Dehydroepiandrosterone modulates T-cell response after major abdominal surgery

Background

The immune balance controlled by T-helper (Th)1 and Th2 cells is critical in protecting the host from pathogenic invasion, and its imbalance may increase susceptibility to infection in patients undergoing major surgery. The differentiation of naive T cells to Th1 and Th2 cells is largely driven by cytokines. In addition, steroid hormones have been shown to affect Th1/Th2 balance, particularly in autoimmune diseases. The regulation of Th1/Th2 balance in patients undergoing surgery and its potential clinical relevance remain unclear.

Materials and methods

Blood samples were obtained from patients both before and 2 h after major abdominal surgery. Peripheral blood mononuclear cells were isolated and cultured in wells coated with either anti-CD3 (direct T-cell stimulation) or phytohemagglutinin (PHA) (indirect T-cell stimulation), with or without 10⁻⁵ M dehydroepiandrosterone (DHEA). The release of interleukin (IL)-2, interferon gamma, and IL-10 was measured by an enzyme-linked immunosorbent assay, and the expression of CD4, CD8, and CD69 was determined by flow cytometry.

Results

DHEA decreased the release of IL-2 and IL-10 in directly (anti-CD3) and indirectly (PHA)-stimulated T cells from postoperative samples, whereas the release of interferon gamma in PHA-stimulated T cells was not affected. The distribution of CD4/CD8 was not significantly different after surgery or DHEA. DHEA was associated with a decrease in the expression of the activation marker CD69 on CD4⁺ T cells, whereas the activation of CD8⁺ T cells remained unchanged.

Conclusions

These results demonstrate that DHEA plays a critical role in controlling Th1/Th2 balance in the immediate postoperative period. Attenuation of both the Th1 and Th2 responses has been suggested to have immunoprotective effects. The role of DHEA in the regulation of Th1/Th2 balance in patients undergoing major abdominal surgery may, therefore, also be of significant clinical relevance and warrants further investigation.     

The promotion of a constructive macrophage phenotype by solubilized extracellular matrix

The regenerative healing response of injured skeletal muscle is dependent upon a heterogeneous population of responding macrophages, which show a phenotypic transition from the pro-inflammatory M1 to the alternatively activated and constructive M2 phenotype. Biologic scaffolds derived from mammalian extracellular matrix (ECM) have been used for the repair and reconstruction of a variety of tissues, including skeletal muscle, and have been associated with an M2 phenotype and a constructive and functional tissue response. The mechanism(s) behind in-vivo macrophage phenotype transition in skeletal muscle and the enhanced M2:M1 ratio associated with ECM bioscaffold use in-vivo are only partially understood. The present study shows that degradation products from ECM bioscaffolds promote alternatively activated and constructive M2 macrophage polarization in-vitro, which in turn facilitates migration and myogenesis of skeletal muscle progenitor cells.     

Integrin-directed modulation of macrophage responses to biomaterials

Macrophages are the primary mediator of chronic inflammatory responses to implanted biomaterials, in cases when the material is either in particulate or bulk form. Chronic inflammation limits the performance and functional life of numerous implanted medical devices, and modulating macrophage interactions with biomaterials to mitigate this response would be beneficial. The integrin family of cell surface receptors mediates cell adhesion through binding to adhesive proteins nonspecifically adsorbed onto biomaterial surfaces. In this work, the roles of integrin Mac-1 (α_Mβ₂) and RGD-binding integrins were investigated using model systems for both particulate and bulk biomaterials. Specifically, the macrophage functions of phagocytosis and inflammatory cytokine secretion in response to a model particulate material, polystyrene microparticles were investigated. Opsonizing proteins modulated microparticle uptake, and integrin Mac-1 and RGD-binding integrins were found to control microparticle uptake in an opsonin-dependent manner. The presence of adsorbed endotoxin did not affect microparticle uptake levels, but was required for the production of inflammatory cytokines in response to microparticles. Furthermore, it was demonstrated that integrin Mac-1 and RGD-binding integrins influence the in vivo foreign body response to a bulk biomaterial, subcutaneously implanted polyethylene terephthalate. A thinner foreign body capsule was formed when integrin Mac-1 was absent (∼30% thinner) or when RGD-binding integrins were blocked by controlled release of a blocking peptide (∼45% thinner). These findings indicate integrin Mac-1 and RGD-binding integrins are involved and may serve as therapeutic targets to mitigate macrophage inflammatory responses to both particulate and bulk biomaterials.     

