T-Cell Receptor (TCR) therapy targets a central regulator of immune mediated inflammation, being the T-helper cell. This new therapeutic strategy is being considered for further development in cats with severe, refractory feline stomatitis.
Introduction: Feline stomatitis, also known as lymphocytic plasmacytic stomatitis or gingivostomatitis, is a chronic inflammatory disease of the oral cavity, the underlying cause of which is likely an atypical immune response. Feline lymphocytic plasmacytic stomatitis represents a frustrating and challenging disease for development of surgical and/or pharmaceutical interventions. The uncertain etiology compounds the problem in designing rational and comprehensive approaches to this condition. Regardless of the triggering etiology, the outcome is an immune based inflammatory condition.
One area of focus is to examine T-helper (Th) cells, the central regulators of the adaptive immune response which coordinate humoral and cell mediated immune activity. In general, T-helper cells can be categorized into Th1 or Th2, depending on which cytokines they release. Th1 cells drive a cell mediated response, while Th2 cells drive a plasmacytic response. Specifically, it has recently been reported that cats with stomatitis begin to have an increase in their Th2 lymphocyte cytokine profile.
TCR Treatment for Stomatitis in Cats: T-helper cells can respond to specific peptides which engage their T-cell receptors (TCR), thus providing for TCR vaccines to be developed. One such technique has been to develop a T-Cell Receptor Peptide Vaccine (TCR vaccine) with immuno-regulatory and stimulatory properties on the adaptive immune system. Over the past decade, peptides corresponding to the T cell receptor Vb complimentary determining region 1 (TCR Vb1) have been synthesized and tested in a variety of animal models.
This TCR vaccine is a therapeutic vaccine, and has been shown to normalize T-helper lymphocyte cytokines towards the Th1 cytokine profile. Immunization of retrovirally-infected mice with TCR peptide vaccines prevented or reversed the virus-induced development of Th2 dominance and corresponding immune dysfunction. In an aging mouse model TCR vaccination reversed the age-related decrease in Th1 and increase in Th2 cytokine profiles. A previous study (unpublished) has also shown this TCR vaccine to have significant effects in dogs with severe atopic dermatitis, a condition also shown to have a Th2 cytokine increase.
Potential Immunological Mechanisms: Although the exact mechanism by which the TCR treatment works remains to be determined, several plausible mechanisms exist including (a) fewer cells are activated to become Th2 cells or (b) fewer cells are permitted to remain as immature Th0 or Th2 cells with their high production of IL-4 and IL-10. This effect would preserve normal function in most bystander cells that were close enough to be affected by cytokines produced by T cell clones stimulated by super or chronic pathogen antigen exposure, without the increased IL-4 production by Th2 cells. In this situation more cells would remain as Th1 cells, producing gamma-interferon and IL-2 during viral-induce immune dysfunction and suppressing Th2 cytokine production by neighboring cells. Another observed outcome during immune dysfunction is an elevated level of Tumor Necrosis Factor-alpha, which is associated with replication of viral pathogens in macrophages/monocytes and T cells. Treatment with TCR peptides has been found to reduce TNF production and restore immune function needed for optimum host defense. Thus prevention of imbalanced Th1 and Th2 cytokine production by TCR administration could contribute to the normalization of the entire immune response, thereby retarding development of immune dysfunction due to age, pathogen infection, or other challenges.
These immunomodulatory effects of TCR treatment in various murine models and the growing evidence that stomatitis is associated with over-expression of Th2 cytokines led to interest in exploring the potential value of this immunological approach in cats with chronic, refractory lymphocytic plasmacytic stomatitis.
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