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  • Considering the fact that OCL induced depletion of T cells

    2022-01-20

    Considering the fact that OCL induced depletion of T PYR-41 in non-stimulated cultures, the only possible explanation of this effect is the elevated mortality of these cells. It was found that OCL at the higher concentration induced the apoptosis of CD4+ and CD8+ T cells. These results strongly suggest that OCL may exert proapoptotic action on canine T cells. Firstly, this action is most clearly responsible for the OCL-induced cytoreductive effect. Secondly, the results support the hypothesis put forth in our study that the anti-inflammatory and anti-allergic effects of OCL, apart from the principal mechanism responsible for these actions, may be additionally related to the induction of the apoptosis of CD4+ and CD8+ Teff cells involved in the immunopathogenesis of canine AD or other allergic diseases (Jassies-Van Der Lee et al., 2014). However, the elucidation of this problem requires further studies. It needs to be added that the available literature does not provide data about the effect of OCL on apoptosis of T cells, while the results of research where other JAK inhibitors were evaluated in this respect are available. Cetkovic-Cvrlje et al. (2012) demonstrated that WHI-P131, a JAK3 inhibitor, induced apoptosis of cultured murine CD4+ T cells. Lee et al. (2018) found that ruxolitinib, a selective JAK1/JAK2 inhibitor, enhanced apoptosis of certain lymphoma cell lines. A weakly expressed reduction in the percentage of CD25-positive CD4+ T cells was observed after the treatment with the higher OCL concentration. However, this was only an apparent decrease, i.e. it did not arise from the loss of expression of CD25 by CD25+CD4+ T cells, but was a consequence of the fact that OCL caused a larger loss of CD25+CD4+ T cells than of CD25−CD4+ ones. Thus, the research results indicate that OCL does not influence the constitutive CD25 expression on CD4+ and CD8+ T cells. Nevertheless, the effect of OCL on the activation-induced CD25 expression on CD4+ T cells is a completely different question. Although the CD25 molecule is typically associated with the Treg cell phenotype, this molecule is also an early T cell activation marker. In the present study it was found that OCL reduced but did not prevent the activation-induced CD25 expression on CD4+ T cells. These results are in line with the ones obtained by Parampalli Yajnanarayana et al. (2015), who reported that ruxolitinib, a JAK1/JAK2 inhibitor, decreased the absolute count of activated CD4+ T cells. As CD4+ Teff cells play a major role in the pathophysiology of allergic disease, these results suggest that the impairment/inhibition of the activation of these cells may play significant role for shaping the anti-inflammatory and anti-allergic properties of OCL. In conclusion, the in vitro exposure of peripheral blood lymphocytes to OCL caused a dramatic loss of CD4+ and CD8+ T cells, both Treg cells and Teff cells. Treg cells rather than Teff cells as well as CD8+ Teff cells rather than CD4+ Teff cells seem to be more sensitive to the OCL-induced cytoreductive effect. Moreover, the results strongly suggest that OCL may exert the proapoptotic action on canine CD4+ and CD8+ T cells. OCL did not affect the constitutive CD25 expression or the Foxp3 expression in CD4+ and CD8+ T cells. However, OCL reduced the activation-induced CD25 expression on CD4+ T cells. On the one hand, these effects can be involved in producing anti-inflammatory and anti-allergic properties of OCL, and in this context they should be regarded as one of the mechanisms responsible for the clinical efficacy of the drug. On the other hand, these effects also represent an immunosuppressive action in the sense of an unwanted effect because CD4+ and CD8+ Teff cells play a major role in the production of cellular immunity. Verification whether the use of OCL actually creates a risk of such action will require further studies.
    A limitation of the studies We are fully aware that much caution must be exercised when drawing conclusions from in vitro studies. The majority of drugs are metabolized in the body and affect cells only for a certain time, and this effect may vary in intensity, depending on the actual metabolism of the drug and its distribution in the body. Under in vitro conditions we are unable to reproduce either the pharmacokinetic processes which a drug is submitted to in a living body, or the regulatory mechanisms which can be activated by the body in response to the drug. Hence, the results must be approached with a good measure of caution until they can be verified in in vivo studies.