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C A Armstrong

Publications and source records attributed to C A Armstrong.

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

Depletion of NK cell activity results in growth of hepatic micrometastases in a murine ocular melanoma model.

PURPOSE: To study the role of natural killer (NK) cells in growth of spontaneous hepatic metastasis in a murine intraocular melanoma model. METHODS: Tissue culture B16-LS9 melanoma cells were analyzed by flow cytometry for MHC class I expression of all haplotypes and inoculated into the posterior compartment (PC) of one eye of C57BL6 mice. The eyes were enucleated at 12 days post-inoculation and histologically examined for tumor growth. One group of mice (n = 10) were given intraperitoneal injections of anti-asialo GM1 for NK cell depletion post-enucleation and a second group of mice (n = 9) served as controls. The mice were sacrificed at 24 days post-inoculation and necropsies were performed to determine the number and size of metastasis. RESULTS: The B16-LS9 cells failed to express MHC class I antigen. Tumor grew in the PC of all eyes and metastasized to the lungs and livers of all mice, with the average number of hepatic micrometastases greater in the NK depleted group versus the control group (p =.009). There was no significant difference in the average number of pulmonary metastases in the treated versus the control group (p =.072). Hepatic metastases grew to an average diameter of 600 microm in diameter in two NK depleted mice. CONCLUSIONS: NK depletion in this model of metastatic ocular melanoma results in increased number and growth of hepatic micrometastases.

Animals↗
PubMed1998

Inhibition of murine melanoma growth by granulocyte-macrophage colony stimulating factor gene transfection is not haplotype specific.

Granulocyte-macrophage colony stimulating factor (GM-CSF) has been shown to inhibit the growth and progression of murine melanoma cells in syngeneic C57BL/6 (H-2b) recipient animals. We now demonstrate that this effect is not specific to melanomas derived from a single strain of mice by examining the subcutaneous growth of K1735 murine melanoma cells (H-2k) transfected with GM-CSF in a syngeneic mouse model. Non-GM-CSF-secreting melanoma cells (parental K1735 and K1735 cells transfected with the GM-CSF gene in antisense orientation) generated tumours that reached a mean volume of 4000 mm3 30-40 days, with a mean survival of 40 days after tumour cell injection. In contrast, 90% of the mice injected with three different clones of GM-CSF-producing K1735 melanomas developed no measurable tumours and were healthy and tumour-free when followed for over 300 days post-inoculation. Additionally, mice injected with GM-CSF-secreting K1735 cells developed long-lasting immunity to the parental melanoma cell line challenge in vivo. A dense neutrophilic and lymphocytic inflammatory infiltrate as well as large numbers of dendritic cells were detected only at the inoculation sites of the GM-CSF-producing melanoma cells. Thus, these studies demonstrate for the first time that GM-CSF inhibits melanoma growth in a second genetically distinct MHC tumour-host model system and further support the use of GM-CSF in clinical trials in the treatment of advanced malignant melanoma in humans.

Animals↗
PubMed1998

In vivo human melanoma cytokine production: inverse correlation of GM-CSF production with tumor depth.

Melanomas produce multiple cytokines which may influence their growth in vivo. Experimental evidence suggests that granulocyte macrophage-colony stimulating factor (GM-CSF) can induce a potent anti-melanoma response. whereas interleukin-8 (IL-8) may act as a growth factor in human melanoma. Little is currently known regarding the production of these cytokines by human melanoma in vivo. In this study we tested the hypothesis that endogenous production of GM-CSF and IL-8 can be correlated with the depth of human malignant melanoma surgical specimens. We examined 45 melanocytic human tissue samples consisting of 27 primary cutaneous melanomas, 9 metastatic melanomas, and 9 dysplastic nevi for in vivo GM-CSF and IL-8 production using immunohistochemistry. The majority of thin melanomas (< or = 0.76 mm) stained highly positive for GM-CSF with little or no staining for IL-8 whereas the medium (>0.76- < or = 4.0 mm) and thick (>4.0 mm) melanoma specimens showed little or no staining for GM-CSF and significant amounts of IL-8 staining. Metastatic melanoma as well as dysplastic nevi specimens had little or no GM-CSF and IL-8 staining. These results support the hypothesis that endogenous melanoma cytokines such as GM-CSF and IL-8 with opposing effects on tumor progression play an important role in melanoma growth and regulation.

