Search PubMed⌕ Search

Biomedical subjects

J W Hadden

Publications and source records attributed to J W 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

Gamma-interferon corrects aberrant protein kinase C levels and immunosuppression in the spontaneously hypertensive rat.

The effects of gamma-interferon (gamma-IFN) on protein kinase C (PKC) levels and immunosuppression in the spontaneously hypertensive rat (SHR) were examined. First, an abnormal PKC distribution was found in spleen, thymus and aorta from SHRs relative to normotensive controls. Biweekly injections of rat recombinant gamma-IFN (1000 U/kg) restored basal or resting PKC levels to those found in normotensive Wistar-Kyoto (WKY) rats. We also examined the effects of in vivo gamma-IFN treatment on nuclear PKC (nPKC) activation in purified, isolated splenocyte nuclei. It was found that basal nPKC levels were higher in untreated SHRs than gamma-IFN SHRs or WKYs. Also, while nuclei from untreated SHRs were relatively unresponsive to various immunoreactive substances and PKC activators, gamma-IFN treatment significantly restored activity. Last, the proliferative response to mitogen challenge of isolated splenocytes from untreated SHRs, gamma-IFN-treated SHRs and WKYs was studied. Although gamma-IFN treatment did not restore the proliferative response to that of WKYs, the mitogen response was significantly enhanced by treatment with gamma-IFN. The data show that gamma-IFN acts to restore normal immune function and corrects aberrant PKC levels and adds to the growing body of knowledge suggesting a role for immune dysfunction in the etiology of hypertension.

Animals↗
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↗
PubMed1992

Thymic endocrinology.

Thymus endocrinology is characterized by the action of various hormones on the thymus endocrine milieu consisting of thymocytes, thymic epithelial cells and thymic stromal cells. Extrathymic hormonal influences include pituitary-derived hormones, such as prolactin and indirectly by ACTH via hydrocortisone from the adrenal, by thyroid-stimulating hormone (TSH) via thyroid hormones from the thyroid, and by LH and RH via sex steroids from gonads and adrenal. In addition, 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 and its functions. These endocrine influences decline with age and are associated with "thymic menopause" and cellular immune senescence contributing to the development of diseases in the aged. The intrathymic environment is characterized by a complex network of paracrine and autocrine endocrine signals involving both interleukins and thymic peptides. Thymic epithelial cells respond to IL-1 with proliferation and secretion of IL6 and GM-CSF. They similarly respond to cellular interactions with the production of IL1. Thymic epithelial cells also secrete thymic hormones, as exemplified by the zinc-thymulin complex, under stimulation with IL1 and other hormonal influences. Thymic stromal cells contribute, at minimum, IL1. These various interleukin and thymic hormone influences can be envisioned to operate in a synergistic interactive network to carry the evolving T-cell through its stepwise development to a mature T-cell.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
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

Report of the symposium on the use of intravenous gammaglobulin in adults infected with the human immunodeficiency virus.

On July 27, 1989, the International Conference on Molecular Aspects of Immune Response and Infectious Diseases devoted a symposium to the subject of the use of intravenous gamma globulin (IVIG) in acquired immunodeficiency syndrome (AIDS). The information presented confirmed that IVIG benefits human immunodeficiency virus (HIV)-infected children with recurrent infections and that much remains to be learned about the influence of IVIG in adult AIDS. The symposium participants recognized the urgent need to develop randomized clinical trials using a control group to assess the efficacy of a treatment with IVIG in PGL (persistent generalized lymphadenopathy), ARC (AIDS-related complex), and AIDS. To prepare this report, a committee was established, including individuals with expertise in immunology, immunopharmacology, microbiology, virology, infectious diseases, general medicine, and pediatrics and representing research experience in academia and hospitals. After an introduction to the report with a summary of immunotherapeutic agents under evaluation to treat HIV infection, section 1 lays out the present understanding of the disease pathogenesis. Section 2 then outlines the treatment of HIV-seropositive individuals, discussing the uncertainties that any treatment entails. Section 3 discusses the rationale for treating HIV-infected individuals with IVIG, and Section 4 examines the major differences between IVIG and hyperimmunoglobulins for the treatment of HIV infection. Section 5 looks at IVIG as a mean to delay the emergence of opportunistic infections and restore immunocompetence in AIDS and related illnesses, and Sections 6 and 7 suggest a pilot protocol on the use of IVIG in association with low-dose or standard-dose zidovudine (AZT).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