Effects of oral administration of 5 immunosuppressive agents on activated T‐cell cytokine expression in healthy dogs

Abstract

Background: Dogs are often adminstered >1 immunosuppressive medication when treating immune-mediated diseases, and determining whether these different medications affect IL-2 expression would be useful when performing pharmacodynamic monitoring during cyclosporine therapy.Hypothesis/Objectives: To determine the effects of 5 medications (prednisone, cyclosporine, azathioprine, mycophenolate mofetil, and leflunomide) on activated Tcell expression of the cytokines IL-2 and interferon-gamma (IFN-γ). Animals: Eight healthy dogs.Methods: Randomized, cross-over study comparing values before and after treatment, and comparing values after treatment among drugs. Dogs were administered each drug at standard oral doses for 1 week, with a washout of at least 21 days. Activated T-cell expression of IL-2 and IFN-γ mRNA was measured by quantitative reverse transcription polymerase chain reaction. Blood drug concentrations were measured for cyclosporine, mycophenolate, and leflunomide metabolites. Results: Least squares means (with 95% confidence interval) before treatment for IL-2 (2.91 [2.32-3.50] ΔCt) and IFN-γ (2.33 [1.66-3.00 ΔCt]) values were significantly lower (both P < .001) than values after treatment (.46] ΔCt, respectively) with cyclosporine. Similarly, least squares means before treatment for IL-2 (1.55 [1.07-2.02] ΔCt) and IFN-γ (2.62 [2.32-2.92] ΔCt)values were significantly lower (both P < .001) than values after treatment (3.55 [3.06-4.00] and 5.22 [4.92-5.52] ΔCt, respectively) with prednisone. Comparing delta cycle threshold values after treatment among drugs, cyclosporine was significantly Abbreviations: ΔCt, delta cycle threshold; HPLC, high-performance liquid chromatography; IFN-γ, interferon-gamma; IL-2, interleukin-2; LOQ, limit of quantification; RT-qPCR, quantitative reverse transcription polymerase chain reaction; UV, ultraviolet.

Description and outcome of dogs with primary immune‐mediated polyarthritis: 73 cases (2012‐2017)

“…2016). Corticosteroids have a rapid onset of action (Whitley & Day 2011, Viviano 2013, Archer 2017), which is particularly useful in a disease that can cause pain and systemic inflammation. However, corticosteroids have the potential to cause significant adverse effects that can impact the quality of life of patients and owners alike (Whitley & Day 2011, Archer 2017).…”

“…Standardised treatment protocols for primary IMPA have not been established and are derived from clinical experience or extrapolated from approaches recommended for other immune‐mediated conditions. While administration of immunosuppressive doses of corticosteroids is considered the standard of care for primary IMPA (Stone 2017), an optimal protocol has not been established, with other immunosuppressive agents sometimes used in combination with corticosteroids (Archer 2017, Stone 2017). A favourable initial response to prednisolone therapy was previously described in 81% of dogs diagnosed with primary IMPA (Clements et al .…”

The Effects of Mycophenolate on the Formation of Granulation Tissue Post-operatively in Canine Tracheal Stent Patients (2014–2020)

“…Mycophenolate mofetil is a lymphocytotoxic immunosuppressive drug used in human and companion animal medicine for the treatment of immune-mediated disease (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Mycophenolate functions as an immunomodulatory agent by inhibiting inosine monophosphate dehydrogenase production by T and B lymphocytes after being hydrolyzed in the intestines to the parent compound, mycophenolic acid (16,(20)(21)(22)(23). Mycophenolic acid thereby leads to inhibition in the synthesis of guanosine nucleotides, without which lymphocytes are unable to differentiate, proliferate, and produce immunoglobulins (16,20,22,23).…”

“…Mycophenolate functions as an immunomodulatory agent by inhibiting inosine monophosphate dehydrogenase production by T and B lymphocytes after being hydrolyzed in the intestines to the parent compound, mycophenolic acid (16,(20)(21)(22)(23). Mycophenolic acid thereby leads to inhibition in the synthesis of guanosine nucleotides, without which lymphocytes are unable to differentiate, proliferate, and produce immunoglobulins (16,20,22,23). Studies have shown that mycophenolic acid can induce the apoptosis of activated T cells and inhibits B-cell lymphocytes and antibody formation (16,(20)(21)(22)(23).…”

“…Mycophenolic acid thereby leads to inhibition in the synthesis of guanosine nucleotides, without which lymphocytes are unable to differentiate, proliferate, and produce immunoglobulins (16,20,22,23). Studies have shown that mycophenolic acid can induce the apoptosis of activated T cells and inhibits B-cell lymphocytes and antibody formation (16,(20)(21)(22)(23). In addition, mycophenolic acid has been shown in vivo to reduce the recruitment of monocytes into sites of graft rejection and inflammation and also increases apoptosis of monocytes (20).…”