Biomarkers, Tumor↗
PubMed1998

Neuropeptide regulation of human dermal microvascular endothelial cell ICAM-1 expression and function.

There is increasing evidence that sensory nerves may participate in cutaneous inflammatory responses by the release of neuropeptides such as substance P (SP). We examined the direct effect of SP on human dermal microvascular endothelial cell (HDMEC) intercellular adhesion molecule 1 (ICAM-1) expression and function. Our results indicated that, although cultured HDMEC expressed mRNA for neurokinin receptors 1, 2, and 3 (NK-1R, NK-2R, and NK-3R), SP initiated a rapid increase in HDMEC intracellular Ca2+ levels, primarily by the activation of NK-1R. Immunohistochemistry studies likewise demonstrated that HDMEC predominantly expressed NK-1R. The addition of SP to HDMEC resulted in a rapid increase in cellular ICAM-1 mRNA levels, followed by a fivefold increase in ICAM-1 cell surface expression. This functionally resulted in a threefold increase in 51Cr-labeled binding of J-Y lymphoblastoid cells to HDMEC. In vivo studies demonstrated a marked increase in microvascular ICAM-1 immunostaining 24 and 48 h after application of capsaicin to the skin. These results indicate that neuropeptides such as SP are capable of directly activating HDMEC to express increased levels of functional ICAM-1 and further support the role of the cutaneous neurological system in modulating inflammatory processes in the skin.

Capsaicin↗
PubMed1998

A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire.

BACKGROUND: The development of effective adjuvant therapies for the treatment of high-risk melanoma patients is critical for the prevention of metastatic disease and improvement of patient survival. Active specific immunotherapy has been tested as an adjuvant treatment in numerous clinical trials with overall limited, but occasionally promising, success rates. Newcastle disease virus (NDV) oncolysate has been utilized as an adjunctive immunotherapeutic agent in the postsurgical management of these patients. A phase II study initiated in 1975 using adjuvant vaccine therapy composed of allogeneic and autologous human melanoma cells infected with live NDV (NDV oncolysate) in patients with AJCC stage III melanoma following therapeutic lymph node dissection has shown >60% survival rate at 10 years with no adverse effects. Continued long-term analysis of trials with promising early results as well as assessment of immunologic responses generated in these patients may result in improved therapeutic decisions for clinical trials in the future. MATERIALS AND METHODS: We analyzed the 15-year survival of patients treated postsurgically with NDV oncolysate in the phase II study described above. In an attempt to understand the immunological effects of this treatment, we have also carried out a comprehensive analysis of the peripheral blood T cell repertoire in these patients. RESULTS: The overall 15-year survival of this group of patients is 55%. Previous studies have suggested that improved outcome in patients undergoing immunotherapy is correlated with increased numbers of CD8(+)CD57(+) cells. In surviving patients, we observed a striking oligoclonality in the CD8(+) T cell population in peripheral blood, which reflects clonal expansions in the CD8(+)CD57(+) subset. CONCLUSIONS: The data suggest that adjuvant vaccination with NDV oncolysates is associated with prolonged survival of patients with lymph node-positive malignant melanoma and that CD8(+) T cells may be an important component of therapeutic efficacy.

Adult↗
PubMed1997

Interactions of the skin and nervous system.

There is increasing experimental evidence that the neurologic system can directly participate in cutaneous inflammation and wound healing. Recent studies indicate that neuropeptides released by cutaneous nerves such as c-fibers can activate a number of target cells including keratinocytes, Langerhans cells, mast cells, and endothelial cells. One such neuropeptide, substance P (SP), is able to specifically bind to murine and human keratinocytes and induce the release of cytokines such as interleukin 1 (IL-1). Other studies demonstrate that SP can also activate mast cells to produce the potent pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha). More recently, we examined the effect of cutaneous neuropeptides on human dermal microvascular endothelial cell (HDMEC) activities. Our studies indicate that the c-fiber-derived calcitonin gene-related peptide (CGRP) is capable of stimulating HDMEC to secrete the neutrophil chemotactic factor interleukin 8 (IL-8). In addition, SP is able to directly activate HDMEC to express high levels of the important cellular adhesion molecule vascular cellular adhesion molecule 1 (VCAM-1). Thus, these studies support the role that the neurologic system may play in mediating the biologic processes that occur during inflammation and wound healing in the skin.

