We have determined in mice the minimum composition required for forming a vaccine adjuvant that stimulates a regulatory T (Treg) cell response to immunization, and we named the adjuvant “complete tolerogenic adjuvant.” This new kind of adjuvant may let us use the well-proven “Ag with adjuvant” form of immunization for inducing Treg cell–mediated Ag-specific immunosuppression. The minimum composition consists of dexamethasone, rapamycin, and monophosphoryl lipid A at a mass ratio of 8:20:3. By dissecting the respective role of each of these components during immunization, we have further shown why immunosuppressive and immunogenic agents are both needed for forming true adjuvants for Treg cells. This finding may guide the design of additional, and potentially more potent, complete tolerogenic adjuvants with which we may form numerous novel vaccines for treating immune diseases.
Atherosclerosis is driven partly by inflammation, mediated mainly by pro-inflammatory mediators/cytokines. Previous studies have revealed the role of HMGB1, a prototypic DAMP (damage-associated molecular pattern) molecule, in atherogenesis. Recently, we have found that there is a spontaneous production of a neutralizing anti-HMGB1 IgM antibody in the Apoe−/− mouse model of atherosclerosis and healthy humans. In the present study, we have determined whether raising the anti-HMGB1 IgM, via immunization targeting HMW4 (a dominant epitope of HMGB1), reduces atherosclerosis. We first showed that the immunization of 8-week-old Apoe−/− C57BL/6 mice increased the HMW4-specific B-1 cells (which produce anti-HMW4 IgM), identified by HMW4-tetramer staining/flow cytometry. Next, we assessed the anti-atherogenic efficacy of the immunization. To the end, 8-week-old Apoe−/− mice were divided into 4 groups (n = 10/group). Each group was treated with: 1) HMW4 (“test”); 2) raHMW4 (randomized control peptide) (“control”); 3) depletion of the HMW4-specific B cells (to prevent the production of anti-HMW4 IgM), followed by the immunization (control for B cell dependence); or 4) none. At 12 weeks of age, mice were fed a western type diet (WTD) for 12 weeks. Lesions in treated mice were then quantified, by both en face analysis of the aortic arch and morphometric analysis of ORO-stained sections of the aortic root. The “test” group showed reduction in atherosclerosis (by ~40%), when compared to the “control” group (p = 0.006) or non-treated group (p = 0.01). Such reduction was diminished when the anti-HMW4 IgM-producing B cells were depleted (p = 0.02). This study raises the possibility to amplify the anti-HMGB1 IgM response to reduce atherosclerosis.
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