Starten Sie Ihre Suche...


Durch die Nutzung unserer Webseite erklären Sie sich damit einverstanden, dass wir Cookies verwenden. Weitere Informationen

Tailoring Transcutaneous Immunization for optimal T–helper cell activation

Laufzeit: 01.01.2017 - 31.12.2018

imported

Kurzfassung


Transcutaneous immunization (TCI) is a novel vaccination strategy that is increasingly used by vaccine developers to overcome the current limitations of standard approaches. Transcutaneous vaccines are particularly attractive as they incorporate all desirable properties of an ideal vaccine: namely making use of defined antigen specificities, targeting skin resident professional antigen-presenting cells (APC) along with well-defined adjuvants. Such non-invasive vaccination procedures via the...Transcutaneous immunization (TCI) is a novel vaccination strategy that is increasingly used by vaccine developers to overcome the current limitations of standard approaches. Transcutaneous vaccines are particularly attractive as they incorporate all desirable properties of an ideal vaccine: namely making use of defined antigen specificities, targeting skin resident professional antigen-presenting cells (APC) along with well-defined adjuvants. Such non-invasive vaccination procedures via the skin are able to elicit potent adaptive immune responses, such as protective antibody formation as pioneered by Glenn and coworkers 1. In transcutaneous vaccination approaches, the dosage and combination of antigens and adjuvants as well as targeting of skin draining lymph node areas can be easily and specifically achieved by the selection of skin areas or body regions. In contrast, parental (subcutaneous or intramuscular) vaccine delivery systems are not well controlled in terms of drug release and targeting of specific immune organs. Thus in parental vaccines, it is very difficult to establish correlations between antigen or adjuvant dosage and vaccination efficacy.
In our previous work, we demonstrate that the concurrent application of a cytotoxic T lymphocyte (CTL) epitope together with imiquimod onto the intact skin elicits potent primary CTL responses 2 by the Toll-like receptor (TLR7) dependent activation of dermal dendritic cells (DC) to initiate adaptive immunity 3. Beyond the proof-of-concept of imiquimod-based TCI demonstrated in an experimental rodent model by us and others, the enhanced efficacy of influenza vaccinations in humans pretreated with imiquimod 4 allows the assumption that such novel vaccination concepts may be also effective in human cancers.
However, CTL responses induced by TCI with imiquimod based on the commercial formulation in Aldara™ rapidly fade away, resulting in poor memory formation and only partial tumor protection. Nevertheless, these T-cell responses and tumor protection can be rescued by additional stimuli, i. e. by CD40 ligation mimicking a CD4-T helper cell responses, highlighting the importance of “high quality” T-cell responses that confer effective memory. This also indicates that imiquimod formulated in Aldara is not an ideal formulation for vaccination purposes. An additional major drawback of the commercially available imiquimod formulation is the limited option to adapt this particular formulation for various peptides or additional immune response modifiers to enhance vaccination efficacy.
To overcome these limitations with the commercial imiquimod formulation, we have developed a novel imiquimod formulation (IMI-Sol). Comparing Aldara TCI with IMI-Sol TCI using the MHC I restricted model antigen peptide OVA257-264 from chicken ovalbumin reveals comparable imiquimod concentrations within the skin, but strongly enhanced primary CTL responses upon IMI-Sol TCI 5. Analyzing the underlying mechanisms of increased CTL responses we confirm a complete dependency of IMI-Sol TCI on TLR7 and the adaptor molecule MyD88. Furthermore, we found an enhanced DC activation phenotype suggesting that imiquimod formulated in IMI-Sol mediates a more pronounced local inflammatory response. Beyond this, using the novel IMI-Sol formulation, we are now able to also elicit CD4-T cell responses against a MHC II restricted model epitope (OVA323-339, derived from ovalbumin). Our unpublished data show that the concurrent transcutaneous application of the MHC I and MHC II peptides formulated in IMI-Sol elicits superior CD8 as well as CD4 T cell responses, in contrast to Aldara based TCI. Thus, our novel formulation IMI-Sol has superior immunological and pharmaceutical properties. This novel formulation will be used for the further preclinical development of a transcutaneous vaccination platform that allows tailoring CD8 and CD4 T-cell responses as desired to modulate protective immune rsponses against cancer or infectious diseases.
 
» weiterlesen» einklappen

Beteiligte Einrichtungen