in cancer. Recent advances in the understanding of the regulation of T-cell development by biologicals and drugs now allow the formulation of better strategies of immune reconstitution to correct these defects. Thymic hormone preparations of several types offer one type of approach; however, they are somewhat limited in their reconstitutive ability. Interleukins (IL), particularly IL-1 and IL-2, appear to be complementary to the actions of thymic hormones in promoting T-cell development. Two classes of thymomimetic drugs have been identified and are represented by levamisole and isoprinosine. These drugs mimic by indirect and direct actions, respectively, the actions of thymic hormones. Newer analogs of these compounds have emerged which appear more effective. Also new factors, e.g. pituitary factors, are emerging which may be potent regulators of the immune system and useful in therapy. These agents may now be more effectively integrated with cytodestructive therapy in cancer treatment.

Biological Factors↗

PubMed1989

Effects of cytokines on human thymic epithelial cells in culture: IL1 induces thymic epithelial cell proliferation and change in morphology.

The role of thymic epithelium in T cell development has given rise to a number of studies, but less information is available concerning the factors regulating thymic epithelial cells (TEC) themselves. Several cytokines, natural or recombinant, were investigated for their effects on human TEC proliferation. This study presents evidence for the first time that human recombinant interleukin 1 (IL1) and IL1-containing mixed cytokine preparations induced DNA synthesis of TEC as measured in a 48-hr stimulation assay. The effects of IL1 were dose dependent and sustained in time. The following recombinant cytokines, IL2, IL3, IL4, interferon-gamma (IFN-gamma), IFN-alpha, tumor necrosis factor-alpha (TNF alpha), and TNF beta, as well as thymosin fraction 5 and Escherichia coli lipopolysaccharide (LPS), were not found to modify TEC proliferation but IFN-gamma and TNF alpha enhanced the effects of IL1. We also report that IL1 induced a profound change in the morphology of TEC. Our observations suggest that TEC are targets for the action of cytokines and emphasize the important role played by IL1 within the thymus.

Cell Division↗

PubMed1989

Thymosin, interleukins, isoprinosine and imuthiol do not reconstitute T-cells in athymic nude mice.

Previous reports suggest that immunotherapy can induce T-cell development in athymic nude mice. Eight-week-old BALB/c nu/nu (athymic nude) mice were treated for 3, 6 and 12 weeks with thymosin fraction 5 (TF-5), buffy coat interleukins (BC-IL), recombinant IL-2 (rIL-2), a combination of TF-5 and BC-IL, isoprinosine or imuthiol. Control animals were treated with sterile saline or were given a syngeneic thymus graft. Spleen weight, cell yields and Thy 1.2+ T-cell markers were monitored and spleen cell proliferative responses to rIL-2, concanavalin A (Con A), Con A + rIL-2, phytohemagglutinin (PHA) and endotoxin (LPS) were assessed. Only mice transplanted with a syngeneic thymus showed progressive increases in both T-cell number and function. Minor changes in proliferative responses were noted at 3 weeks with all treatments; however, no biologically significant reconstitution of T-cell number or function was observed.

Animals↗

PubMed1989

A pituitary factor induces thymic epithelial cell proliferation in vitro.

Human thymic epithelial cells (TEC) were grown in culture and confirmed to be keratin positive (98-100%) and epidermal growth factor (EGF) responsive. Bovine pituitary extracts (BPE) stimulated the proliferation of TEC. The proliferation of TEC was confirmed by cell counts and radioautography. The BPE was active as measured by tritiated thymidine incorporation in the absence of serum and in the absence of EGF. Individual anterior pituitary hormones (growth hormone, prolactin, ACTH, FSH, LH, TSH) and posterior pituitary hormones (vasopressin and oxytocin) were inactive alone to stimulate TEC proliferation. The effect of EGF but not BPE was blocked by an antibody to EGF suggesting that the active component of BPE is not EGF. Purification of the factor is in progress. The observations suggest that this pituitary-derived factor(s) may regulate thymic function in vivo.

Animals↗

PubMed1987

Interleukin II increases cyclic GMP levels in immature thymocytes and mitogen-primed T-lymphocytes.

Interleukin II, also called T-cell growth factor, induces proliferation of immature peanut agglutinin positive murine thymocytes (PNA+) and renders them responsive to concanavalin A. It also, as shown by others, provides a second signal to induce phytohemagglutinin-primed mature human T-lymphocytes to enter DNA synthesis. Both actions are associated with early increases (2-60 min) in cellular levels of cyclic 3'5' guanosine monophosphate (cyclic GMP) without change of cyclic 3'5' adenosine monophosphate (cyclic AMP) levels. Cyclic GMP is postulated to represent part of the mechanism by which IL-2 acts.

Animals↗

PubMed1979