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Biomedical subjects

J C Keith

Publications and source records attributed to J C Keith.

At least 37 records · Page 2Linked to original sources
PubMed1999

Hematopoietic, immunomodulatory and epithelial effects of interleukin-11.

Interleukin 11 (IL-11) is a pleiotropic cytokine with biological activities on many different cell types. Recombinant human IL-11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown effects on multiple hematopoietic cell types. Its predominant in vivo hematopoietic activity is the stimulation of peripheral platelet counts in both normal and myelosuppressed animals. This activity is mediated through effects on both early and late progenitor cells to stimulate megakaryocyte differentiation and maturation. rhIL-11 has been approved for the treatment of chemotherapy-induced thrombocytopenia. The hematopoietic effects of rhIL-11 are most likely direct effects on progenitor cells and megakaryocytes in combination with other cytokines or growth factors. rhIL-11 also induces secretion of acute phase proteins (ferritin, haptoglobin, C-reactive protein, and fibrinogen) from the liver. The induction of heme oxidase and inhibition of several P450 oxidases have been reported from in vitro studies. In vivo, rhIL-11 treatment decreases sodium excretion by the kidney by an unknown mechanism and induces hemodilution. rhIL-11 also exhibits anti-inflammatory effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, inflammatory skin disease, autoimmune joint disease, and various infection-endotoxemia syndromes. rhIL-11 has trophic effects on non-transformed intestinal epithelium under conditions of mucosal damage. The mechanism of the anti-inflammatory activity of rhIL-11 has been extensively studied. rhIL-11 directly affects macrophage and T cell effector function. rhIL-11 inhibits tumor necrosis factor-alpha (TNF alpha), interleukin 1beta (IL-1beta), interleukin 12 (IL-12), interleukin 6 (IL-6), and nitric oxide (NO) production from activated macrophages in vitro. The inhibition of cytokine production was associated with inhibition of nuclear translocation of the transcription factor, nuclear factor kappa B (NF-kappaB). The block to NF-kappaB nuclear translocation correlates with the ability of rhIL-11 to maintain or enhance production of the inhibitors of NF-kappaB, IkappaB-alpha and IkappaB-beta. In addition to effects on macrophages, rhIL-11 also reduces CD4+ T cell production of Th1 cytokines, such as IFN gamma induced by IL-12, while enhancing Th2 cytokine production. rhIL-11 also blocks IFN gamma production in vivo. The molecular effects of rhIL-11 have also been studied in a clinical trial. Molecular analysis of skin biopsies of patients with psoriasis before and during rhIL-11 treatment demonstrates a decrease in mRNA levels of TNF alpha, IFN gamma and iNOS. These activities suggest that in addition to its thrombopoietic clinical use, rhIL-11 may also be valuable in the treatment of inflammatory diseases. The clinical utility of the anti-inflammatory properties of rhIL-11 is being investigated in patients with Crohn's disease, psoriasis and rheumatoid arthritis. These diseases are believed to be initiated and maintained by activated CD4+ Th1 cells in conjunction with activated macrophages.

Acute-Phase Reaction↗
PubMed1998

Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation.

Administration of IL-11 prevented lethal graft-versus-host disease (GVHD) in a murine bone marrow transplant (BMT) model (B6 --> B6D2F1) across MHC and minor H antigen barriers (survival at day 50: 90 vs 20%, P < 0.001). Surpisingly, IL-11 administration polarized the donor T cell cytokine responses to host antigen after BMT with a 50% reduction in IFNgamma and IL-2 secretion and a 10-fold increase in IL-4. This polarization of T cell responses was associated with reduced IFNgamma serum levels and decreased IL-12 production in mixed lymphocyte cultures (MLC). In addition, IL-11 prevented small bowel damage and reduced serum endotoxin levels by 80%. Treatment with IL-11 also reduced TNFalpha serum levels and suppressed TNFalpha secretion by macrophages to LPS stimulation in vitro. IL-11 thus decreased GVHD morbidity and mortality by three mechanisms: (a) polarization of donor T cells; (b) protection of the small bowel; and (c) suppression of inflammatory cytokines such as TNFalpha. We conclude that brief treatment with IL-11 may represent a novel strategy to prevent T cell-mediated inflammatory processes such as GVHD.