Engineering vaccines and niches for immune modulation

Controlled modulation of immune response, especially the balance between immunostimulatory and immunosuppressive responses, is critical for a variety of clinical applications, including immunotherapies against cancer and infectious diseases, treatment of autoimmune disorders, transplant surgeries, regenerative medicine, prosthetic implants, etc. Our ability to precisely modify both innate and adaptive immune responses could provide new therapeutic directions in a variety of diseases. In the context of vaccines and immunotherapies, the interplay between antigen-presenting cells (e.g. dendritic cells and macrophages), B cells, T helper and killer subtypes, and regulatory T- and B-cell responses is critical for generating effective immunity against cancer, infectious diseases and autoimmune diseases. In recent years, immunoengineering has emerged as a new field that uses quantitative engineering tools to understand molecular-, cellular- and system-level interactions of the immune system and to develop design-driven approaches to control and modulate immune responses. Biomaterials are an integral part of this engineering toolbox and can exploit the intrinsic biological and mechanical cues of the immune system to directly modulate and train immune cells and direct their response to a particular phenotype. A large body of literature exists on strategies to evade or suppress the immune response in implants, transplantation and regenerative medicine. This review specifically focuses on the use of biomaterials for immunostimulation and controlled modulation, especially in the context of vaccines and immunotherapies against cancer, infectious diseases and autoimmune disorders. Bioengineering smart systems that can simultaneously deliver multiple bioactive agents in a controlled manner or can work as a niche for in situ priming and modulation of the immune system could significantly enhance the efficacy of next-generation immunotherapeutics. In this review, we describe our perspective on the important design aspects for the development of biomaterials that can actively modulate immune responses by stimulating receptor complexes and cells, and delivering multiple immunomodulatory biomolecules.     

Experimental immunotherapeutic approaches for atherosclerosis

Therapeutic options in atherosclerosis have largely been limited to the control of risk factors, such as hypercholesterolemia, hypertension, or diabetes. However, atherosclerosis is a chronic inflammatory disease in which dyslipidemia and inflammation are equally involved in disease pathogenesis. Moreover, abundant epidemiological and experimental evidence point to an important modulatory role of innate and adaptive immunity in atherogenesis, providing novel therapeutic targets for this disease. Indeed, there is now accumulating data in animal models demonstrating the potential for immunotherapeutic approaches to treat atherosclerosis. These include both general and antigen-specific ways of modulating immune functions, and they show great promise for the development of alternative and/or adjuvant therapies for atherosclerosis.     

苦参碱对免疫功能低下小鼠免疫功能的影响

目的观察苦参碱对免疫低下小鼠免疫功能的影响,寻找苦参碱治疗慢性乙型肝炎的可能机制。方法采用环磷酰胺建立免疫低下小鼠模型,小鼠腹腔注射苦参碱后,观察苦参碱对小鼠网状内皮系统吞噬廓清能力、对T淋巴细胞酯酶染色率、对二硝基氯苯所致迟发型超敏反应的影响、和对小鼠血清溶血素抗体的影响。结果苦参碱能抑制T淋巴细胞酯酶染色率,增强网状内皮系统的吞噬能力,但对迟发型超敏反应和血清溶血素抗体无明显影响。结论苦参碱对免疫低下小鼠的细胞免疫具有明显抑制作用,并增强其非特异性免疫。     

A synthetic heparin-mimicking polyanionic compound inhibits central nervous system inflammation

The immunomodulating capacity of heparin led us to test the effect of the synthetic heparin-mimicking and low anticoagulant compound RG-13577 on the course of experimental autoimmune encephalomyelitis (EAE) and central nervous system (CNS) inflammation. EAE was induced in SJL mice by inoculation with whole mouse spinal cord homogenate. RG-13577, delivered intraperitoneally, inhibited the clinical signs of acute EAE and markedly ameliorated inflammation in the spinal cord, primarily by inhibiting heparanase activity in lymphocytes and astrocytes and thus impairing lymphocyte traffic. RG-13577 treatment was effective when started on day of disease induction or day 7 after induction. The low molecular weight heparin, enoxaparin, tested under the same conditions, exerted only a minor insignificant inhibitory effect. RG-13577 also inhibited the tyrosine phosphorylation of several proteins, particularly Erk1 and Erk2 of the MAP kinase signaling pathways associated with inflammation and cell proliferation. RG-13577 blocked the activity of sPLA(2) and inhibited CNS PGE(2) production both in vivo and in vitro.     

