Abstract
IntroductionThe ability to ameliorate murine lupus renders regulatory T cells (Treg) a promising tool for the treatment of systemic lupus erythematosus (SLE). In consideration to the clinical translation of a Treg-based immunotherapy of SLE, we explored the potential of CD4+Foxp3+ Treg to maintain disease remission after induction of remission with an established cyclophosphamide (CTX) regimen in lupus-prone (NZBxNZW) F1 mice. As a prerequisite for this combined therapy, we also investigated the impact of CTX on the biology of endogenous Treg and conventional CD4+ T cells (Tcon).MethodsRemission of disease was induced in diseased (NZBxNZW) F1 mice with an established CTX regimen consisting of a single dose of glucocorticosteroids followed by five day course with daily injections of CTX. Five days after the last CTX injection, differing amounts of purified CD4+Foxp3+CD25+ Treg were adoptively transferred and clinical parameters, autoantibody titers, the survival and changes in peripheral blood lymphocyte subsets were determined at different time points during the study. The influence of CTX on the numbers, frequencies and proliferation of endogenous Treg and Tcon was analyzed in lymphoid organs by flow cytometry.ResultsApart from abrogating the proliferation of Tcon, we found that treatment with CTX induced also a significant inhibition of Treg proliferation and a decline in Treg numbers in lymphoid organs. Additional adoptive transfer of 1.5 × 106 purified Treg after the CTX regimen significantly increased the survival and prolonged the interval of remission by approximately five weeks compared to mice that received only the CTX regimen. The additional clinical amelioration was associated with an increase in the Treg frequency in the peripheral blood indicating a compensation of CTX-induced Treg deficiency by the Treg transfer.ConclusionsTreg were capable to prolong the interval of remission induced by conventional cytostatic drugs. This study provides valuable information and a first proof-of-concept for the feasibility of a Treg-based immunotherapy in the maintenance of disease remission in SLE.
Highlights
The ability to ameliorate murine lupus renders regulatory T cells (Treg) a promising tool for the treatment of systemic lupus erythematosus (SLE)
CTX inhibits Treg proliferation and causes a gap in Treg numbers As a precondition for the sequential therapeutic approach with CTX and Treg, we explored the impact of the cytostatic agent CTX on the biology and homeostasis of endogenous CD4+Foxp3+ Treg in comparison to CD4+Foxp3- conventional T cells (Tcon) in our disease model
Frequencies and in vivo proliferation rates of CD4+Foxp3+ Treg and CD4+Foxp3- Tcon were determined in lymphoid organs and the peripheral blood by BrdU incorporation during a seven-day treatment course with CTX in (NZBxNZW) F1 mice with established disease
Summary
The ability to ameliorate murine lupus renders regulatory T cells (Treg) a promising tool for the treatment of systemic lupus erythematosus (SLE). Monthly pulses of the cytostatic agent cyclophosphamide (CTX) are commonly applied in combination with high doses of GC to induce remission of severe disease and active nephritis [8,9,10]. Immunosuppressive treatments are usually very effective but can be accompanied by severe adverse events, infections and toxicity, especially when applied over a longer period of time [11]. This has become a major prognostic issue nowadays. The search for more specific therapeutic strategies to minimize side effects and to allow a better quality of life for the patients is an important focus of current research efforts
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