Acute Disease↗
PubMed1998

Immunolocalization of tumour necrosis factor-alpha (TNF-alpha) in the placental bed of normotensive and hypertensive human pregnancies.

To identify tumour necrosis factor (TNF)-alpha immunopositive cells, third trimester human placental bed biopsies were selected from nine normotensive control women, 16 severely pre-eclamptic patients and seven patients with pre-existing hypertension with superimposed pre-eclampsia. In addition, five first and early second trimester specimens were included in the study. Immunostaining was performed with a mouse IgG1 monoclonal antibody (J1D9) reactive specifically with human TNF-alpha (1:300 ascitic fluid), using a biotin-streptavidin-peroxidase technique. Variable staining of stromal cells was noted in all biopsies. Specimens of early pregnancy showed marked immunostaining for TNF-alpha on proliferating tips of anchoring villi, invasive interstitial cytotrophoblast (but not the multinuclear giant cells), and endovascular trophoblast invading the spiral arteries. At term, weak staining was found in trophoblast incorporated within spiral artery walls. In biopsies from pre-eclamptic patients, spiral arteries without physiological change showed very little staining except in atherotic vessels where the infiltrated lipophages often showed intense immunolabelling. The marked presence of TNF-alpha in extravillous cytotrophoblast of young specimens is suggestive of a role in early invasion. Immunostaining of foam cells in non-invaded spiral arteries in pre-eclampsia at or near-term indicates a potential role of this cytokine in the development of atherotic lesions.

Animals↗
PubMed1998

Recombinant human interleukin-11 in experimental Pseudomonas aeruginosa sepsis in immunocompromised animals.

The therapeutic potential of recombinant human interleukin-11 (rhIL-11) was tested in a neutropenic rat model that mimics the clinical consequences of myelosuppressive chemotherapy complicated by Pseudomonas aeruginosa sepsis. rhIL-11-treated animals (150 micrograms/kg intravenously every 24 h for 3 days) had reduced endotoxin levels (P < .05) and less pulmonary edema fluid (P < .001) and were protected (P < .01) against thinning and necrosis of the intestinal mucosa compared with the control group. The survival rate in rhIL-11-treated animals was 40% (19/47), whereas it was 0 (0 of 19) in the control group (P < .01). The addition of ciprofloxacin (10 mg/kg every 12 h) resulted in a survival rate of 9 (60%) of 15, while the combination of rhIL-11 and ciprofloxacin resulted in 100% survival (15/15; P < .05). These results indicate that rhIL-11 supports mucous membrane integrity of the alimentary tract and decreases the systemic inflammatory response to experimental gram-negative infection in immunocompromised animals.

Animals↗
PubMed1998

Recombinant human interleukin-11 does not modify biochemical parameters of bone remodeling and bone mineral density in adult ovariectomized rats.

Interleukin (IL)-11 stimulates osteoclast formation and inhibits osteoblast function in vitro and has been implicated in estrogen deficiency-induced bone loss. Herein we report the in vivo effect of recombinant human IL-11 (rHU-IL-11), administered s.c. in doses between 10 and 200 microg/kg/day for 6 weeks into 6-month-old rats after ovariectomy. There was no difference between vehicle-treated and rHu-IL-11 treated rats in the ovariectomy-induced increase in the urinary excretion of pyridinoline and deoxypyridinoline. Neither was there a significant effect of rHu-IL-11 on the plasma concentrations of osteocalcin and on bone mineral density (BMD) measured at a metaphyseal area of the distal femur after 6 weeks. At all dosages tested, rHu-IL-11 increased the femoral diaphyseal area. In conclusion, IL-11 has no deleterious in vivo effect on biochemical parameters of bone remodeling and BMD in estrogen-deficient rats.

