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Summary: Current treatments for systemic autoimmune diseases partially improve the health of patients displaying low pharmacological efficacy and systemic immunosuppression. Here, the therapeutic potential of transferring tolerogenic dendritic cells (tolDCs) generated with heme‐oxygenase inductor cobalt (III) protoporphyrin IX (CoPP), dexamethasone and rosiglitazone for the treatment of systemic autoimmunity was evaluated in two murine models of systemic lupus erythematosus (SLE), MRL‐Faslpr and NZM2410 mice. Dendritic cells treated ex vivo with these drugs showed a stable tolerogenic profile after lipopolysaccharide stimulation. Regular doses of tolDCs were administered to anti‐nuclear antibody‐positive mice throughout 60–70 days, and the clinical score was evaluated. Long‐term treatment with these tolDCs was well tolerated and effective to improve the clinical score on MRL‐Faslpr lupus‐prone mice. Additionally, decreased levels of anti‐nuclear antibodies in NZM2410 mice were observed. Although tolDC treatment increased regulatory T cells, no significant reduction of renal damage or glomerulonephritis could be found. In conclusion, these results suggest that the transfer of histone‐loaded tolDCs could improve only some SLE symptoms and reduced anti‐nuclear antibodies. This is the first study to evaluate antigen‐specific tolDC administration to treat SLE. Our report strengthens the clinical relevance of tolDC generation with CoPP, dexamethasone and rosiglitazone and the use of these modified cells as a therapy for systemic autoimmunity. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease with unrestrained T-cell and B-cell activity towards self-antigens. Evidence shows that apoptotic cells (ApoCells) trigger an autoreactive response against nuclear antigens in susceptible individuals. In this study, we focus on generating and characterizing tolerogenic dendritic cells (tolDCs) to restore tolerance to ApoCells. Monocyte-derived dendritic cells (DCs) from healthy controls and patients with SLE were treated with dexamethasone and rosiglitazone to induce tolDCs. Autologous apoptotic lymphocytes generated by UV irradiation were given to tolDCs as a source of self-antigens. Lipopolysaccharide (LPS) was used as a maturation stimulus to induce the expression of co-stimulatory molecules and secretion of cytokines. TolDCs generated from patients with SLE showed a reduced expression of co-stimulatory molecules after LPS stimulation compared with mature DCs. The same phenomenon was observed in tolDCs treated with ApoCells and LPS. In addition, ApoCell-loaded tolDCs stimulated with LPS secreted lower levels of interleukin-6 (IL-6) and IL-12p70 than mature DCs without differences in IL-10 secretion. The functionality of tolDCs was assessed by their capacity to prime allogeneic T cells. TolDCs displayed suppressor properties as demonstrated by a significantly reduced capacity to induce allogeneic T-cell proliferation and activation. ApoCell-loaded tolDCs generated from SLE monocytes have a stable immature/tolerogenic phenotype that can modulate CD4+ T-cell activation. These properties make them suitable for an antigen-specific immunotherapy for SLE. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a heterogeneous disease in which excessive inflammation, autoantibodies and complement activation lead to multisystem tissue damage. The contribution of the individual genetic composition has been extensively studied, and several susceptibility genes related to immune pathways that participate in SLE pathogenesis have been identified. It has been proposed that SLE takes place when susceptibility factors interact with environmental stimuli leading to a deregulated immune response. Experimental evidence suggests that such events are related to the failure of T-cell and B-cell suppression mediated by defects in cell signalling, immune tolerance and apoptotic mechanism promoting autoimmunity. In addition, it has been reported that dendritic cells (DCs) from SLE patients, which are crucial in the modulation of peripheral tolerance to self-antigens, show an increased ratio of activating/inhibitory receptors on their surfaces. This phenotype and an augmented expression of co-stimulatory molecules is thought to be critical for disease pathogenesis. Accordingly, tolerogenic DCs can be a potential strategy for developing antigen-specific therapies to reduce detrimental inflammation without causing systemic immunosuppression. In this review article we discuss the most relevant data relative to the contribution of DCs to the triggering of SLE. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus ( SLE) is an autoimmune disease characterized by multiple alterations affecting the normal function of immune cells, such as lymphocytes, dendritic cells ( DCs) and monocytes. Although the understanding of autoimmunity has significantly increased, the breakthrough in effective therapies has been modest, making necessary the development of new therapeutic strategies. Here we propose that a new potential target for therapy is haem oxygenase-1 ( HO-1), an enzyme that catalyses the degradation of the haem group into biliverdin, carbon monoxide ( CO) and Fe2+. These products exhibit immunosuppressive and anti-inflammatory effects, which can contribute to improving tolerance during organ transplantation. Because HO-1 is highly expressed by immune cells involved in SLE pathogenesis, such as monocytes and DCs, we evaluated whether induction of HO-1 expression or the administration of CO could ameliorate disease in the Fcγ RIIb knockout ( KO) mouse model for SLE. We found that CO administration decreased the expansion of CD11b+ cells, prevented the decline of regulatory T cells and reduced anti-histone antibodies observed in untreated Fcγ RIIb KO mice. Furthermore, CO-treated animals and HO-1 induction showed less kidney damage compared with untreated mice. These data suggest that HO-1 modulation and CO administration can ameliorate autoimmunity and prevent the lupus symptoms shown by Fcγ RIIb KO mice, highlighting HO-1 as a potential new target for autoimmune therapy. [ABSTRACT FROM AUTHOR]

The prostate is the seat of three major causes of morbidity: benign prostatic hyperplasia, prostate cancer and prostatitis, three conditions in which inflammation has been implicated. A state of inflammation of the prostate gland, originally incited by an infection, an autoimmune response, a neurogenic stimulus or another trigger may have consequences on prostate functionality. In fact, male fertility depends intrinsically on the content of prostatic fluid factors secreted by the prostatic epithelium. Taking into account that the prostate gland is the major male accessory gland that exerts essential functions for male fertility, a state of local inflammation can alter male fertility by either directly impairing sperm quality or, indirectly, by causing prostate dysfunction. In the present review, we summarise the current knowledge regarding prostatitis due to well‐known infections such as Escherichia coli, Chlamydia trachomatis and other commonly identified microorganisms focusing on inflammatory markers detected during these infections and seminal quality and male fertility alterations reported. We also focused on type III prostatitis or chronic nonbacterial prostatitis/chronic pelvic pain syndrome, of unknown aetiology, in which inflammation of an autoimmune origin, neurogenic stimuli or another trigger have been proposed and fertility alterations reported. [ABSTRACT FROM AUTHOR]