Biomedical subjects

Scott N Byrne

Publications and source records attributed to Scott N Byrne.

10 recordsLinked to original sources

PubMed2006

A role for inflammatory mediators in the induction of immunoregulatory B cells.

UV exposure suppresses the immune response to a variety of microbial, fungal, and viral Ags. In addition, UV radiation is a complete carcinogen and the immune suppression induced by UV radiation is a major risk factor for skin cancer induction. In this study, we examined the mechanisms underlying the induction of immune suppression and tolerance induction by UV radiation. Transferring lymph nodes cells from UV-irradiated, FITC-sensitized mice into normal recipients transferred immune tolerance. Contrary to expectations, the cell responsible was an FITC(+), IL-10-secreting, CD19(+), B220(+) B cell. Because the lipid mediator of inflammation, platelet-activating factor (PAF) is released by UV-irradiated keratinocytes and is essential for the induction of immune suppression, we determined its role in tolerance induction. When UV-irradiated mice were injected with PCA 4248, a selective PAF receptor (PAFR) antagonist, transfer of tolerance was suppressed. However, immune suppression was not transferred when FITC(+) cells from the draining lymph nodes of UV-irradiated, PAFR-deficient donor mice were injected into the recipients. Because PCA 4248 also blocks serotonin receptor binding, we measured the effect that blocking both serotonin and PAFR binding has on the transfer of immune suppression. Only when both PAF and serotonin binding were blocked could we inhibit tolerance induction. These data identify a novel function for PAF and serotonin in modulating immune function, the activation of immunoregulatory B cells.

Adoptive Transfer↗

PubMed2006

The induction of immunity to a protein antigen using an adjuvant is significantly compromised by ultraviolet A radiation.

Ultraviolet (UV) radiation from sunlight causes skin cancer and inhibits priming of the immune system during vaccination. However the dose related effects of the different components of sunlight (UVA and UVB) are complex and require further investigation. Using ovalbumin as a model protein vaccine with saponin as adjuvant we show that both UVA and UVB can suppress the DTH response to a poorly immunogenic protein. Increasing doses of UVB induced increased levels of immunosuppression and tolerance. UVA however, caused a bi-phasic dose response with intermediate but not low or high doses causing primary immunosuppression. No dose of UVA caused significant tolerance. Similar results were observed in both C57BL/6 and Balb/c mice. Our data confirms the complex immunomodulatory dose effects of UVA and UVB for a protein antigen, and shows that both UVB and UVA can suppress immunity induced by a protein with adjuvant. This highlights the importance of considering sun exposure patterns in the future success of both preventing skin cancer development and enhancing vaccination regimes.

Adjuvants, Immunologic↗

PubMed2005

Transforming growth factor-beta1 immobilises dendritic cells within skin tumours and facilitates tumour escape from the immune system.

Human skin tumours often regress spontaneously due to immune rejection. Murine skin tumours model this behaviour; some regress and others progress in syngeneic immunocompetent hosts. Previous studies have shown that progressor but not regressor skin tumours inhibit dendritic cell (DC) migration from the tumour to draining lymph nodes, and transforming growth factor-beta1 (TGF-beta1) has been identified as a responsible factor. To determine whether increased production of TGF-beta1 in the absence of other differences inhibits DC migration from the tumour and enables it to evade immune destruction, a murine regressor squamous cell carcinoma clone was transfected with the gene for TGF-beta1. This enhanced growth in vitro and in vivo, causing it to become a progressor. TGF-beta1 transfection reduced the number of infiltrating DCs by about 25%. Quantitation of CD11c+ E-cadherin+ (epidermally derived) DCs in lymph nodes determined that TGF-beta1 reduced the number of DCs that migrated from the tumour to undetectable levels. This was supported by showing that TGF-beta1 reduced DC migration from cultured tumour explants by greater than tenfold. TGF-beta1 transfection also reduced the number of infiltrating CD4 and CD8 T cells. Thus, TGF-beta1 production by skin tumours is sufficient to immobilise DCs within the tumour, preventing their migration to lymph nodes. This reduces the number of T cells that infiltrate the tumour, preventing regression. Thus, TGF-beta1 is a key regulator of whether skin tumours regress or progress.

Animals↗

PubMed2005

B cells activated in lymph nodes in response to ultraviolet irradiation or by interleukin-10 inhibit dendritic cell induction of immunity.

