PS1543 RELIEVING IMMUNOSUPPRESSION IMPROVES VΔ2+ T CELLS RECOVERY AND DECREASES EBV REACTIVATION AFTER HEMATOPOIETIC TRANSPLANTATION
Authors: Gao H. , Liu J. , Xu L.‐P. , Wang M. , Chang Y.‐J. , Mo X.‐D. , Wang Z. , Gao Y. , Wang Y. , Zhang X.‐H. , Huang X.‐J. 
Published: June 2019

Background:

Immunosuppressive drugs have been widely used for transplantation over the last decade. Mycophenolate mofetil (MMF) and cyclosporine A (CsA) are usually used to prevent and treat graft‐versus‐host disease (GVHD) in the context of hematopoietic stem cell transplantation (HSCT). With the numerous studies reported the clinical efficacy of immunosuppressants, attentions for their side effects, such as opportunistic infections, are increasing. Epstein–Barr virus (EBV) reactivation and its related diseases are the common threats with high mortality after haploidentical HSCT (haploHSCT). Although the immunosuppression was associated with EBV infection after solid organ transplantation, this correlation has been less reported in the scenario of hematopoietic transplantation. We previously showed that recovery of Vδ2+ T cells inversely correlated to EBV reactivation after haploHSCT and Vδ2+ T cells isolated from haploHSCT recipients were not expanded by aminobisphosphonates stimulation. The influence of immunosuppressants on the Vδ2+ T cells recovery and anti‐EBV cytotoxicity post‐HSCT are unknown.

Aims:

To investigate the impacts of immunosuppressive drugs on the Vδ2+ T cells expansion and function, and whether relieving the immunosuppression can improve Vδ2+ T cells recovery and decrease EBV reactivation in the setting of allogeneic HSCT.

Methods:

Mycophenolic acid (MPA) is an active form of MMF and usually used in the in‐vitro functional experiments. Pamidronate was used to trigger the expansion of Vδ2+ T cells in peripheral blood mononuclear cells isolated from healthy donors, with or without immunosuppressants (MPA and CsA). The activation, proliferation, functional receptor expression, cytokines production, and EBV‐specific cytotoxicity of Vδ2+ T cellswere detected by flow cytometry. This study also included a cohort of 165 patients undergoing haploHSCT. These patients were divided into 2 groups based on the different courses of MMF administration for GVHD prophylaxis. The recoveries of T‐cell subsets and incidences of EBV reactivation were statistically compared.

Results:

Peripheral Vδ2+ T cells from healthy donors were dramatically expanded by pamidronate stimulation for 10 days, with the percentage of Vδ2+ T cells in total MNCs was increased from 2.8% to 89%. In contrast, MPA and CsA treatment profoundly attenuated this expansion given that Vδ2 cells levels were even lower than baseline under the same condition. The activation (expression of CD25) and IFN‐γ production of Vδ2 cells were inhibited while NKG2D expression was moderately decreased by both drugs. Consistently, EBV‐specific cytotoxicity of Vδ2 cells were also impaired after treatment with MPA and CsA. The recoveries of T‐cell subsets were monitored in patients with different courses of MMF following haploHSCT. Recoveries of other detected T‐cell subpopulations at day 30 were significantly faster in the shorter MMF group than the longer MMF group. The level of Vδ2 cells was continuously increased from 30 to 90 days post‐haploHSCT after reducing the course of MMF, accompanied with a decreased incidence of EBV reactivation. Day‐30 Vδ2 levels remained an independent factor for EBV reactivation in patients with different MMF durations.

Summary/Conclusion:

Reliving the suppression of MMF and CsA is favorable to anti‐EBV immunity probably through recovering Vδ2 cells expansion and function. These findings will help improve the outcome of hematopoietic transplant.