Amino Acids↗
PubMed1998

Molecular effects of recombinant human interleukin-11 in the HLA-B27 rat model of inflammatory bowel disease.

Recombinant human interleukin-11 (rhIL-11) is a pleiotropic cytokine with effects on multiple cell types. In addition to thrombopoietic activity, rhIL-11 has demonstrated anti-inflammatory activity in vitro and in vivo. rhIL-11 treatment reduces clinical signs and histologic lesions of colitis in transgenic rats expressing the human major histocompatibility complex (MHC) Class I allele, HLA-B27. We have investigated the effects of rhIL-11 at the molecular and cellular level in this model of inflammatory bowel disease. RT-PCR analysis of colonic RNA revealed that treatment with rhIL-11 down-regulated expression of proinflammatory cytokines including TNF-alpha, IL-1beta, and IFN-gamma. rhIL-11 also reduced the level of myeloperoxidase activity in the cecum indicating reduced inflammation. After stimulation in vitro with anti-CD3 antibody, spleen cell cultures derived from rhIL-11-treated rats produced less IFN-gamma, TNF-alpha, and IL-2 than cultures derived from vehicle-treated rats. These molecular and cellular effects correlated with amelioration of disease as measured by stool character and histologic lesion scores. These findings suggest that rhIL-11 acts to reduce inflammation through modulation of multiple proinflammatory mediators including products of activated T cells. This study has identified pharmacodynamic markers of rhIL-11 anti-inflammatory activity in vivo and supports rhIL-11 therapy to treat inflammatory bowel disease.

Animals↗
PubMed1997

Immunoreactive macrophage colony-stimulating factor is increased in atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits after recombinant human macrophage colony-stimulating factor therapy.

Infiltration of monocytes into arteries is an early event in the pathogenesis of atherosclerosis. This recruitment is interpreted as enhancing lesion development, but it could also be a host response limiting lipid accumulation. The ability of macrophages to limit cholesterol uptake, however, can be reduced by the impaired mobility and metabolic activity associated with foam cell development. As lesions enlarge, foam cells die and become the nidus for the necrotic core. Treatments to improve viability might improve foam cell function and promote regression. Macrophage colony-stimulating factor (M-CSF) is vital to monocyte/macrophage differentiation, proliferation, and activation. We found that foam cells of Watanabe heritable hyperlipidemic (WHHL) rabbits had faint staining for M-CSF. Treatment of rabbits with recombinant human M-CSF (rhM-CSF) increased M-CSF staining, which correlated with reduced cholesterol content of these foam cells.

Adipose Tissue↗
PubMed1997

Detection of immunoreactive interleukin-11 in human follicular fluid: correlations with ovarian steroid, insulin-like growth factor I levels, and follicular maturity.

OBJECTIVE: To prove the presence of interleukin-11 (IL-11) in the follicular fluid (FF), to determine its source and the correlation between IL-11 and fertilization outcome, follicular size, number of follicles per patient, steroids, and insulin-like growth factor-1 (IGF-I) levels. DESIGN: Interleukin-11 levels were measured in FFs, aspirated during oocyte pickup for IVF. SETTING: Academic hospital and research environment. PATIENT(S): Follicular fluid and serum were obtained with informed consent from 44 patients undergoing IVF-ET. Granulosa cells were isolated from 17 patients. MAIN OUTCOME MEASURE(S): We hypothesized that IL-11 might play a role in follicular development, as do other related cytokines present in FF. Interleukin-11 was measured with ELISA. RESULT(S): Interleukin-11 was absent in the serum but present in FF and in conditioned medium from granulosa cells. Atretic follicles had higher concentrations of IL-11. No correlation was found between IL-11 and fertilization outcome, follicular size, steroid, IGF-I, and total protein concentrations. CONCLUSION(S): We conclude that IL-11 is present in FF. The role of IL-11 in follicular development should be the object of further investigations.