Animals↗
PubMed1997

Ultraviolet irradiation induces the production of multiple cytokines by human corneal cells.

PURPOSE: Ultraviolet (UV) irradiation exposure represents a significant environmental and occupational hazard that can cause acute and chronic inflammatory changes in the exposed cornea. Acute exposure to solar UV irradiation or to UV irradiation from such artificial sources as tanning lamps can result in severe pain and inflammation in the cornea. Chronic exposure to solar UV irradiation is associated with several external eye diseases including pterygium and squamous metaplasia or carcinoma. In the skin, inflammatory responses to UV exposure appear to be mediated by the release of inflammatory cytokines. The role of corneal-derived cytokines in UV-mediated corneal inflammation has not been established. In this study, the effect of UV exposure on the production of proinflammatory cytokines by corneal cells was examined. METHODS: Cultured human corneal stroma cells and whole human corneas received UV irradiation (10 to 100 mJ/cm2), and the production of the proinflammatory cytokines interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor alpha (TNF alpha) was measured by Northern blot analysis, enzyme-linked immunosorbent assay, cytokine bioassays, and immunohistochemical analysis. RESULTS: The results indicate that acute UV exposure leads to a significant increase in the production of IL-1, IL-6, IL-8, and TNF alpha in human corneal stroma cells. Similarly, acute UV irradiation of whole human corneas ex vivo induces a significant increase in the production of IL-1, IL-6, IL-8, and TNF alpha. CONCLUSIONS: Acute UV irradiation exposure results in the induction of cornea-derived proinflammatory cytokines. The local release of these proinflammatory cytokines by cells in the irradiated cornea may be responsible for UV-mediated corneal inflammation.

Blotting, Northern↗
PubMed1996

Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells.

The use of immunomodulating gene therapy in the treatment of malignant disease is under intensive investigation. In this study, we examined the potential of melanoma-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) to inhibit melanoma progression in a murine model. The HGH18 murine melanoma cell line was transfected with the murine GM-CSF gene in a SV40 expression vector that resulted in melanoma clones that produced varying amounts of GM-CSF. Syngeneic mice inoculated s.c. with HFH18 parental melanoma cells or HFH18 cells transfected with the GM-CSF gene n the noncoding 3'-5' orientation [HFH18/GM-CSF(-) cells] develop large tumors that reach a mean tumor volume of 3300 mm3 by day 30. In contrast, animals inoculated with two melanoma clones producing high levels of GM-CSF [HFH18/GM-CSF(++) and HFH18/GM-CSF(+ + +)] either completely reject the tumor cells or develop tumors with a mean volume of only 40 mm3. In comparison, animals inoculated with a melanoma clone producing low levels of GM-CSF [HFH18/GM-CSF(+)] develop large tumors averaging 2000 mm3, thus demonstrating a dose-response effect of tumor inhibition by melanoma-derived GM-CSF. Additionally, vaccination with irradiated GM-CSF-producing melanoma cells conferred optimal immunogenicity against a subsequent challenge with HFH18 cells. Tissue sections from excised GM-CSF-producing tumor cell inoculation sites but not from HFH18 parental or HFH18/GM-CSF(-) inoculation sites demonstrate a dense inflammatory infiltrate composed of neutrophils, tissue macrophages, and numerous CD4- and CD8-positive lymphocytes but few melanoma cells. Large numbers of dendritic cells and cells expressing the B7-2 costimulatory molecule are detected only within HFH18/GM-CSF(+ + +) melanoma inoculation sites. Our results lend further support to clinical trials of GM-CSF gene therapy in the treatment of advanced malignant melanoma, possibly by the recruitment of dendritic antigen-presenting cells.

Animals↗
PubMed1995

Novel production of interleukin-1 receptor antagonist peptides in normal human cornea.

