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. 2008 Feb 1;111(3):1472-9.
doi: 10.1182/blood-2007-10-117184. Epub 2007 Nov 20.

"VSports最新版本" The endogenous danger signal, crystalline uric acid, signals for enhanced antibody immunity

Marshall D Behrens  1 , Wolfgang M Wagner, Christopher J Krco, Courtney L Erskine, Kimberly R Kalli, James Krempski, Ekram A Gad, Mary L Disis, Keith L Knutson
Affiliations

The endogenous danger signal, crystalline uric acid, signals for enhanced antibody immunity

Marshall D Behrens et al. Blood. .

Abstract

Studies have shown that the immune system can recognize self-antigens under conditions (eg, cell injury) in which the self-tissue might elaborate immune-activating endogenous danger signals. Uric acid (UA) is an endogenous danger signal recently identified to be released from dying cells. Prior work has shown that UA activates immune effectors of both the innate and adaptive immune system, including neutrophils and cytotoxic T-cell immunity. However, it was unclear whether UA could enhance antibody immunity, which was examined in this study. When added to dying tumor cells or with whole protein antigen, UA increased IgG1-based humoral immunity. Further, UA blocked growth of tumor in subsequent tumor challenge experiments, which depended on CD4, but not CD8, T cells. Sera derived from UA-treated animals enhanced tumor growth, suggesting it had little role in the antitumor response. UA did not signal for T-cell expansion or altered tumor-infiltrating leukocyte populations VSports手机版. Consistent with the lack of T-cell expansion, when applied to dendritic cells, UA suppressed T-cell growth factors but up-regulated B cell-activating cytokines. Understanding the nature of endogenous danger signals released from dying cells may aid in a better understanding of mechanisms of immune recognition of self. .