Biomarkers↗
PubMed1996

Recombinant human factor IX: replacement therapy, prophylaxis, and pharmacokinetics in canine hemophilia B.

Recombinant human factor IX (rFIX) has been expressed in transduced cultured cell systems since 1985. Because there has been limited in vivo testing of rFIX in hemophilia B subjects, this study was undertaken using the severe hemophilia B canines of the Chapel Hill strain. Three groups of hemophilic dogs received either 50, 100, or 200 IU/kg of rFIX. As a control, a fourth group of hemophilic dogs received 50 IU/kg of a high purity, plasma-derived human FIX (pdFIX). The coagulant and hemostatic effects of rFIX and pdFIX were similar with all comparative dosing regimens. Based on activity data, the elimination half-life of rFIX was 18.9 +/- 2.3 hours and pdFIX was 17.9 +/- 2.1 hours. A prophylactic regimen administering rFIX daily resulted in a continuous therapeutic level of plasma FIX and was accompanied by a two-fold increase in recovery levels by day 5, compared to that observed with administration of a single bolus. The mechanisms of the high to complete recovery of FIX with the prophylactic regimen could depend not only on the degree of saturation of the vascular endothelial binding sites but also on the altered dynamics of the balance of FIX distribution between the intravascular and extravascular compartments. The pharmacokinetic (PK) parameters for rFIX and pdFIX were similar. However, the relative PK values for V1 and V5s of both products on day 5 differed greatly from day 1 and may reflect the changing equilibrium of FIX between compartments with elevated levels of plasma FIX. Neutralizing antihuman FIX antibodies resulting from human FIX antigen being administered to FIX deficient dogs were observed beginning at 14 days. The antigenicity of rFIX and pdFIX appeared to be comparable. Despite the very different procedures used for production of rFIX and pdFIX products, in vivo testing in hemophilia B dogs showed the functional behavior of these products is similar; they are highly effective for replacement therapy and for prophylaxis.

Animals↗
PubMed1996

Protection by recombinant human interleukin-11 against experimental TNB-induced colitis in rats.

The potential effect of recombinant human interleukin-11 (rhIL-11) on trinitrobenzene sulfonic acid (TNB)-induced colitis was investigated in rats. Intrarectal TNB (40 mg in 0.25 ml 40% ethanol) produced significant ulcerative colitis. The lesions were most severe at three days after TNB instillation, and then declined, but lesions were still observed after two weeks. TNB administration also significantly enhanced the colonic mucosal myeloperoxidase (MPO) levels, which paralleled the severity of colitis. The rhIL-11 at subcutaneous doses of 300 or 1000 micrograms/kg daily for seven days, or 1000 micrograms/kg for three days when given after TNB significantly decreased lesion formation in TNB-induced colitis. These treatments also significantly reduced colonic mucosal MPO levels. TNB enhanced colonic mucosal levels of PGE2, LTB4, and TxB2, but these arachidonic acid derivatives were not affected by the present rhIL-11 treatments. TNB administration for three days caused a body weight loss that returned to normal after 14 days. The rhIL-11 significantly reduced colonic lesion severity and reduced colonic fecal blood loss. Given alone, rhIL-11 did not influence body weight. It can be concluded that rhIL-11 was protective against TNB-induced colitis and reactions of colonic MPO, but that these responses were not mediated through modulation of eicosanoid metabolism.

Animals↗
PubMed1996

Immune system-neuroendocrine dysregulation in spinal cord injury.

