scholarly journals PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy.

1994 ◽  
Vol 180 (1) ◽  
pp. 283-296 ◽  
Author(s):  
V P Vallat ◽  
P Gilleaudeau ◽  
L Battat ◽  
J Wolfe ◽  
R Nabeya ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Interleukin 2 ◽  
Epidermal Keratinocytes ◽  
Therapeutic Effects ◽  
Sustained Remission ◽  
Puva Therapy ◽  
Cellular Basis ◽  
Bath Therapy ◽  
Puva Treatment

Psoriasis is characterized by alterations in both the epidermis and dermis of the skin. Epidermal keratinocytes display marked proliferative activation and differentiate along an "alternate" or "regenerative" pathway, while the dermis becomes infiltrated with leukocytes, particularly interleukin 2 (IL-2) receptor-bearing "activated" T cells. Psoralens, administered by the oral route, have therapeutic effects in psoriasis when photochemically activated by ultraviolet A light (PUVA therapy). Recently psoralen bath therapy has been introduced to more effectively deliver this agent to the diseased skin. We have correlated the efficacy of PUVA bath therapy with its effects on specific molecular and cellular parameters of disease, in 10 consecutive patients with recalcitrant psoriasis. Rapid clearing of lesions occurred in 8 out of 10 patients. Biopsies were taken from lesional and nonlesional skin before and after a single round of therapy, and observation was continued in our Clinical Research Center at The Rockefeller University. Enumeration of cycling keratinocytes with the Ki-67 monoclonal antibody showed that PUVA reduced cell proliferation by 73%. The pathological increase in insulin-like growth factor 1 (IGF-1) receptors was reversed, whereas epidermal growth factor (EGF) receptors, which are also increased in psoriasis, remained unchanged. Keratinocyte proteins that are expressed in abnormal sites of the epidermis during psoriasis, i.e., keratin 16, filaggrin, and involucrin, were, after PUVA treatment, localized to their normal sites. Epidermal and dermal T-lymphocytes (CD3+), as well as CD4+, CD8+, and IL-2 receptor+ subsets, were strongly suppressed by PUVA, with virtual elimination of IL-2 receptor+ T cells in some patients. Consistent with diminished lymphocyte activation, HLA-DR expression by epidermal keratinocytes was markedly reduced in treated skin. In comparison to cyclosporine treatment of psoriasis, PUVA therapy leads to more complete reversal of pathological epidermal and lymphocytic activation, changes which we propose to be the cellular basis for a more sustained remission of disease after PUVA treatment.

scholarly journals Identification of transforming growth factor-beta as a contaminant in factor VIII concentrates: a possible link with immunosuppressive effects in hemophiliacs

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 2021-2030
Author(s):  
M Wadhwa ◽  
P Dilger ◽  
J Tubbs ◽  
A Mire-Sluis ◽  
T Barrowcliffe ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Factor Viii ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Contributory Factor ◽  
Tgf Beta ◽  
Factor Viii Concentrates ◽  
Growth Factor Beta

In previous studies, we have shown that some, but not all low-, intermediate-, and high-purity factor VIII concentrates inhibit interleukin-2 (IL-2) secretion from phytohemagglutinin (PHA)-stimulated T lymphocytes. We now present evidence that this inhibitory action of concentrates is, at least in part, due to contamination with transforming growth factor-beta (TGF-beta). Originally identified in platelets, TGF-beta is a 25-kD homodimer that has been shown to be a natural and potent inhibitor of many immunologic responses. Using a specific bioassay, we have measured TGF-beta in various factor VIII concentrates. While some concentrates contained substantial amounts of the cytokine, there was a wide variation in concentrations of TGF-beta in different products. These levels correlated with the degree of inhibition of IL-2 secretion from T cells exhibited by each product (P = .0001). Noninhibitory concentrates contained no detectable TGF-beta. Addition of a specific TGF-beta 1 antibody reversed the inhibitory effect of some concentrates on IL-2 secretion by PHA-stimulated Jurkat T cells and interleukin-5 (IL-5)-induced proliferation of an erythroleukemic cell line. These findings suggest that TGF-beta contamination is a major contributory factor to the inhibitory activity of some factor VIII concentrates on cytokine secretion or activity, and may partially explain the reported immunosuppressive effects in recipients of these blood products.

scholarly journals Dendritic cells initiate a two-stage mechanism for T lymphocyte proliferation.