Changes in lymphocytic cluster distribution during extracorporeal immunoadsorption

The success of apheresis treatment is often measured as a decrease in the detected antibodies and an improvement in different disease-related scores. Sometimes, however, the seriousness of the disease does not correlate with the antibody level. During a period of 8 years, 15 patients (3 myasthenia gravis, 1 multiple sclerosis, 2 systemic lupus erythematosus, 3 alloimmunized kidney transplant, 6 rheumatoid arthritis) were treated by protein A immunoadsorption. Lymphocyte subpopulations (activated T cells, cytolytic T cells, B cells, natural killer cells) and inflammatory proteins (ferritin, C-reactive protein, alpha1-antitrypsin, alpha2-macroglobulin) were analyzed. After observing clinical outcomes, the patients could be divided into 2 groups, respectively: Group 1, responding patients with remission of disease; and Group 2, delayed-responding patients, who required chronic treatment. Group 1 patients characteristically showed a greater increase in activated T and cytolytic T cells which correlated with a greater decrease of B cells. It might be possible that protein A immunoadsorption induced immunomodulation. Further immunological investigation is required to verify these findings.     

DMXAA: an antivascular agent with multiple host responses

: To measure host responses to the antivascular agent DMXAA (5,6-dimethylxanthenone-4-acetic acid) and to compare them with those of other antivascular agents.

: Induction of tumor necrosis was measured in s.c. murine Colon 38 carcinomas growing in normal or tumor necrosis factor (TNF) receptor-1 knockout mice. Plasma and tumor tissue TNF concentrations were measured by ELISA. Plasma concentrations of 5-hydroxyindoleacetic acid (as a measure of serotonin release) and nitrite (as a measure of nitric oxide release) were measured by high-performance liquid chromatography.

: Administration of DMXAA to tumor-bearing mice increased plasma and tumor tissue-associated TNF, in addition to increasing plasma nitric oxide, distinguishing its action from that of mitotic poisons that had an antivascular action. Results from TNF receptor-1 knockout mice showed that TNF played an important role in both its antitumor action and its host toxicity. Release of serotonin occurred in response to mitotic poisons, as well as to DMXAA.

: The antivascular action of DMXAA involves in situ production in tumor tissue of a cascade of vasoactive events, including a direct effect on vascular endothelial cells and indirect vascular effects involving TNF, other cytokines, serotonin, and nitric oxide. Now that Phase I clinical trials of DMXAA are completed, the optimization of this cascade in cancer patients is a major challenge. Plasma 5-hydroxyindoleacetic acid concentrations may provide a useful surrogate marker for the antivascular effects of DMXAA and other antivascular agents.     

Adverse effects of perioperative transfusion on patients with stage III and IV gastric cancer

BACKGROUND: The degree of immunomodulation by perioperative blood transfusion and its resultant effects on cancer surgery are a subject of controversy. We evaluated the prognostic effects of perioperative blood transfusion on gastric cancer surgery. METHODS: A total of 1710 patients who underwent curative gastrectomy for gastric cancer from 1991 to 1995 were retrospectively reviewed. Uni- and multivariate analyses of the incidence, amount, and timing of perioperative blood transfusions and a comparison of the clinicopathological features were performed. RESULTS: A higher incidence of blood transfusions was associated with female sex, large tumors, upper-body location, Borrmann type III or IV lesions, longer operations, total gastrectomies, splenectomies, and D3 or more extended lymphadenectomy. The tumors in the transfused group were more advanced in depth of invasion and nodal classification. More frequent tumor recurrences were found in the transfused group. A dose-response relationship between the amount of transfused blood and prognosis was evident. Subgroup analyses of prognosis according to stage showed significant differences in stages III and IV between the transfused and nontransfused groups. On multivariate analysis, transfusion was shown to be an independent risk factor for recurrence and poor prognosis. CONCLUSIONS: These results suggest that perioperative transfusion is an unfavorable prognostic factor. It is thus better to refrain from unnecessary blood transfusion and to give the least amount of blood to patients with gastric cancer when transfusion is inevitable, especially for those with stage III and IV gastric cancers.