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Induction of immune tolerance is one of the recent novel immunomodulatory strategies to directly intervene the autoimmune-driven atherosclerosis. Aspirin is a prototypic non-steroidal anti-inflammatory drug, which is now being regarded as a life-saver in variety of atherosclerotic cardiovascular complications. Considerable amount of data emerged during last few years clearly suggests that aspirin can cause immunomodulation by several mechanisms, particularly, its ability to induce tolerogenic dendritic cells (DCs) and to upregulate T regulatory (Treg) cells is especially appealing with respect to induction of immunological self-tolerance. Based on this fact, we hypothesize that aspirin, in addition to its anti-inflammatory effect, may also specifically inhibit autoimmune response in atherosclerosis by actively increasing CD4+CD25+FOXP3+Treg cells as well as by inducing tolerogenic DCs which induce hyporesponsiveness in responder naïve T cells. If proved to be correct, this hypothesis will provide an opportunity to medical community with an already available aspirin-based immunotherapeutic approach for inducing immune tolerance against atherosclerosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The time-tested gradual exploration of aspirin's diverse pharmacological properties has made it the most reliable therapeutic agent worldwide. In addition to its well-argued anti-inflammatory effects, many new and exciting data have emerged regarding the role of aspirin in cells of the immune system and certain immunopathological states. For instance, aspirin induces tolerogenic activity in dendritic cells and determines the fate of naive T cells to regulatory phenotypes, which suggests its immunoregulatory potential in relevance to immune tolerance. It also displays some intriguing traits to modulate the innate and adaptive immune responses. In this article, the immunomodulatory relation of aspirin to different immune cells, such as neutrophils, macrophages, dendritic cells (DCs), natural killer (NK) cells, and the T and B lymphocytes has been highlighted. Moreover, the clinical prospects of aspirin in terms of autoimmunity, allograft rejection and immune tolerance have also been outlined., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective and Design: The effect of acetylsalicyclic acid (ASA) on the phagocytosis and immunogenicity of macrophages remains to be determined., Material or Subjects: BALB/c mice and peritoneal macrophages were used., Treatment: BALB/c mice were treated with ASA (0, 6, or 60 mg/kg/day) intraperitoneally for 1 week., Methods: Flow cytometry and phagocytosis assay were employed., Results: ASA significantly decreased cell numbers, nonopsonic phagocytosis, and immunogenicity as well as changing the phenotypes of peritoneal macrophages in vivo. After in vitro treatment with ASA, macrophages expressed low levels of MHC-II, CD80, and CD47 molecules, and showed significantly decreased phagocytosis. Importantly, ASA blocked the differentiation of macrophages from bone marrow cells in vitro as indicated by decreased macrophage cell numbers and phenotype alteration., Conclusions: The present study provides basic information on the direct effect of ASA on macrophages, supporting the potential application of ASA in patients with allo-grafts or autoimmune diseases.

CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells, produced in the thymus or periphery as a functionally mature T cell subpopulation, play pivotal roles in maintenance of self-tolerance and negative regulation of immune responses. Aspirin (ASA) is widely used to reduce pain, the risk of cardiovascular diseases and allo-graft rejection. However, the effect of ASA on CD4(+)CD25(+)Foxp3(+) Treg cells has yet to be determined. The frequency, phenotype and immunosuppressive function of CD4(+)CD25(+)Foxp3(+) Treg cells were detected in BALB/c mice treated with low or high doses of ASA for 4 weeks. ASA significantly decreased the percentage and number of CD4(+) T cells in the periphery, while ASA remarkably increased the percentage of CD4(+)CD25(+)Foxp3(+) Treg cells in CD4(+)T cells. The total cell numbers of thymocytes were significantly decreased in ASA-treated mice, but the number of CD4(+) CD25(+)Fxop3(+) cells and its ratio in CD4(+)CD8(-) thymocytes were markedly enhanced in the thymi of ASA-treated mice. The phenotype of CD4(+)CD25(+) Treg cells, including the expressions of CD44, CD45RB, CD62L, CD69, GITR and CTLA-4, did not show detectable changes in ASA-treated mice. CD4(+)CD25(+) Treg cells in ASA-treated mice exhibited unimpaired immunosuppressive function on CD4(+)CD25(-) T effector cells. ASA significantly enhanced the frequency of functional CD4(+)CD25(+)Foxp3(+) Treg cells in mice in a therapeutic dose range. The different effects of ASA on CD4(+)CD25(+)Foxp3(+) Treg cells and CD4(+)CD25(-) T cells may potentially make hosts susceptible to tolerance induction which would be beneficial for tolerance induction in patients with autoimmune diseases or allo-grafts. This study may have potential impacts in the clinical application of ASA.

Abstract: The pathobiology of allergic bronchial asthma is mediated by over-expressed T helper type 2 (Th2)-biased immune responses to harmless environmental antigens, leading to airway inflammation and hyper-responsiveness. These Th2 responses are normally suppressed by functional T regulatory cells (Tregs), which maintain the airway tolerance. However, the Tregs activity is conceived to be compromised in allergic asthmatics. The curative therapy to counteract this immune dysregulation is not available so far, and to devise such a remedy is the current research impetus in allergic asthma therapeutics. One of the novel insights is to consider a Tregs-directed immunoregulatory therapy that could harness endogenous Tregs to redress the Th2/Tregs imbalance, thus enhancing the airway tolerance. Aspirin or acetylsalicylic acid (ASA) is a prototype non-steroidal anti-inflammatory drug that possesses intriguing immunopharmacological attributes. For example, it can enhance the number or the frequency of functional Tregs, especially natural CD4+ CD25+ FoxP3+ Tregs, either directly or by inducing tolerogenic activity in dendritic cells (DCs). It is also considered to be beneficial for the induction of immunological tolerance in autoimmunity and graft rejection. This raises the question whether ASA, if exploited optimally, may be used to induce and harness endogenous Tregs activity for redressing Th2/Tregs imbalance in allergic asthma. In this paper, we hypothesise that ASA may help to counteract the underlying immune dysregulation in allergic asthma by promoting airway tolerance. Nevertheless, the future research in this regard will selectively need to be targeted to allergic asthma models, which are ASA insensitive, as ASA has some adverse background and is contraindicated in asthmatics who are sensitive to it. [Copyright &y& Elsevier]