Multiple communicative pathways among the nervous, endocrine and immune systems facilitate physiological immunoregulation. Spinal cord injury (SCI) patients have decreased natural (NK cell) and adaptive (T cell) immune function and reduced blood levels of cellular adhesion molecules (CAMs) that participate in immune function and wound healing. We found decreased LFA-1 and VLA-4 on peripheral blood leukocytes in SCI patients and lower levels of CAMs in SCI patients with pressure ulcers than in those without them. SCI might affect immune cells and immune responsiveness by: (1) disrupting the outflow of signals from the sympathetic nervous system to lymphoid tissues and their blood vessels as well as the returning afferent signals from these tissues to the brain; (2) immunosuppression caused by the stressors affecting SCI patients; (3) interrupting returning signals to the CNS from the periphery thereby reducing facilitation of immunoregulatory CNS neurons and decreasing their activity; or a combination of all three. SCI patients may develop dysregulation of the sympathetic nervous system that is intimately involved in immune function. Chronic stress mediates immunosuppression by corticosteroids, catecholamines, endorphins and met-enkephalin. The hypothalamus coordinates the response to stress through the release of soluble products from the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Whereas the nervous and endocrine systems are not concerned with immunological specificity, they do influence the intensity, kinetics and localization of immune responses. Products of an activated immune system may generate feedback circuits capable of inhibiting, enhancing or regulating neuronal input. Immune system cells can produce neurologically active peptides including ACTH, CRF, growth hormone, thyrotropin, prolactin, human chorionic gonadotropin, endorphin, enkephalins, substance P, somatostatin and VIP. Cytokines are likely important mediators of the HPA response to immune stimuli.

Humans↗
PubMed1996

Adhesion molecules and wound healing in spinal cord injury.

The purpose of this study was to design and test a model that could identify and define which cellular adhesion molecules (CAMs) present on peripheral blood leukocytes were depressed in spinal cord injury (SCI) patients. CAMs on peripheral blood cells of SCI patients with pressure ulcers were measured by flow cytometry and compared with those of age-matched healthy controls and SCI patients on physical rehabilitation therapy (PRT) protocols without pressure ulcers. The latter patients had normal levels (97%) of lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) and a low incidence of infection. By contrast, prior to undergoing rehabilitation therapy, SCI patients with pressure ulcers had significantly diminished LFA-1 levels (62%). Very late antigen 4 (VLA-4; alpha 4 beta 1; 34%) levels (i.e., alpha 4 = 34% and beta 1 = 44%) were approximately half those in controls (72%). Expression of alpha 2 and alpha 3 was also diminished in patients. Patients receiving PRT after debridement developed increased levels of LFA-1 and VLA-4 by the 6th week but alpha 2 and alpha 3 remained relatively low. These results combined with data from previous studies suggest that patients not receiving PRT developed severe pressure ulcers which required debridement surgery and healed more slowly due, in part, to reduced levels of CAMs.

Adult↗
PubMed1995

Evaluation of recombinant human factor IX: pharmacokinetic studies in the rat and the dog.

The pharmacokinetics of intravenously administered recombinant human factor IX (rhFIX) were studied in Sprague-Dawley rats and Beagle dogs. Rats received rhFIX (50 IU/kg once daily) for 28 days, and the plasma half-life was 5 h. Anti-Human Factor IX serum antibody levels were found in only 1 of 12 rats. The pharmacokinetic profiles of rhFIX or Mononine, a purified human plasma-derived factor IX, after single 100 IU/kg i.v. doses in dogs, were similar. Peak plasma concentrations of rhFIX and Mononine were 4-5 micrograms/ml. The mean plasma half-lives were 13.2 +/- 1.6 h for rhFIX and 13.3 +/- 1.6 h for Mononine. Dogs also received rhFIX (40 IU/kg i.v., daily) for 28 days or Mononine (40 IU/kg i.v. daily) for 14 days. Anti-human Factor IX serum antibody levels were determined for each compound. Pharmacokinetic half-lives decreased in these treated dogs which developed antihuman Factor IX antibodies. The antibody responses in 28 day rhFIX (40 IU/kg) dogs were similar to 14 day Mononine (40 IU/kg) dogs.

