The aim of this study was to investigate the effects of systemically administered bone-marrow-derived mesenchymal stromal cells (MSCs) on the early acute phase of inflammation in the alkali-burned eye. Mice with damaged eyes were either untreated or treated 24 h after the injury with an intravenous administration of fluorescent-dye-labeled MSCs that were unstimulated or pretreated with interleukin-1α (IL-1α), transforming growth factor-β (TGF-β), or interferon-γ (IFN-γ). Analysis of cell suspensions prepared from the eyes of treated mice on day 3 after the alkali burn revealed that MSCs specifically migrated to the damaged eye and that the number of labeled MSCs was more than 30-times higher in damaged eyes compared with control eyes. The study of the composition of the leukocyte populations within the damaged eyes showed that all types of tested MSCs slightly decreased the number of infiltrating lymphoid and myeloid cells, but only MSCs pretreated with IFN-γ significantly decreased the percentage of eye-infiltrating cells with a more profound effect on myeloid cells. Determining cytokine and NO production in the damaged eyes confirmed that the most effective immunomodulation was achieved with MSCs pretreated with IFN-γ, which significantly decreased the levels of the proinflammatory molecules IL-1α, IL-6, and NO. Taken together, the results show that systemically administered MSCs specifically migrate to the damaged eye and that IFN-γ-pretreated MSCs are superior in inhibiting the acute phase of inflammation, decreasing leukocyte infiltration, and attenuating the early inflammatory environment.

• MeSH
• alkálie toxicita   MeSH
• alografty MeSH
• antivirové látky farmakologie   MeSH
• chemické popálení patologie   terapie   MeSH
• interferon gama farmakologie   MeSH
• interleukin-1alfa metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nika kmenových buněk * MeSH
• popálení oka chemicky indukované   metabolismus   patologie   terapie   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• transplantace mezenchymálních kmenových buněk * MeSH
• zánět chemicky indukované   metabolismus   terapie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alkálie MeSH
• antivirové látky MeSH
• interferon gama MeSH
• interleukin-1alfa MeSH
• transformující růstový faktor beta MeSH

In spite of intensive research, the molecular basis of allograft and xenograft rejection still remains not fully understood. The acute rejection of an allograft is associated with the intragraft Th1 cytokine response, while tolerance of an allograft or xenograft rejection is accompanied by a higher production of the Th2 cytokines interleukin (IL)-4 and IL-10. Nevertheless, these cytokines are not the final regulatory and effector molecules mediating transplantation reactions. Data indicate that the functioning of common molecules with enzymatic activities, such are inducible nitric oxide synthase (iNOS), arginase, heme oxygenase-1 (HO-1) or indoleamine-2,3-dioxygenase (IDO), the bioavailability of their substrates (L-arginine, tryptophan, heme) and the cytotoxic and regulatory actions of their small gaseous products (NO, CO) can be the ultimate mechanisms responsible for effector or regulatory reactions. Using models of transplantation immunity and tolerance we show that T cell receptor-mediated recognition of allogeneic or xenogeneic antigens as well as the balance between immunity/tolerance induces distinct cytokine production profiles. The ratio between Th1 and Th2 cytokines efficiently regulates the expression of genes for common enzymes, such as iNOS, arginase, HO-1 and IDO. These enzymes may compete for substrates, such as L-arginine or tryptophan, and the final product of their activity are small molecules (NO, CO) displaying effector or regulatory functions of the immune system. Thus, it is suggested that in spite of the high immunological specificity of transplatation reaction, the ultimate players in regulatory and effector functions could be small and common molecules.

• Klíčová slova
• Arginase, Graft rejection, Immunoregulation, Macrophages, Nitric oxide, Th1/Th2 balance, Tolerance,
• Publikační typ
• časopisecké články MeSH

