Uric Acid; a Possible Mediator of the Adjuvant Effect of Alum in Mice Immunized with Ovalbumin

Abstract

One proposed mechanism by which alum enhances an immune response is by its ability to induce an inflammatory response that results in the release of uric acid from necrotic cells. Uric acid is thought to be a mediator in enhancing the immune response. The aim of this study was to investigate the immunopotentiating effect of uric acid. Groups of BALB/c mice were injected intraperitoneally with ovalbumin, ovalbumin + alum, ovalbumin + uric acid, uric acid, alum, or allopurinol. Two other groups were pretreated with allopurinol and were given ovalbumin + alum, or ovalbumin + uric acid 24 hours later. An additional two groups served as controls. On days 4, 7 and 10 post-injection, the numbers of Interleukin 4(IL-4) and Interferon-γ (IFN-γ) secreting spleen cells were determined by the ELISPOT assay. Serum uric acid levels were determined using an autoanalyser and nitric oxide using the Greiss reagent. The groups that received alum + ovalbumin or uric acid + ovalbumin had the highest numbers of IL-4 and INF-γ secreting cells as compared to all the groups. Allopurinol administration one day prior to alum + ovalbumin or uric acid + ovalbumin resulted in a decrease in the number of IL-4 and INF-γ secreting cells when compared to alum+ ovalbumin or uric acid + ovalbumin allopurinol - untreated groups. Groups that received alum, alum + ovalbumin, uric acid, and uric acid + ovalbumin had high serum uric acid levels as compared to all the groups. All groups that received alum had the highest levels of nitric oxide when compared to the groups that were not given alum. In conclusion, it appears that uric acid might be a mediator in the adjuvant effect of alum.

