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Author Topic: PD-1 what modifies it what effects it what turns it off is there anything?  (Read 3509 times)

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Offline bimazek

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I have been thinking about this question for 10 months and searching and i think it is important to talk about

I have a theory that retinoids or a molecule related to a retinoid can have an effect but I am not sure,
if anyone can guess why i will be very happy

I found this oxford univ. paper 


The work presented in this study demonstrates that anti-IgM-induced PD-1 expression on B cells is diminished by treatment with LPS, CpG and cytokines such as IL-4, IL-12, IL-18 and IFN{gamma}. Further, this loss of PD-1 expression is accompanied by loss of PD-L1-induced inhibition of BCR-stimulated proliferation. Thus, we have shown for the first time that PD-L1 inhibits the behavior of primary B cells expressing physiological levels of PD-1, that induction of PD-1 expression is counteracted by specific receptor signaling, and that diminished PD-1 expression is accompanied by modulated PD-1 function      The stimuli that we found diminished PD-1 expression and function can, for the most part, be grouped together as ‘danger’ signals. However, the degree of concurrence delineated in this study between stimuli that diminish PD-1 expression and danger stimuli is not perfect. Typical danger cytokines of IL-1{alpha}, IL-1ß and TNF{alpha} (6) had no effect on PD-1 expression, at least by themselves. Conversely, IL-4 produced dramatic reduction in PD-1 expression and is not always thought of as a ‘danger’ signal, although it shares important ‘danger’ characteristics (19), including a role in inflammation (20,21).  Danger signal-triggered reduction of PD-1 expression fits with a speculative model for the function of PD-1 in normal and aberrant immune responses. According to this model, in the event that autoreactive B cell receptors interact with self-antigen in the periphery, expression of PD-1 would be upregulated and B cell activity would be suppressed through PD-L binding to PD-1. This is supported by the observation that PD-L is widely distributed on many peripheral tissues (22,23). Conversely, B cell responses would be enhanced by loss of PD-1 expression, which, as we show here, could occur through the influence of bacterial or macrophage products that are associated with danger signaling. In this light, reduction of PD-1 expression and function by CpG and IL-4 might be viewed as an appropriate facilitation of anti-bacterial and T-dependent responses, respectively.

since ctla has been around longer i want to study if there are any changes that can be done with ctla, can any substances effect these receptors

Offline bimazek

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this is very interesting
i found a fungus from so america that shuts down tcells and involve ctla perhaps pd-1


The mechanism that leads to the remarkable T cell unresponsiveness to antigens in paracoccidioidomycosis is unknown. We investigated the involvement of cytokines, of Fas-Fas ligand (Fas-FasL)–induced apoptosis, and of cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement, in the mediation of this phenomenon. T cell unresponsiveness was not associated with imbalanced cytokine production or with absence of CD28 expression. Only patient T cells expressed higher levels of CTLA-4, Annexin V+, and FasL. The addition of anti-FasL decreased the levels of apoptosis, suggesting an activation-induced cell death triggered through the Fas-FasL pathway. Blockage of CTLA-4 and FasL resulted in increased production of interferon-γ. Moreover, concomitant inhibition of FasL and of CTLA-4, but not of transforming growth factor–β, resulted in significant T cell proliferation in patients, in response to phytohemagglutinin. Together, these data show that apoptosis mediated by Fas-FasL and engagement of CTLA-4 are involved in modulation of the immune response in patients infected with Paracoccidioides brasiliensis.

Offline bimazek

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what i am trying to do is find a substance that effects pd-1 or ctla that may have been hinted at in an article...

here again is relation to immune issues, pd-1 and  multiple sclerosis and muscular dystrophy
search on here for muscular dystrophy and bimazek in the nutrient area


Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis.

