A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy

Abstract

Epitope-based peptide vaccines encompass minimal immunogenic regions of protein antigens to allow stimulation of precisely targeted adaptive immune responses. However, because efficacy is largely determined by the functional status of antigen-presenting cells (APCs) that acquire and present peptides to cells of the adaptive immune system, adjuvant compounds are needed to enhance immunogenicity. We present here a vaccine consisting of an allergen-derived peptide conjugated to a prodrug of the natural killer-like T (NKT) cell agonist α-galactosylceramide, which is highly effective in reducing inflammation in a mouse model of allergic airway inflammation. Unlike other peptide-adjuvant conjugates that directly activate APCs through pattern recognition pathways, this vaccine encourages third-party interactions with NKT cells to enhance APC function. Therapeutic efficacy was correlated with marked increases in the number and functional activity of allergen-specific cytotoxic T lymphocytes (CTLs), leading to suppression of immune infiltration into the lungs after allergen challenge in sensitized hosts.

Immunomodulatory spherical nucleic acids

“…Promising early results have been observed in preclinical and clinical studies, particularly in infectious disease (1,2), cancer (3)(4)(5), allergy (6)(7)(8), and autoimmune disease applications (9,10). Several classes of agents are currently being evaluated for their ability to stimulate or repress immunity, but few are as versatile as nucleic acids.…”

Antigen-specific cytotoxic T lymphocytes target airway CD103+ and CD11b+ dendritic cells to suppress allergic inflammation

“…Use of this model was necessary to enable a precise quantitation of allergen-specific, IL-4-and IL-13-producing CD4 þ T cells in the lung. Importantly, the conditions for adoptive transfer experiments were chosen to closely recapitulate findings in normal C57BL/6 or PKO mice primed with allergen to elicit a Th2 response, and vaccinated with DC þ allergen peptides 7 (Figure 1) or a-Gal-Cer-peptide conjugates 14 to elicit a CTL response. In all cases, allergenspecific CTLs were found to mediate suppression of airway inflammation, whereas CTLs of irrelevant specificity had a modest or undetectable effect.…”

“…[6][7][8][9][10][11][12][13][14] We focused our study on allergen-specific CTLs as they are profoundly inhibitory, and they could potentially form the basis of allergen-specific immunotherapies. Our previous work showed that Ag-specific CTLs can inhibit the priming of naïve CD4 þ T cells in vivo, 21 and that their cytotoxic function is critical to their ability to inhibit allergic airway inflammation.…”

“…[6][7][8][9][10][11][12][13] In particular, allergen-specific CTLs are especially effective at suppressing disease 7,13 and can be primed through appropriate vaccination to reduce airway eosinophilia and mucus production. 14 Studies to establish how CTLs might be reducing inflammation showed that expression of the cytotoxic mediator perforin in the CTL population was essential, whereas interferon (IFN)-g was neither necessary nor sufficient to suppress inflammation. 7 These studies point to CTL-mediated killing as being critical for inhibition, however, the precise identity and location of the targets of allergen-specific CTLs were not established.…”

Selective quantitation of the incorporation of the immunomodulator α-galactosylceramide in liposomes using LC–MS/MS

“…Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an analytical technique with high selectivity and sensitivity able to detect and quantify analytes such as pharmaceutical actives and excipients [11] that has been used to analyse the chemical synthesis of α-GalCer and analogues [12]. The multiple reaction monitoring (MRM) mode of the tandem mass spectrometer allows for high selectivity by measuring the unique fragmented species of the original molecule.…”