Interleukin-1 receptor antagonist (IL-1ra) is an important modulator of IL-1 activity in a variety of tissues. IL-1ra is differentially produced by different cell types as a 22-26-kD secreted peptide (sIL-1ra) and/or a smaller 16- or 18-kD intracellular peptide (icIL-1ra). This study was undertaken to evaluate the production of IL-1ra in the human cornea. IL-1ra mRNA can be detected in early passage human corneal epithelial cells and corneal stromal fibroblasts and is significantly enhanced by IL-1. Corneal endothelial cells do not express IL-1ra mRNA. Immunohistochemical studies of cultured corneal cells and whole human cornea demonstrate IL-1ra protein production by both the epithelial and stromal cells but not the endothelial cells. Reverse transcriptase polymerase chain reaction, ELISA, and immunoprecipitation studies indicate that corneal epithelial cells are capable of producing both icIL-1ra and sIL-1ra forms of IL-1ra whereas the corneal stromal cells produce only icIL-1ra. In addition to the larger 18-kD icIL-1ra, both corneal epithelial and stromal cells are also capable of producing a smaller recently described 16-kD icIL-1ra. Thus, the differential production of IL-1ra in the human cornea is unique; whereas both epithelial and stromal cells produce icIL-1ra (type 1 and type 2), the epithelial cells appear to also produce sIL-1ra. It is proposed that these IL-1ra proteins may play an important role in regulating IL-1-induced corneal inflammation.

Adult↗
PubMed1994

Spatial-frequency-tuned channels in early infancy: VEP evidence.

Spatial frequency (SF) adaptation of 3-, 6-, and 12-week-old infants produced changes in steady-state VEP amplitude to SF sweeps that closely resemble post-adaptation changes reported previously in adults. Following SF adaptation, VEP amplitude was attenuated to SFs near the adapting SF, and enhanced at SFs removed from the adapting SF in all age groups. This is interpreted as evidence for bandpass SF-tuned channels with coinhibitory interactions. The data presented here, in combination with VEP estimates of infant acuity, imply the existence of multiple bandpass SF-tuned channels with inhibitory relationships by 3 weeks of age. We hypothesize that neonatal spatial frequency filters are qualitatively adultlike.

Adaptation, Ocular↗
PubMed1994

Melanoma-derived interleukin 6 inhibits in vivo melanoma growth.

Malignant melanomas are capable of producing a wide range of cytokines with multiple biologic functions, including interleukin 6 (IL-6). We have observed an inverse relationship between IL-6 production of three B16-derived murine melanoma cell lines (NP133, HFH18, and HFH(M)) and the tumorigenicity of these melanoma cells in syngeneic mice. To further test the effect of IL-6 on melanoma growth, a non-IL-6-producing murine B16-derived melanoma cell line (HFH18) was transfected with a murine IL-6 expression vector, resulting in stable transfectants (HFH18/IL-6(+)) that expressed significant amounts of IL-6 mRNA and secreted high levels of bioactive IL-6. Syngeneic C57BL/6 mice inoculated subcutaneously with HFH18/IL-6(+) cells developed tumors that reached a final mean diameter of less than half the size of tumors that developed in mice inoculated with either HFH18 parental or HFH18 cells transfected with the IL-6 cDNA in the non-coding 3'-5' orientation (HFH18/IL-6(-) cells). In addition, mice bearing IL-6-producing HFH18/IL-6(+) tumors survived twice as long as mice bearing HFH18 parental or HFH18/IL-6(-) tumors. The specificity of melanoma growth inhibition by IL-6 was confirmed by the reversal of the slow-growing phenotype of HFH18/IL-6(+) cells by local peritumoral administration of neutralizing alpha-murine IL-6 antibody. IL-6-producing melanoma cells exerted a growth-inhibitory effect on distant parental tumors in a dose-dependent manner. The growth of HFH18/IL-6(+) melanomas was also decreased in nude mice, suggesting that melanoma-derived IL-6 may mediate this anti-tumor effect independently of a normal host B- and T-cell immune response. Thus, melanoma-derived IL-6 exerts a significant inhibitory effect on cutaneous melanoma growth and progression. These results indicate that melanoma cytokines may have a profound effect on tumor pathogenesis.

