T cells and immunomodulation in canine atopic dermatitis

Abstract

Atopic dermatitis (AD) in dogs is defined as “a genetically-predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features.” It is associated most commonly with IgE antibodies specific for common environmental allergens such as house dust mites, grass and plant pollens. The etiology of cAD is considered as multifactorial. An epidermal barrier dysfunction combined with dysregulation of the immune system leads to the development of clinical disease in dogs with a suggested genetic background for AD. T-lymphocytes (T cells) with effector functions play a dominant role in the development of atopic skin lesions. T cells with regulatory functions (Tregs) also exist. However, whether absence or reduction in number and function of Tregs may contribute to the development of canine AD skin lesions, was unknown. The only disease-modifying treatment available is the allergen-specific immunotherapy (ASIT). Success of ASIT in atopic dogs is currently only achieved in 50-80%, hence, potentiation of ASIT in order to improve its efficacy would be beneficial for future therapeutic interventions of cAD. A better understanding of immunoregulatory mechanisms may be at the basis for more successful ASIT. Tregs are thought to contribute to the beneficial effects of ASIT in AD. For that reason, the research questions addressed in this thesis focussed on the dysbalance of T cell responsiveness, with emphasis on the possible roles of Tregs and CD8+ T cells within the etiology of cAD.In addition, the effects of two different immunomodulatory compounds (Hsp and CpG ODN), potentially capable of restoring the dysbalance in T cell responsiveness in cAD, were evaluated. This thesis shows that cells of not only the subpopulation of CD4+ T cells, but also the subpopulation of CD8+ T cells likely contribute to the disease by producing inflammatory cytokines. First evidence for presence of allergen-specific CD8+ T cells was found in the peripheral blood of AD dogs. In addition to a role as effector T cell, CD8+ T cells may also have a regulatory function. Presence of T cells of both CD4+ and CD8+ lineages with regulatory markers (CD25+FoxP3+) have been found in the peripheral blood and skin of AD dogs. However, at this moment, we don’t know their role in the immunopathogenesis of cAD, since their numbers were largely similar to those in healthy dogs. The Treg function could be diminished or Tregs could have been functionally overruled by the high numbers or activation status of effector T cells in lesional atopic skin. Future functional studies, including suppression assays, need to be performed to determine the relevance of the T cells with regulatory markers and their usefulness as targets in new immunomodulatory strategies for dogs with AD.