The eye has been described as an immunologically privileged site where immunity is purely expressed. It has been demonstrated that administration of antigen into the eye induces only a weak immune response. However, the anterior part of the eye represents an important protective barrier against pathogens and other harmful invaders from the outer environment. Therefore, effective immune mechanisms, which operate locally, need to be present there. Because the cornea has been shown to be a potent producer of various cytokines and other molecules with immunomodulatory properties, we investigated a possible regulatory role for the individual corneal cell types on cytokine production by activated T cells. Mouse spleen cells were stimulated with the T cell mitogen concanavalin A in the presence of either corneal explants or cells of corneal epithelial or endothelial cell lines and the production of T helper 1 (Th1) or Th2 cytokines was determined by enzyme-linked immunosorbent assay (ELISA) or reverse transcription-polymerase chain reaction (RT-PCR). We found that the cornea possesses the ability to inhibit, in a dose-dependent manner, production of the inhibitory and anti-inflammatory cytokines interleukin (IL)-4 and IL-10 by activated T cells. The production of cytokines associated with protective immunity [IL-2, IL-1beta, interferon (IFN)-gamma ] was not inhibited under the same conditions. Corneal explants deprived of epithelial and endothelial cells retained the ability to suppress production of anti-inflammatory cytokines. This suppression was mediated by a factor produced by corneal stromal cells and occurred at the level of cytokine gene expression. We suggest that by this mechanism the cornea can potentiate a local expression of protective immune reactions in the anterior segment of the eye.

• MeSH
• aktivace lymfocytů MeSH
• cytokiny biosyntéza   MeSH
• ELISA metody   MeSH
• interferon gama analýza   genetika   MeSH
• interleukin-1 biosyntéza   MeSH
• interleukin-10 biosyntéza   MeSH
• interleukin-2 biosyntéza   MeSH
• interleukin-4 biosyntéza   genetika   MeSH
• kokultivační techniky MeSH
• konkanavalin A farmakologie   MeSH
• kultivační techniky MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• slezina MeSH
• stroma rohovky imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• interferon gama MeSH
• interleukin-1 MeSH
• interleukin-10 MeSH
• interleukin-2 MeSH
• interleukin-4 MeSH
• konkanavalin A MeSH

Heroin treatment or abusive drug addiction influences many physiological functions, including the reactions of the immune system. Although suppression of various manifestations of the immune system after heroin (or morphine) administration has been reported, we show here that production of proinflammatory cytokines and nitric oxide (NO) was enhanced and allotransplantation reactions were accelerated significantly in heroin-treated recipients. Mice were treated by a subcutaneous administration of heroin (diacetylmorphine) given in one or repeated daily doses. The ability of spleen cells from treated mice to respond in vitro to alloantigens and to produce IL-2, IL-4, IL-10 and IFN-gamma, and the production of IL-1beta, IL-12 and NO by peritoneal macrophages, were tested. Within 2 h after heroin administration, proliferative responses to alloantigens and the production of IL-1beta, IFN-gamma, IL-12 and NO were enhanced significantly. In contrast, the production of anti-inflammatory cytokines IL-4 and IL-10 was at the same time rather decreased. As a consequence, skin allografts in heroin-treated mice were rejected more promptly than in untreated or vehicle-treated recipients. Similarly, the growth of allogeneic tumours induced by high doses of tumour cells was suppressed significantly in heroin-treated mice. The enhancing effects of heroin on the production of proinflammatory cytokines were antagonized by naltrexone, a specific inhibitor of classic opioid receptors. These results show that heroin treatment augments production of proinflammatory cytokines and accelerates allotransplantation reactions. The observations thus illustrate the complexity of the effects of heroin on the immune system and should be taken into account during medical treatment of opiate addicts and in the use of morphine to decrease pain in various clinical situations.

• MeSH
• cytokiny krev   MeSH
• experimentální nádory farmakoterapie   imunologie   MeSH
• fibrosarkom farmakoterapie   imunologie   MeSH
• heroin farmakologie   MeSH
• homologní transplantace MeSH
• interferon gama biosyntéza   MeSH
• interleukin-1 biosyntéza   MeSH
• interleukin-10 biosyntéza   MeSH
• interleukin-12 biosyntéza   MeSH
• interleukin-2 biosyntéza   MeSH
• interleukin-4 biosyntéza   MeSH
• kultivované buňky MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• naltrexon farmakologie   MeSH
• narkotika - antagonisté farmakologie   MeSH
• narkotika farmakologie   MeSH
• oxid dusnatý metabolismus   MeSH
• peritoneální makrofágy metabolismus   MeSH
• slezina imunologie   MeSH
• transplantace kůže imunologie   MeSH
• transplantační imunologie účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• heroin MeSH
• interferon gama MeSH
• interleukin-1 MeSH
• interleukin-10 MeSH
• interleukin-12 MeSH
• interleukin-2 MeSH
• interleukin-4 MeSH
• naltrexon MeSH
• narkotika - antagonisté MeSH
• narkotika MeSH
• oxid dusnatý MeSH