The development of chimeric antigen receptor(CAR)-based therapeutic interventions represented a breakthrough in cancer treatment.Following the success of the CAR-T-cell strategy,this novel therapeutic approach has bee...The development of chimeric antigen receptor(CAR)-based therapeutic interventions represented a breakthrough in cancer treatment.Following the success of the CAR-T-cell strategy,this novel therapeutic approach has been applied to other diseases,including autoimmune diseases.Using CAR-T cells to deplete pathological immune cells(i.e.,B cells,autoreactive B or T cells,and accessory antigen-presenting cells(APCs))has resulted in favorable outcomes in diseases characterized by excessive autoantibody levels or hyperactive lymphocyte cell numbers.The importance of immunosuppressive regulatory Tcells(Tregs)in restoring immune tolerance has been well established,and CAR-Tregs have shown promising therapeutic potential in treating autoimmune diseases.Moreover,prior experience from the cancer field has provided sufficient paradigms for understanding how to optimize the structure and function of CARs to improve their function,persistence,stability and safety.In this review,we describe the potential application of CAR-T cells and CAR-Tregs in the treatment of autoimmune diseases,and we summarize the currently available strategies of gene editing and synthetic biological tools that have improved the practical application of CAR-based therapies.展开更多
Interleukin-2(IL-2)is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells(Tregs)and effector cells,leading to paradoxical consequences.Here,we report a strategy that exploite...Interleukin-2(IL-2)is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells(Tregs)and effector cells,leading to paradoxical consequences.Here,we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine(FSY)into IL-2 for proximity-enabled covalent binding to IL-2Rαto selectively promote Treg activation.We found that FSY-bearing IL-2 variants,such as L72-FSY,covalently bound to IL-2Rαvia sulfur-fluoride exchange when in proximity,resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells.Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation,as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3(LAG-3)and enhanced expression of programmed cell death protein-1(PD-1).Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease(GvHD)resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment.The efficacy of L72-FSY was further improved by N-terminal PEGylation,which increased its circulatory retention for preferential and sustained effects.This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.展开更多
基金supported by the National Natural Science Foundation of China(82230060,81788101)the CAMS Innovation Fund for Medical Sciences(CIFMS)(2022-I2M-2-002,2021-I2M-1-017,2021-I2M-1-047,2021-I2M-1-040,2021-I2M-1-016,2021-I2M-1-026)+1 种基金Beijing Capital Health Development Fund(2020-2-4019)the Natural Science Foundation of Beijing(7222263)。
文摘The development of chimeric antigen receptor(CAR)-based therapeutic interventions represented a breakthrough in cancer treatment.Following the success of the CAR-T-cell strategy,this novel therapeutic approach has been applied to other diseases,including autoimmune diseases.Using CAR-T cells to deplete pathological immune cells(i.e.,B cells,autoreactive B or T cells,and accessory antigen-presenting cells(APCs))has resulted in favorable outcomes in diseases characterized by excessive autoantibody levels or hyperactive lymphocyte cell numbers.The importance of immunosuppressive regulatory Tcells(Tregs)in restoring immune tolerance has been well established,and CAR-Tregs have shown promising therapeutic potential in treating autoimmune diseases.Moreover,prior experience from the cancer field has provided sufficient paradigms for understanding how to optimize the structure and function of CARs to improve their function,persistence,stability and safety.In this review,we describe the potential application of CAR-T cells and CAR-Tregs in the treatment of autoimmune diseases,and we summarize the currently available strategies of gene editing and synthetic biological tools that have improved the practical application of CAR-based therapies.
基金This study was supported by grants from the National Key Research and Development Program of China(2019ZX09739)National Natural Science Foundation of China(82230060,82271831,81788101,82204258)+3 种基金Chinese Academy of Medical Science Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-016,2021-I2M-1-017,2021-I2M-1-047,2021-I2M-1-040,2021-I2M-1-016,2021-I2M-1-026)Natural Science Foundation of Beijing(7222263)Beijing Capital Health Development Fund(2020-2-4019)Fundamental Research Funds for the Central Universities(3332022108).
文摘Interleukin-2(IL-2)is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells(Tregs)and effector cells,leading to paradoxical consequences.Here,we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine(FSY)into IL-2 for proximity-enabled covalent binding to IL-2Rαto selectively promote Treg activation.We found that FSY-bearing IL-2 variants,such as L72-FSY,covalently bound to IL-2Rαvia sulfur-fluoride exchange when in proximity,resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells.Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation,as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3(LAG-3)and enhanced expression of programmed cell death protein-1(PD-1).Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease(GvHD)resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment.The efficacy of L72-FSY was further improved by N-terminal PEGylation,which increased its circulatory retention for preferential and sustained effects.This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.