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N. Al-Akl, M. Chakhtoura, N. Kazzi, J. Usta, C. Chamoun and A. Abdelnoor, "Uric Acid; a Possible Mediator of the Adjuvant Effect of Alum in Mice Immunized with Ovalbumin," World Journal of Vaccines, Vol. 1 No. 4, 2011, pp. 148-155. doi: 10.4236/wjv.2011.14015.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] H. HogenEsch, “Mechanisms of Stimulation of the Immune Response by Aluminum Adjuvants,” Vaccine, Vol. 20, Suppl. 3, 2002, pp. 34-39. doi:10.1016/S0264-410X(02)00169-X
[2] M. Kool , T. Soullié ,M. Van Nimwegen, M.A. Willart, F. Muskens, S. Jung, H.C. Hoogsteden, H. Hammad and B. Lambrecht, “Alum Adjuvants Boosts Adaptive Immunity by Inducing Uric Acid and Activating Inflammatory Dendritic Cells,” The Journal of Experimental Medicine, Vol. 205, No. 4, 2008, pp. 869-882. doi:10.1084/jem.20071087
[3] E. B. Lindblad, “Aluminum Adjuvants in Retrospect and Prospect,” Vaccine, Vol. 13, No. 22, 2004, pp. 3658-3668. doi:10.1016/j.vaccine.2004.03.032
[4] E. DeGregorio, E. Tritto and R. Rappuoli, “Alum Adjuvanticity: Unraveling a Century Old Mystery,” European Journal of Immunology, Vol. 38, No. 8, 2008 pp. 2068- 2071. doi:10.1002/eji.200838648
[5] J. N. Francis and S. R. Durham, “Adjuvants for Allergen Immunotherapy: Experimental Results and Clinical Perspectives,” Current Opinion in Allergy and Clinical Immunology, Vol. 4, No. 6, 2004, pp. 543-548. doi:10.1097/00130832-200412000-00012
[6] M. B. Jordan, D. M. Mills, J. Kappler, P. Marrack and J. C. Cambier, “Promotion of B Cell Immune Responses via an Alum-Induced Myeloid Cell Population,” Science, Vol. 304, No. 5678, 2004, pp. 1808-1810. doi:10.1126/science.1089926
[7] H. Li, S. Nookala and F. Re, “Aluminum Hydroxide Adjuvants Activate Caspase-1 and Induce IL-1 Beta and IL-18 Release,” Journal of Immunology, Vol. 178, No. 8, 2001, pp. 5271-5276.
[8] J. C. Cox and A. R. Coulter, “Adjuvants—A Classification and Review of Their Modes of Action,” Vaccine, Vol. 15, No. 3, 1997, pp. 248-256. doi:10.1016/S0264-410X(96)00183-1
[9] M. Ulanova, A. Tarkowski, M. Hahn-Zoric and L. Hanson, “The Common Vaccine Adjuvant Aluminum Hydroxide Up-Regulates Accessory Properties of Human Monocytes via an Interleukin-4-Dependent Mechanism,” Infection and Immunity, Vol. 69, No. 2, 2001, pp. 1151- 1159. doi:10.1128/IAI.69.2.1151-1159.2001
[10] R. G. White, A. H. Coons and J. M. Connoly, “Studies on Antibody Production. III. The Alum Granuloma,” Journal of Experimental Medicine, Vol. 102, No. 1, 1955, pp. 73- 82. doi:10.1084/jem.102.1.73
[11] G. L. Morefield, A. Sokolovska, D. Jiang, H. HegenESch, J. P. Robison and S. L. Hem, “Role of Aluminum-Con- taining Adjuvants in Antigen Internalization by Dendritic Cells in Vitro,” Vaccine, Vol. 23, No. 13, 2005, pp. 1588- 1595. doi:10.1016/j.vaccine.2004.07.050
[12] E. Tritto, F. Mosca and E. De Gregorio, “Mechanism of Action of Licensed Vaccine Adjuvants,” Vaccine, Vol. 27, No. 25-26, 2009, pp. 3331-3334. doi:10.1016/j.vaccine.2009.01.084
[13] S. Galluci, M. Lolkema and P. Matzinger, “Natural Adjuvants: Endogenous Activators of Dendritic Cells,” Nature Medicine, Vol. 5, No. 11, 2000, pp. 1249-1255. doi:10.1038/15200
[14] D. E. Hu, A. Moore, L. Thomsen and K. Brindle, “Uric Acid Promotes Tumor Immune Rejection,” Cancer Research, Vol. 64, No. 15, 2004, pp. 5059-5062. doi:10.1158/0008-5472.CAN-04-1586
[15] Y. Shi, J. E. Evans and K. L. Rock, “Molecular Identification of a Danger Signal That Alerts the Immune System to Dying Cells,” Nature, Vol. 425, No. 6957, 2003, pp. 516-521. doi:10.1038/nature01991
[16] M. Behrens, W. Wagner, C. Krco, C. Erskine, K. Kalli , J. Krempski, E. Gad, M. Disis and K. Knutson, “The Endogenous Danger Signal, Crystalline Uric Acid, Signals for Enhanced Antibody Immunity,” Blood, Vol. 111, No. 3, 2008, pp. 1472-1479. doi:10.1182/blood-2007-10-117184
[17] R. L. Hunter, “Overview of Vaccine Adjuvants: Present and Future,” Vaccine, Vol. 20, No. 3, 2002, pp. 7-12. doi:10.1016/S0264-410X(02)00164-0
[18] F. Martinon, V. Petrilli, A. Mayor, A. Tardivel and J. Tschopp, “Gout Associated Uric Acid Crystals Activate the NALP3 Inflammasome,” Nature, Vol. 440, No. 7081, 2006, pp. 237-241. doi:10.1038/nature04516
[19] Y. Shi, W. Zheng and K. L. Rock, “Cell Injury Releases Endogenous Adjuvants That Stimulate Cytotoxic T Cell Responses,” Proceedings of the National Academy of Science, Vol. 97, No. 26, 2000, pp. 14590-14595. doi:10.1073/pnas.260497597
[20] Y. Shi, S. A. Galusha and K. L. Rock, “Cutting Edge: Elimination of an Endogenous Adjuvant Reduces the Activation of CD8 T Lymphocytes to Transplanted Cells and in an Autoimmune Diabetes Model,” Journal of Immunology, Vol. 176, No. 7, 2006, pp. 3905-3908.
[21] R. Webb, M. Jeffries and A. H. Sawalha, “Uric Acid Directly Promotes Human T-Cell Activation,” The American Journal of the Medical Sciences, Vol. 337, No. 1, 2009, pp. 23-27. doi:10.1097/MAJ.0b013e31817727af
[22] G. Vielhauer, E. Gad, W. Wagner, M. L. Disis and K. L. Knutson, “The Endogenous Danger Signaling Molecule, Uric Acid, Converts Immunity from Non-Protective to Protective When Used as a Vaccine Adjuvant,” American Association for Cancer Research, Vol. 46, 2005, Abstract 5167.
[23] J. M. Brewer, M. Conacher, A. Satoskar, H. Bluethmann and J. Alexander, “In Interleukin-4 Deficient Mice, Alum Not Only Generates T Helper-1 Responses Equivalent to Freund’s Complete Adjuvant, But Continues to Induce T Helper-2 Cytokine Production,” Journal of Immunology, Vol. 26, No. 9, 1996, pp. 2062-2066.
[24] W. S. Waring, J. D. Webb and R. J. S. Maxwell, “Systemic Uric Acid Administration Increases Serum Antioxidant Capacity in Healthy Volunteers,” Journal of Cardiovascular Pharmacology, Vol. 38, No. 3, 2001, pp. 365-371. doi:10.1097/00005344-200109000-00005
[25] G. B. Elion, “The Purine Path to Chemotherapy,” Bioscience Reports, Vol. 9, No. 5, 1989, pp. 509-529. doi:10.1007/BF01119794
[26] G. B. Elion, “Enzymatic and Metabolic Studies with Allopurinol,” Annals of the Rheumatic Diseases, Vol. 25, No. 6, 1966, pp. 608-614.
[27] J. R. Parratt, “Nitric Oxide in Sepsis and Endotoxaemia,” Journal of Antimicrobial Chemotherapy, Vol. 41, Suppl. A, 1998, pp. 31-39. doi:10.1093/jac/41.suppl_1.31

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