Antigen-presenting cells (APC) are considered to play a critical role in promoting the (re)activation of potentially autoreactive T cells in multiple sclerosis (MS), an inflammatory demyelinating disorder of the central nervous system (CNS). B7-H1 (PD-L1) is a novel member of the B7 family proteins which exert costimulatory and immune regulatory functions. Here we characterize the expression and functional activity of B7-H1 expressed on monocytes and dendritic cells (DC) of healthy donors and MS patients. B7-H1 is constitutively expressed on monocytes and differentially matured DC, but not on B cells. IFN-beta, the principle immune modulatory agent used for the treatment of MS, strongly enhances B7-H1 expression on monocytes and semi-matured DC, but not B cells, in vitro. Importantly, B7-H1 expressed on APC strongly inhibits autologous CD4 T-cell activation. Neutralization of B7-H1 on monocytes or differentially matured monocyte-derived DC markedly increases the secretion of the pro-inflammatory cytokines, IFN-gamma and IL-2, T-cell proliferation, and the expression of T-cell activation markers. B7-H1 exhibits strong inhibitory effects when expressed on monocytes, immature or semi-mature DC, but less so when expressed on fully matured DC. B7-H1-dependent immune inhibition is in part mediated by CD4/CD25+ regulatory T cells. There is no difference in the baseline expression levels of monocytic B7-H1 between untreated MS patients and healthy donors. However, both groups show a significant concentration-dependent up-regulation of B7-H1 mRNA and protein in response to IFN-beta in vitro. Serial measurements of B7-H1 mRNA in MS patients before and 6 months after initiation of IFN-beta therapy corroborated the relevance of these results in vivo: Nine of nine patients showed a significant increase in B7-H1 mRNA levels after 6 months of IFN-beta therapy (median 1.04 vs. 8.78; p<0.05, two-sided t-test). Accordingly, protein expression of B7-H1 on monocytes was up-regulated after 24 h of IFN-beta application. In summary, B7-H1 expressed on APC acts as a strong inhibitor of autologous CD4 T-cell activation and may thus contribute to the maintenance of peripheral immune tolerance. IFN-beta up-regulates B7-H1 in vitro and in MS patients in vivo and might represent a novel mechanism how IFN-beta acts as a negative modulator on APC T-cell interactions in the periphery.

ONO-4538 / MDX-1106 (injection)
ONO-4538, a fully human anti-PD-1
antibody, is expected to be a potential
treatment for cancer. PD-1 is one of the
receptors expressed on activated
lymphocytes, and is involved in th

Offline bimazek

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does this mean that if they could find a anti-fungal antigen
then this might stim. immune system...

CD-28 and CTLA-4 expression, by PBMCs from patients with paracoccidioidomycosis.     Previous studies have determined that cell proliferative responses and IL-2 production, by T cells from patients, are depressed in response to fungal antigen and PHA [4, 19]. In fact, our results indicate that PBMCs from patients were unable to proliferate in response to fungal lysate, CW, or heat-inactivated yeast forms. The patients also exhibited a significantly lower T cell proliferative response to PHA than did control subjects

Offline bimazek

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Here we have presented data that show, for the first time, that Fas- and FasL-mediated apoptosis and engagement of the down-regulatory molecule CTLA-4 are clearly involved in modulating T cell unresponsiveness in patients with paracoccidioidomycosis


Recently, evidence has emerged that shows that, because it provides an additional stimulus for both IL-2 production and IL-2 receptor expression, the costimulatory molecule CD28 is a crucial modulator of T cell activation [27]. Considering that cells from patients with paracoccidioidomycosis show decreased IL-2 receptor expression [6], we hypothesized that CD28 expression could be down-regulated in T cells from patients with paracoccidioidomycosis, as has been demonstrated to occur in T cells from persons infected with other parasites, such as T. cruzi [28]. However, we found normal levels of CD28 expression in the cells from patients, both ex vivo and after culture with fungal antigens, LPS, or PHA. Alternatively, the decreased ability of T cells to proliferate in response to specific or polyclonal stimulation could be due to increased expression of CTLA-4, a molecule that also binds to B7, promotes anergy, and negatively influences T cell effector function by inhibiting cell-cycle progression

Interestingly, increased expression of CTLA-4 has also been observed in cells from patients with malaria and from patients with human immunodeficiency virus (HIV) infection [30, 31]. In HIV-infected patients, the proliferation of T cells was inversely correlated with CTLA-4 expression, a correlation that suggests that CTLA-4 may be involved in the elimination and anergy of T cells in HIV-1 infection [31]. Also, increased CTLA-4 expression was correlated with decreased proliferative activity and IL-2 production, in T cells from patients with Hodgkin's disease [32]. However, in contrast with what was observed in HIV-infected patients, addition of anti–CTLA-4 neutralizing monoclonal antibody to the cultures of PBMCs from patients with paracoccidioidomycosis did not restore the T cell proliferative response

in fact, we found high levels of Annexin V+ T cells in PBMCs from patients.

Although our data point to a clear correlation between T cell unresponsiveness and Fas-FasL–mediated AICD, during P. brasiliensis infection, we observed that blockage of Fas-FasL interaction was unable to restore the proliferative response of T cells from patients with paracoccidioidomycosis. Although we do not fully understand this result, one possible explanation is that CTLA-4 expression remains increased in these cells (figure 1), a conclusion reinforced by the results showing that simultaneous inhibition of FasL and CTLA-4 resulted in a significant increase in the T cell proliferative response. Therefore, the blockage, via Fas-FasL interaction, of cell death is not sufficient to overcome the inhibitory antiproliferative effects of CTLA-4. Nevertheless, although the blockage of CTLA-4 and FasL led to an increased lymphoproliferation in response to PHA, it did not result in any improvement of fungal antigen-driven proliferative T cell response

Another important aspect of our study is the finding that blockage of CTLA-4 and FasL lead to an increased IFN-γ production by PBMCs from patients with paracoccidioidomycosis


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