Utilising a Human Skin Model to Optimise Transcutaneous Delivery as a Vaccine Strategy

Overview

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Background

Transcutaneous immunization (TCI) involves the direct application of adjuvant plus antigen to skin, taking advantage of the large numbers of Langerhans cells (LC) resident in the epidermis. LCs are bone marrow–derived antigen presenting cells that migrate to and reside in the epidermis where they act as sentinels monitoring the skin environment.

Due to their morphology LC cover about 25% of the skin surface area even though they constitute only 3% of the total epidermal cell number. Recruitment of LC precursors to, and their retention in the epidermis is dependent upon chemokine–mediated signalling (CXCL14 and CCL20) and adhesion molecule dependent (E–cadherin) interactions with structural cellular components of the epidermis such as keratinocytes. The cytokine environment of the epidermis also contributes to the final differentiation of LC and involves GM–CSF, IL–15 and TGFb. upon contact of the skin with foreign antigen a range of pro–inflammatory cytokines and chemokines (including IL–1b, IL–6, TNFa, GM–CSF, CXCL2/CXCL3) are produced.

These cytokines alter adhesion molecule expression (loss of E–cadherin, changes in CD324, CD54/ICAM–1) on LC facilitating their migration out of the epidermis. Inflammatory cytokines also induce production of matrix metalloproteinases by LC to enable their passage across the basement membrane. Recruitment of activated LC to the T cell areas of regional draining lymph nodes is then induced by the interaction of CCR7–CCL21. The function of LC in monitoring the skin environment for signs of danger, then presenting a “snapshot” of this danger, in the form of phagocytosed antigen to naïve immune cells in the LN to induce an active immune response is essential to the success of TCI.

Benefits

The majority of studies involving TCI have been carried out in mouse models, even though a limited number of human trials have been performed. To optimise transcutaneous delivery as a vaccine strategy in humans a human skin model would be of great benefit in order to study ways of:

enhancing antigen/adjuvant penetration of the stratum corneum
recruiting/activating LC in the epidermis
regulating migration of activated DC out of the epidermis
enhancing LC–T cell interactions.

Proposed studies

In the proposed studies we will adapt the skin culture model developed by TRR to incorporate immune system cells (LCs and T cells) and use this model to evaluate mechanisms of antigen presentation using a model antigen tetanus toxoid.

Study level

Honours

Supervisors

QUT

Organisational unit