Animals↗
PubMed1994

Ridogrel improves maternal/fetal homeostasis in an ovine model of pregnancy-induced hypertension.

The effects of ridogrel (a thromboxane synthetase inhibitor/endoperoxide receptor antagonist) were assessed in an ovine model of pregnancy-induced hypertension. Maternal serum prostacyclin and thromboxane levels were quanitiated using RIA, and maternal and neonatal coagulation status was assessed. Pregnancy and neonatal outcome were recorded. Ridogrel, (E)-5-[[[3-pyridinyl)[3-(trifluoromethyl)phenyl]methylen]amin++ +] oxy]pentanoic acid, was administered in one bolus dose at 0.1 or 1.0 mg/kg IV, three hours following the onset of a 27 hour magnesium sulfate infusion given hypertensive ewes to prevent maternal seizures. At both doses, ridogrel improved neonatal outcome (0% neonatal mortality in each ridogrel group versus 67% neonatal mortality in the magnesium sulfate group), and ridogrel at 0.1 mg/kg IV normalized birth weights. Abnormalities of maternal platelet function (abnormal or no response to collagen), occurring during the ovine syndrome, resolved following ridogrel treatment. Ridogrel's effects on maternal and neonatal coagulation were more dramatic at the 0.1 mg/kg IV dose. Ridogrel appeared to be beneficial in this model of pregnancy-induced hypertension.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology.

Recombinant human interleukin 11 (rhIL-11) is a pleiotropic cytokine that stimulates bone marrow stem cells to proliferate and decreases intestinal mucosal injury produced by cytoablative drugs and radiation in animals. The effects of rhIL-11 were studied in a hamster model of oral mucositis and in two rat models of inflammatory bowel disease (IBD). Oral mucositis was induced in male Golden Syrian hamsters with 5-fluorouracil 60 mg/kg intraperitoneal, days 0 and 2. Peak mucositis occurred by day 10 in vehicle treated animals. rhIL-11, given twice daily subcutaneously, decreased the mucositis in a dose-dependent manner and increased animal survival at all doses tested. In two models of IBD, the acetic acid-induced acute colonic injury model in Sprague-Dawley rats and the transgenic Fischer 344 rats expressing human HLA-B27 and beta 2-microglobulin, rhIL-11 decreased the gross and microscopic damage in the colons of these animals. These data suggest that rhIL-11 exerts effects on the gastrointestinal mucosa which ameliorate responses to injurious stimuli.

Acetates↗
PubMed1993

Effects of ridogrel on the prostacyclin-thromboxane ratio in nulliparous third trimester-pregnant rhesus monkeys.

The effects of ridogrel, a thromboxane synthetase inhibitor and endoperoxide receptor antagonist, were studied in twelve pregnant, nulliparous Rhesus monkeys (Macaca mulatta) during the last trimester of pregnancy. Ridogrel was administered intravenously in two groups of animals (n = 6), at either 0.1 mg/kg or 1.0 mg/kg. Ultrasonic assessment of the fetuses during and after the infusion period revealed no obvious changes in fetal condition. Both dosages reduced serum thromboxane levels 30 minutes after administration, 96.6% and 99.6% suppression, 0.1 mg/kg and 1.0 mg/kg, respectively (P < 0.0001), while the 1.0 mg/kg dose produced continued suppression for 24 hours (78% suppression, P < 0.0001) and was lower than the 0.1 mg/kg 24 hour value (P < 0.008). Prostacyclin levels increased to 340% and 472% of baseline values, 0.1 mg/kg and 1.0 mg/kg, respectively at 30 minutes and to 928% and 255% of baseline at 24 and 48 hours after treatment in the 1.0 mg/kg group (P < 0.0003). Ridogrel caused no changes in maternal or neonatal outcome. The potential for the use of this compound for the treatment of preeclampsia is discussed.

6-Ketoprostaglandin F1 alpha↗