+ cells were mostly cd T cells, while ab T helper cells were much less frequent. Successful treatment rendering TAO inactive apparently downregulates monocyte influx, macrophage differentiation, and T cell receptor expression. Similar trends were recorded for adipose tissue. Interestingly, RFD1+ DCs were completely absent from all conditions examined. Conclusion: A-TAO coincides with periorbital monocyte infiltration and de novo differentiation of macrophages, but not DCs. The authors discuss a novel potential role for inflammatory CD4+ cd T cells in TAO. Successful treatment apparently downregulates orbital monocyte recruitment and effects functional T cell knockout.
Because thyroidal dendritic cells (t-DC) may be implicated in the pathogenesis of Graves' disease (GD), we compared t-DC in thyroid sections of patients with GD (n 15) and control patients with toxic (TG; n 12) or non-toxic goitre (NG; n 12). Goitres in GD, but not TG or NG, were populated with three discernible t-DC phenotypes. (i) Immature t-DC (major histocompatibility complex (MHC) II /CD40 ± /CD80 ± ) were located perifollicularly (95% of the patients with GD, but only 55% of TG and 51% of NG patients); numbers of such t-DC were significantly elevated in GD (P < 0.001). (ii) Partially matured CD80 t-DC were present in connective tissue (73% of the patients) and focal interstitial clusters (40% of the patients). In 53% of the patients with GD, single as well as clustered interstitial t-DC expressed CD40. (iii) However, phenotypically mature t-DC (MHC II /CD40 / CD80 /RFD1 ) were only present in clusters and colocalized with activated CD4 /MHC class II T-helper (Th) cells. Expression of CD54 and CD83 did not significantly differ among the groups. The phenotype of intrathyroidal DC in GD thus supports their role as potential (co)stimulators of thyroid autoimmunity.
Conventional treatment approaches for malignant tumors are highly invasive and sometimes have only a palliative effect. Therefore, there is an increasing demand to develop novel, more efficient treatment options. Increased efforts have been made to apply immunomodulatory strategies in antitumor treatment. In recent years, immunizations with naked plasmid DNA encoding tumor-associated antigens have revealed a number of advantages. By DNA vaccination, antigen-specific cellular as well as humoral immune responses can be generated. The induction of specific immune responses directed against antigens expressed in tumor cells and displayed e.g., by MHC class I complexes can inhibit tumor growth and lead to tumor rejection. The improvement of vaccine efficacy has become a critical goal in the development of DNA vaccination as antitumor therapy. The use of different DNA delivery techniques and coadministration of adjuvants including cytokine genes may influence the pattern of specific immune responses induced. This brief review describes recent developments to optimize DNA vaccination against tumor-associated antigens. The prerequisite for a successful antitumor vaccination is breaking tolerance to tumor-associated antigens, which represent “self-antigens.” Currently, immunization with xenogeneic DNA to induce immune responses against self-molecules is under intensive investigation. Tumor cells can develop immune escape mechanisms by generation of antigen loss variants, therefore, it may be necessary that DNA vaccines contain more than one tumor antigen. Polyimmunization with a mixture of tumor-associated antigen genes may have a synergistic effect in tumor treatment. The identification of tumor antigens that may serve as targets for DNA immunization has proceeded rapidly. Preclinical studies in animal models are promising that DNA immunization is a potent strategy for mediating antitumor effects in vivo. Thus, DNA vaccines may offer a novel treatment for tumor patients. DNA vaccines may also be useful in the prevention of tumors with genetic predisposition. By DNA vaccination preventing infections, the development of viral-induced tumors may be avoided.
Graves’ disease (GD) coincides with the occurrence of disease‐associated intrathyroidal dendritic cells (DC) and intraorbital inflammatory macrophages (Mφ). Physiologically, tumour necrosis factor‐α (TNF‐α) strongly affects the differentiation of DC and Mφ from monocytic precursors; we thus hypothesized that dysregulation of the TNF/TNFR superfamilies may provide a systemic pathogenic link in GD. In patients without eye symptoms, percentages of TNF‐α‐stimulated blood monocytes were highly significantly (P < 0.001) elevated, corresponding to both intrathyroidal DC maturation as well as increases in mature blood DC (MHC‐IIhi/CD40+/RFD1hi) and B cells (CD20hi/CD40+). GD patients also displaying eye symptoms revealed a striking reduction in blood monocytes, yet significantly (P < 0.05) increased CD40hi and TNF‐αhi leucocytes. These findings suggest for GD that excess TNF‐α induces monocytes to differentiate into hyperactivated thyroidal DC that, once emigrated, initiate systemic humoral autoimmunity associated with CD40/TNF‐α upregulation. Such overexpression may instigate differentiation of periorbital inflammatory Mφ from CD14hi/CD16+ monocytes as a likely precursor subset. These results indicate that dysregulation of TNF/TNFR superfamily members provides a systemic pathogenic link in GD in that hyperactivated circulating monocytic precursors give rise to locally restricted, disease‐associated DC and Mφ. Monocytes, therefore, may serve as a suitable target to therapeutically address the common precursor of key promoters of GD.
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