Ultraviolet (UV) radiation suppresses systemic immunity. We explored these cellular mechanisms by exposing mice to systemically immunosuppressive doses of UV radiation and then analyzing cell phenotype and function in the lymphoid organs. Although UV radiation increased total cell number in the draining lymph nodes (DLN), it did not alter the activation state of dendritic cells (DC). Rather, UV radiation selectively activated lymph node B cells, with these cells being larger and expressing higher levels of both anti-major histocompatibility complex II and B220 but not co-stimulatory molecules. This phenotype resembled that of a B cell geared toward immune tolerance. To test whether UV radiation-activated B cells were responsible for immunosuppression, DC and B cells were conjugated to antigen ex vivo and transferred into naive hosts. Although DC by themselves activated T cells, when the B cells from UV radiation-irradiated mice were co-injected with DC, they suppressed DC activation of immunity. Interleukin (IL)-10-activated B cells also suppressed DC induction of immunity, suggesting that IL-10 may be involved in this suppressive effect of UV radiation. These results demonstrate a new mechanism of UV radiation immunosuppression whereby UV radiation activates B cells in the skin-DLN that can suppress DC activation of T cell-mediated immunity.

Animals↗

PubMed2004

The suppression of immunity by ultraviolet radiation: UVA, nitric oxide and DNA damage.

We have examined the mechanism by which solar-simulated ultraviolet radiation (ssUV) suppresses memory immunity to nickel in allergic humans. In initial studies, we used inbred mice to determine the contribution of different wavebands to sunlight-induced immunosuppression. We found that low dose UVA can enhance memory, medium dose UVA (half the amount in one minimum erythemal dose of ssUV) is immunosuppressive, but higher doses protect from UVB. This is genetically dependent, as it is not observed in all mouse strains. UVA caused a similar dose-related change in recall immunity in humans. ssUV dose responses determined the limits of protection provided by sunscreens from immunosuppression in humans. Immune protection factors calculated from these data correlated with UVA protection, but not with sun protection factor, showing that in commercial sunscreens that provide good UVB protection, UVA protection limits prevention of immunosuppression. N(G)-monomethyl-l-arginine acetate (l-NMMA) was used to inhibit nitric oxide (NO) production and T4N5 liposomes containing T4 endonuclease V to enhance DNA repair. Sub-erythemal ssUV caused a dose-related local suppression of recall immunity to nickel in humans. l-NMMA and the liposomes protected the nickel reaction, suggesting that NO and DNA damage are mediators of UV-induced immunosuppression in humans.

Animals↗

PubMed2003

Phagocytosis by dendritic cells rather than MHC IIhigh macrophages is associated with skin tumour regression.

Dendritic cells (DC) are important for the induction of anti-tumour immunity and are currently being used in clinical trials. Whether DC in tumours behave the same as DC in normal tissues or whether the tumours subvert DC phenotype and function remains unknown. To address this, we have used a unique animal tumour model to compare the DC infiltrating regressing tumours with the DC infiltrating progressing skin tumours. Compared to progressor tumours, the regressor tumours were infiltrated by greater numbers of DC that were also less mature, based on MHC II expression. Apart from this, the phenotype of DC in both tumours was similar. However, compared to various control DC, they could not be classed as either mature or immature. Similar to terminally maturated DC but in contrast to fresh DC, tumour-derived DC did not express CCR5 or CXCR4, suggesting that they most closely resembled terminally matured DC. Macrophages that expressed high MHC II levels were found infiltrating progressor but not regressor tumours and in vivo were the major phagocytic cell. In contrast, DC were found to be the major phagocytic cell in regressor tumours. The results show that immune destruction and eventual regression of skin tumours occurs if DC rather than MHC II(high) macrophages are the major phagocytic cell.

Animals↗

PubMed2003

High levels of Fas ligand and MHC class II in the absence of CD80 or CD86 expression and a decreased CD4+ T cell Infiltration, enables murine skin tumours to progress.

