Driven by constantly increasing knowledge about skin immunology, vaccine delivery via the cutaneous route has recently gained renewed interest. Considering its richness in immunocompetent cells, targeting antigens to the skin is considered to be more effective than intramuscular or subcutaneous injections. However, circumvention of the superficial layer of the skin, the stratum corneum, represents the major challenge for cutaneous immunization. An optimal delivery method has to be effective and reliable, but also highly adaptable to specific demands, should avoid the use of hypodermic needles and the requirement of specially trained healthcare workers. The P.L.E.A.S.E.® (Precise Laser Epidermal System) device employed in this study for creation of aqueous micropores in the skin fulfills these prerequisites by combining the precision of its laser scanning technology with the flexibility to vary the number, density and the depth of the micropores in a user-friendly manner. We investigated the potential of transcutaneous immunization via laser-generated micropores for induction of specific immune responses and compared the outcomes to conventional subcutaneous injection. By targeting different layers of the skin we were able to bias polarization of T cells, which could be modulated by addition of adjuvants. The P.L.E.A.S.E.® device represents a highly effective and versatile platform for transcutaneous vaccination.
BackgroundSpecific immunotherapy via the subcutaneous or oral route is associated with local and, in some cases, systemic side effects and suffers from low patient compliance. Due to its unique immunological features, the skin represents a promising target tissue for effective and painless treatment of type I allergy. The current study was performed to compare the efficacy of transcutaneous immunotherapy via laser-generated micropores to subcutaneous injection.MethodsBALB/c mice were sensitized by intraperitoneal injection of recombinant grass pollen allergen Phl p 5 together with alum. Subsequently, lung inflammation was induced by repeated intranasal challenge. During the treatment phase, adjuvant-free Phl p 5 was applied in solution to microporated skin or was subcutaneously injected. Lung function and cellular infiltration; Phl p 5–specific serum levels of IgG1, IgG2a, and IgE; and cytokine levels in bronchoalveolar lavage fluids as well as in supernatants of splenocyte cultures were assessed.ResultsBoth therapeutic approaches reduced airway hyperresponsiveness and leukocyte infiltration into the lungs. Whereas subcutaneous immunotherapy induced a systemic increase in Th2-associated cytokine secretion, transcutaneous application revealed a general downregulation of Th1/Th2/Th17 responses. Successful therapy was associated with induction of IgG2a and an increase in FOXP3+ CD4+ T cells.ConclusionsTranscutaneous immunotherapy via laser microporation is equally efficient compared with conventional subcutaneous treatment but avoids therapy-associated boosting of systemic Th2 immunity. Immunotherapy via laser-microporated skin combines a painless application route with the high efficacy known from subcutaneous injections and therefore represents a promising alternative to established forms of immunotherapy.
The major histocompatibility complex (MHC) in several species is highly polymorphic with several different alleles and many different antigens associated with each MHC. Studying the graft-versus-host (GVH) response in the chicken, in which lymphocytes respond to MHC differences, Simonsen noted that up to 3% of lymphocytes respond to a single difference in the MHC (1). A similar high frequency of responding units exists in the mixed leukocyte culture (MLC) test (2-4), a model of the recognition phase of the GVH reaction. In the MLC test, responding lymphocytes of one animal enlarge, exhibit enhanced incorporation of radioactive thymidine, and divide if they encounter MHC differences on allogeneic stimulating cells.With the very great number of different alleles (and therefore antigens) associated with the MHC, possibly compounded by the existence of still different antigens to be recognized which are associated with xenogeneic MHC's, it has been suggested that the very high frequency of initially responding units in MLC is not consistent with clonal selection theory-. Many different explanations have been offered to explain this apparent inconsistency. Most recently the suggestion has been made that the normal MLC response is directed only at allogeneic differences since xenogeneic responses in MLC were markedly lower than allogeneic ones using conventional (cv) animals (5) and further, germfree (gf) animals showed no xenogeneic response while responding normally in allogeneic mixtures (6). If the number of different allogeneic antigens which must be recognized is not too great, and only allogeneic antigens can cause MLC activation, these findings would help resolve the inconsistency. We have presented data which show that the xenogeneic and allogeneic responses in cv animals are in many cases comparable (7).I n t h e p r e s e n t p a p e r we p r e s e n t d a t a which show t h a t a xenogeneic response c a n be o b t a i n e d in gf animals. O u r findings argue a g a i n s t t h e c o n c e p t t h a t t h e n o r m a l M L C response is aimed only at allogeneic MHC differences.
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