Atopy – Atopic Dermatitis

Finally, a targeted therapy that addresses canine atopy (atopic dermatitis) at its CORE!

TCR Vaccines are a brand new therapeutic approach which targets the central regulator of atopic dermatitis, being the T-helper cell.

Technical Summary: Canine Atopic Dermatitis (AD, atopy) is one of the most common dermatological conditions in dogs, and is mediated by T-helper (Th) cells.  Immune dysregulation, and particularly Th2-cell dominance, is considered the pivotal factor in the immunopathology of atopy. The etiology of AD has not been fully elucidated but certainly multifactorial, involving complex interplay among IgE-mediated allergic reactions to environmental allergens, antigen-presenting cells, T lymphocytes, eosinophils, and mast cells.  One current concept is  that AD  is the result of a systemic inflammatory reaction triggered by type 2 T helper (Th2) lymphocyte mediated immune response against innocuous environmental allergens (Romagnini, 2004)[1].   Some support for the Th2 dominance hypothesis in dogs with AD has recently been reported. Skin lesions in dogs with atopic dermatitis expressed higher levels of interleukin (IL) -4 mRNA and reduced transcription of transforming growth factor beta (TGFbeta) compared with healthy skin or non-lesional AD skin (Nuttall et al, 2002)[2], consistent with Th2 dominance.  Expression of mRNA for the Th1 cytokine  interferon gamma (IFNgamma) was lower and the Th2 cytokine IL-5 was higher in peripheral monocytes of dogs with AD compared to healthy controls (Hayashiya et al, 2002)[3].   The ratio of IFNgamma/IL-4 was found to be lower in monocytes of atopic compared to healthy dogs (Shida et al, 2004)[4].

If it is correct that an underlying immunopathology in AD is T cell dysregulation, and particularly Th2 dominance, what therapeutic interventions might be rational? Systemic and topical corticosteroids are the most consistently effective palliative treatment for canine AD (Scott et al, 2001)[5], likely because they inhibit a broad range of cellular functions and inflammatory pathways.  More recently, cyclosporine, a calcineurin inhibitor that inhibits T cell activation, thus affecting many other pathways (Marsella, 2005)[6] has been demonstrated to be effective in dogs with AD in randomized, controlled clinical trials (Olivry et al, 2002[7]; Olivry et al, 2002[8]; Steffan et al, 2005[9]).  However, none of these strategies address T-cell dysregulation, but rather produce their effects by suppressing T-cell function. Recent interest in “therapeutic vaccines” targeting specific T cell epitopes in order to influence T cell populations and function ( Larché & Wraith, 2005)[10] is one such approach that may be of therapeutic relevance in AD.

Over the past decade, peptides corresponding to the human T cell receptor Vβ complimentary determining region 1 (TCR Vβ1) have been synthesized and tested in a variety of animal models (reviewed by Marchalonis, 2005)[11]. Immunization of retrovirally-infected mice with LTCI prevented or reversed the virus-induced development of Th2 dominance and corresponding immune dysfunction (Watson et al, 1995[12]; Yu et al, 2005[13]). In a coxsackievirus-induced model of cardiopathology in mice, LTCI peptide treatment promoted IL-2 production by T cells thereby enhancing a cell mediated immune response and retarding development of cardiopathology (Sepulveda et al, 2003)[14]. These immunotherapeutic effects of LTCI in various murine models and the evidence that canine AD is associated with over-expression of Th2 cytokines led to interest in exploring the potential value of this immunological approach in dogs with AD. The immunological objective of the TCR Vaccine treatment is to repolarize T helper lymphocyte populations from Th2 dominance characteristic of AD toward more Th1 dominance.  This, in turn, should produce a profound clinical effect.