It is still not clear why some tumours will be recognized and destroyed by the immune system, and others will persist, grow, and eventually kill the host. It has been hypothesized that tumour cells might evade immunological destruction by expressing Fas ligand (FasL), a molecule which induces apoptosis in Fas(+) target cells. However, the role of FasL in creating an immune privileged status within a tumour remains controversial. To determine whether FasL is associated with skin tumour progression, we developed a tumour model enabling us to compare two squamous cell carcinomas (SCC). One is a regressor SCC which spontaneously regresses after injection into syngeneic mice. The other is a progressor SCC which evades immunological destruction. Detailed flow cytometric analysis was used to study tumour cell expression of FasL, Fas, CD80, CD86 and MHC class II. We also analysed the percentage of apoptotic tumour cells in vivo using annexin V and correlated skin tumour progression with CD4 and CD8 T cell infiltration. Progressor tumours expressed high levels of FasL in vivo, which was virtually absent from regressor tumours. The percentage of progressor tumours expressing MHC II was significantly greater than regressor tumours, while neither tumour expressed CD80 or CD86 costimulatory molecules. Consistent with a regressor phenotype, the percentage of viable tumour cells was significantly lower for regressor compared to progressor tumours which coincided with a significantly larger CD4(+) T cell infiltrate into the tumour mass. The results suggest that progression of skin tumours occurs if tumour cells express high levels of MHC II but not costimulatory molecules such as CD80 or CD86. This implies that tumours may induce anergy in CD4(+) T cells via MHC II antigen presentation in the absence of costimulation. To ensure escape from the immune system, tumours may then kill these T cells via a FasL-dependent mechanism.

Animals↗

PubMed2002

Dendritic cells: making progress with tumour regression?

Due to their potent ability to activate the immune system, dendritic cells (DC) are showing promise as potential adjuvants for tumour immunotherapy of cancer patients. However, little is known about the effect tumour cells can have on DC function. Indeed, the discovery of different DC subsets with different immunological functions indicates that the relationship between tumour cells and tumour-infiltrating DC subtypes is likely to be complex. There remains a lot to be understood about the effects of tumours on DC before we can expect to benefit from DC-based tumour immunotherapy of cancer patients. Here we review the recent advances being made in understanding DC phenotype and function in relation to interactions with different types of tumours.

Animals↗

PubMed2002

Ultraviolet a irradiation of C57BL/6 mice suppresses systemic contact hypersensitivity or enhances secondary immunity depending on dose.

Ultraviolet radiation is the most common environmental carcinogen humans are exposed to. It is now known that in order for skin cancers to develop, both genetic damage and immunosuppression is required. Ultraviolet-induced immunosuppression is therefore a key contributor to the development of skin cancer. Little is known about the relative contributions of the different ultraviolet spectra (A and B), however. Therefore detailed ultraviolet dose-response curves for systemic suppression of contact hypersensitivity in two mouse strains were determined to examine the relative contributions of each of these spectral components of sunlight to primary and secondary immunity. Whereas ultraviolet B caused a linear dose-related immunosuppression in both C57BL/6 and Balb/c mice, only C57BL/6 mice were immunosuppressed by medium doses of ultraviolet A. At higher ultraviolet A doses, C57BL/6 mice were protected from immunosuppression, suggesting a genetic predisposition to ultraviolet-A-induced immunomodulation. Surprisingly, we found that, in contrast to primary immunosuppression, low dose ultraviolet A enhanced the secondary immune response, whereas ultraviolet B caused antigen-specific tolerance. When ultraviolet A and ultraviolet B were combined to mimic sunlight (solar-simulated ultraviolet), immunosuppression and tolerance were only observed over a narrow dose range as the memory-enhancing effect of low dose ultraviolet A and the immunoprotective effect of higher dose ultraviolet A prevented the suppressive effects of ultraviolet B. These studies suggest that complex relationships between ultraviolet dose, immunomodulation, spectra, and genetic background are likely to be important for skin cancer induction. We also describe for the first time that low doses of ultraviolet A are able to enhance secondary immunity, which has important implications for vaccination strategies.

Animals↗

PubMedDate not supplied

Ultraviolet B but not A radiation activates suppressor B cells in draining lymph nodes.

Immunosuppressive doses of solar-simulated UV radiation activate lymph node B cells that can suppress primary immunity by inhibiting the function of dendritic cells. The aim of this study was to determine the waveband responsible for activation of these suppressor B cells. We exposed C57BL/6 mice to various doses of either UVA or UVB radiation and analyzed the number and activation state of lymph node antigen-presenting cells (APC). Immunosuppressive doses of UVB but not UVA activated B cells as assessed by major histocompatibility complex II (MHC II) expression and doubled their numbers in draining lymph nodes. Higher doses of UVA that were not immunosuppressive actually suppressed B cell activation. Our results show that UVA and UVB suppress systemic immunity via different mechanisms. Lymph node B cells are activated in response to immunosuppressive doses of UVB but not UVA. Thus, the activation state of lymph node APC appears to be important for UV immunomodulation.

Animals↗