Animals↗
PubMed1994

The skin as an immune organ.

As a protective interface between internal organs and the environment, the skin encounters a host of toxins, pathogenic organisms, and physical stresses. To combat these attacks on the cutaneous microenvironment, the skin functions as more than a physical barrier: it is an active immune organ. Immune responses in the skin involve an armamentarium of immune-competent cells and soluble biologic response modifiers including cytokines. Traversed by a network of lymphatic and blood vessels, the dermis contains most of the lymphocytes in the skin, other migrant leukocytes, mast cells, and tissue macrophages. Although the epidermis has no direct access to the blood or lymphatic circulation, it is equipped with immune-competent cells: Langerhans cells, the macrophage-like antigen-presenting cells of the epidermis; keratinocytes, epithelial cells with immune properties; dendritic epidermal T lymphocytes, resident cells that may serve as a primitive T-cell immune surveillance system; epidermotropic lymphocytes, migrants from vessels in the dermis; and melanocytes, epidermal pigment cells with immune properties. Although the components of the epidermis and dermis work in concert to execute immune responses in the skin, for purposes of this review, we focus on the cells and cytokines of the epidermal immunologic unit, the frontline of immune protection against environmental toxins and microbes.

Animals↗
PubMed1992

Heterogeneity of cytokine production by human malignant melanoma cells.

Recent investigations indicate that malignant melanoma cells can produce distinct cytokines. While differences in the production of single cytokines have been observed among different melanoma cell lines, the extent of variability in the production of single and multiple cytokines between individual melanoma cell lines has not been as thoroughly investigated. A heterogeneity in melanoma cell cytokine production could have important implications for the biology of this aggressive neoplasm since certain cytokines may act as autocrine growth factors or be potent modulators of host immune response to the developing tumor. The purpose of this study is to assess the cytokine production profile of two widely available human melanoma cell lines, A375 and G361. The A375 cell line constitutively expressed the mRNA for IL-1 alpha, IL-1 beta and PDGF-A, with increased expression of these cytokines after induction with PMA. GM-CSF mRNA was expressed by the A375 melanoma line only after induction with PMA. No IL-6 mRNA was detected in the A375 melanoma cell line. The cell culture supernatants from the A375 cells likewise contained a parallel increase in IL-1 activity as determined in the D10 bioassay and secreted GM-CSF and PDGF-AA as measured by ELISA. In contrast, the G361 cell line did not express IL-1, GM-CSF or PDGF-A mRNA (constitutively or after PMA induction) but expressed only IL-6 mRNA and secreted IL-6 activity after PMA induction. These results demonstrate a significant heterogeneity in the production of IL-1 alpha, IL-1 beta, IL-6, GM-CSF, and PDGF in two distinct melanoma cell lines. This study demonstrates that individual melanoma cell lines express and secrete multiple cytokines both constitutively and after stimulation with PMA. The immunodulating and mitogenic properties of these melanoma-derived cytokines may have implications in determining the biologic behavior of different malignant melanomas.

Cytokines↗
PubMed1991

Spatial-frequency-tuned attenuation and enhancement of the steady-state VEP by grating adaptation.

Steady-state visual evoked potentials (VEPs) were recorded from adults using 10% C fast spatial frequency (SF) sweeps of horizontal gratings under two conditions: (a) after exposure to a 40% C grating of 6 or 4 c/deg, and (b) after exposure to a blank screen equalling the adapting gratings in space-averaged luminance. SF adaptation attenuated VEP amplitude near the adapting SF, but maximum attenuation was displaced from the adapting SF for 6 c/deg adaptation. Small displacements in maximum attenuation would be expected if underlying neural subunits are tuned to a small number of different center SFs. In addition, SF adaptation caused amplitude enhancement 1.0-2.0 octaves below the adapting SF, providing electrophysiological evidence in humans for coinhibitory relationships among neural mechanisms that have been postulated on the basis of analogous psychophysical findings. The results are consistent with coinhibition between SF-tuned subunits and between transient and sustained mechanisms.

Adaptation, Ocular↗