1983 ◽  
Vol 157 (4) ◽  
pp. 1101-1115 ◽  
Author(s):  
J M Austyn ◽  
R M Steinman ◽  
D E Weinstein ◽  
A Granelli-Piperno ◽  
M A Palladino
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Interleukin 2 ◽  
Two Stage ◽  
Second Stage ◽  
T Lymphocyte Proliferation ◽  
Accessory Function ◽  
Accessory Cells ◽  
Cell Medium

T cells oxidized with sodium periodate proliferate polyclonally in response to accessory cells. We confirmed previous work showing that DC are potent stimulators of this response. In addition, the accessory function of unfractionated mouse spleen and spleen adherent cells was markedly reduced after elimination of DC with a specific monoclonal antibody and complement. Therefore oxidative mitogenesis was used as a model to study the mechanism by which DC stimulate T cell proliferative responses. A two-stage mechanism was identified. The first stage occurred during the first 20 h of culture, required live DC, and involved the progressive release of interleukin 2 (IL-2) into the medium and acquisition of responsiveness to this growth factor. The second stage occurred between 20 and 40 h, did not require live DC, and involved DNA synthesis in response to IL-2. Similar events occurred during culture of DC with unmodified T cells (syngeneic MLR) but were quantitatively reduced. The experimental approach was to co-culture DC and T cells for up to 20 h and then kill the DC with specific antibody, or anti-Ia antibody, and complement. Subsequent proliferation was inhibited if the T cells were cultured in fresh medium. However, proliferation was restored when the lymphocytes were cultured in the original DC-T cell medium, or with a crude or a purified preparation of IL-2. IL-2 did not induce the proliferation of T cells that had been cultured in the absence of DC, and did not synergize with viable DC. We conclude that DC induce proliferation by tightly coordinating the release of, and responsiveness to, T cell growth factor or IL-2.

scholarly journals Examining the effector mechanisms of Xuebijing Injection on COVID-19 based on network pharmacology

2020 ◽  
Author(s):  
Wenjiang Zheng ◽  
Qian Yan ◽  
Yongshi Ni ◽  
Shaofeng Zhan ◽  
Liuliu Yang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Cellular Response ◽  
Interleukin 2 ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Therapeutic Effects ◽  
Active Ingredients ◽  
Effector Mechanisms

Abstract Objective To examine the potential effector mechanisms of Xuebijing (XBJ) on coronavirus disease 2019 (COVID-19) based on network pharmacology.Methods We searched Chinese and international papers to obtain the active ingredients of XBJ. Then, we compiled COVID-19 disease targets from the GeneCards gene database and via literature searches. Next, we used the SwissTargetPrediction database to predict XBJ’s effector targets and map them to the abovementioned COVID-19 disease targets in order to obtain potential therapeutic targets of XBJ. Cytoscape software version 3.7.0 was used to construct a “XBJ active-compound–potential-effector target” network and protein–protein interaction (PPI) network, and then to carry out network topology analysis of potential targets. We used the ClueGO and CluePedia plugins in Cytoscape to conduct gene ontology (GO) Biological Process (BP) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis of XBJ’s effector targets.Results We obtained 147 potential COVID-19 effector targets of XBJ. Fourteen of these targets—glyceraldehyde 3-phosphate dehydrogenase (GAPDH), albumin (ALB), tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), Caspase-3 (CASP3), signal transducer and activator of transcription 3 (STAT3), MAPK8, prostaglandin-endoperoxide synthase 2 (PTGS2), JUN, interleukin-2 (IL-2), Estrogen Receptor 1 (ESR1), and MAPK14—had degree values > 40 and therefore could be considered key targets. They participated in extracellular signal–regulated kinase 1 and 2 (ERK1, ERK2) cascade, the T-cell receptor signaling pathway, activation of MAPK activity, cellular response to lipopolysaccharide (LPS), and other inflammation- and immune-related BPs. XBJ exerted its therapeutic effects through the renin–angiotensin system (RAS), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), MAPK, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)–protein kinase B (Akt)–vascular endothelial growth factor (VEGF), toll-like receptor (TLR), TNF, and inflammatory-mediator regulation of transient receptor potential (TRP) signaling pathways to ultimately construct a “ingredient–target–pathway” effector network. Conclusion: The active ingredients of XBJ regulated different genes, acted on different pathways, and synergistically produced anti-inflammatory and immune-regulatory effects, which fully demonstrated the synergistic effects of different components on multiple targets and pathways. The results of this study validated current pharmacological mechanistic studies of XBJ in the treatment of sepsis and severe pneumonia and could better explain XBJ’s effector mechanisms in the clinical treatment of COVID-19.

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