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Figure 1
Figure 1
Uric acid signals for enhanced antitumor immunity. (A) Tumor growth measurements for animals treated with dying tumor cells, either alone or along with various concentrations of uric acid (UA) prior to tumor challenge. Control animals (none) received 25 μg UA. Each data point is a mean (± SEM) tumor measurement calculated from 6 animals per group. A similar experiment yielded similar results. (B) Survival curves for mice, treated the same as in panel A, over a course of 75 days. The experiment is representative of 2 similar independent experiments. (C) Tumor growth measurements in animals treated with dying tumor cells and 25 μg UA alone or following depletion of either CD8 or CD4 T cells. Control animals received no treatments. Measurements are the mean (± SEM) of 4 animals per group. A repeat experiment gave identical results.
Figure 2
Figure 2
UA signals for enhanced tumor-specific IgG1 antibodies. (A) The tumor-specific antibody concentration in the serum 14 days after 2 injections of dying tumor cells alone (T), tumor cells with UA (T + UA) or with UA alone (UA). Each bar represents the mean (± SEM) of 12 replicates calculated from the optical densities (× 1000) in the ELISA assay. Similar to panel A, panels B and C show the levels of IgG1 and IgG2a, respectively. Each mean (± SEM) is calculated from 2 to 7 replicates. (D) The mean fluorescent intensity (MFI) of tumor cells stained with IgG from sera of animals. Each bar represents the mean (± SEM) of 3 replicates; *P = .05. (E) Rat neu-specific IgG levels in animals treated as determined by capture sandwich ELISA. Each bar is the mean (± SEM) of 3 determinations. (F) Western immunoblot analysis of rat neu immunoprecipitated with sera. Numbers shown are the position of the molecular weight markers (KDa). (G-I) The serum levels of total IgG (F), IgG1 (G), and IgG2a (H) specific for ovalbumin from control mice (Cont), ovalbumin-immunized (Oval), or OVAL/UA-immunized (Oval + UA) mice (n = 5-7). The levels of IgG and IgG1 obtained following ovalbumin immunization were not significantly different (P > .05).
Figure 3
Figure 3
UA did not augment T-cell expansion or alter tumor-infiltrating leukocytes levels. (A) The levels of IL-4–secreting cells that responded to either ConA or tumor cell lysates. Splenocytes for the ELIspot assay were obtained from animals injected with tumor cells alone (▭), tumor cells with 25 μg UA (formula image), and 25 μg UA alone (formula image). Each bar represents the mean (± SEM) of 12 determinations. (B) The levels of IFN-γ–secreting T cells responding to no antigen, ConA, or neu-derived MHC class I peptide p420-429. Splenocytes were derived from animals that received dying tumor cells with various levels of UA. Each bar is the mean of 9 determinations. (C) The numbers of neu peptide p420-429 tetramer-positive T cells in draining nodes or splenocytes from mice depicted in panel F. Each is the mean (± SEM) of triplicate determinations calculated from 3 mice. (D,E) The frequencies of Oval(323)-specific CD4+DO11.10 T cells (D) and Oval(257)-specific CD8+OT-I T cells (E) as percentage of all CD3+ splenocytes in untreated control (Cont), ovalbumin cognate peptide/UA (UA), or cognate ovalbumin peptide/GM-CSF (GM). Each bar represents the mean (± SEM) of 7 replicates and represents 2 identical experiments, which yielded similar results. (F-L) The levels of various leukocytes in tumors from mice that received either no treatment (Cont) or pretreatment with tumor cells and 25 μg UA (T + UA), prior to tumor injection. Each bar is the mean (± SEM) of 3 replicates. Each graph represents a unique intratumoral leukocyte population from control, untreated mice and from mice pretreated with dying tumor cells containing UA. All are calculated from 100 000 total events. Results are expressed as the percentage of total cells, both tumor cells and leukocytes, collected following tumor mincing.
Figure 4
Figure 4
UA favors an IL-5–based Th2 immune response. (A,B) The cytokine concentrations of cell culture supernatants from purified antigen-stimulated DO11.10 CD4 T cells stimulated by DCs stimulated with either control media (control) or 10 μg/mL UA (UA) and ovalbumin antigen (OVAL). Each represents the mean (± SEM) cytokine concentration from duplicate wells. Experiment was reproduced twice with similar results. (C,D) Cytokine concentrations of cell culture supernatants from purified CD11C+ splenic dendritic cells stimulated with UA (UA) or media alone (CONT). Each represents the mean (± SEM) cytokine concentration from duplicate wells. Experiment was reproduced twice with similar results.
Figure 5
Figure 5
UA may induce growth-promoting antibodies. (A) In vivo tumor growth of MMC tumor cells following intratumoral injection (day 0) of sera from naive animals or from animals from either pretreated with irradiated tumor with (T + UA) or without (T) uric acid. Calculated from 3 separate tumors for each data point. Curves overlap. (B) The thymidine incorporation in live MMC tumor cells exposed to media (■) or various concentrations of serum from animals treated with UA alone (U alone, ▴), irradiated tumor alone (T, ♦), or with UA (T + UA, •). Each determination represents the mean (± SEM) of 3 determinations; *P = .01.
Figure 6
Figure 6
UA does not prevent increased T-cell immunity induced by other means. (A) The peripheral levels of Tregs (CD4+CD25+Foxp3+ or CD8+CD25+Foxp3+) in animals injected with dying tumor cells alone (T) or with tumor cells with UA (T + UA). Each bar is the mean (± SEM; *P < .05) of 3 mice. (B) Levels of neu peptide tetramer+ CD8+CD62Llo T cells (ie, effector or effector memory) in control animals, or animals injected with tumor cells (T) with or without UA (UA) or ONTAK (On). Each bar is the mean (± SEM) of 3 to 4 mice. (C) The tumor growth rates in mice pretreated with tumor cells alone and tumor cells with or without UA, ONTAK, or both. Each data point is the mean (± SEM) of 3 to 5 mice. *P < .05 compared with all other groups.
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