Allergen specific immunotherapy(AIT)has a history spanning over 110 years and represents the only diseasemodifying treatment for allergic diseases,with potential preventive effects.Nevertheless,the broader application...Allergen specific immunotherapy(AIT)has a history spanning over 110 years and represents the only diseasemodifying treatment for allergic diseases,with potential preventive effects.Nevertheless,the broader application of AIT is limited by the inherent drawbacks of natural allergen extracts,such as variability in composition,risk of side effects,and complex,lengthy treatment regimens.Advances in molecular allergology have enabled the development of novel vaccine strategies-including recombinant allergens,hypoallergenic derivatives,allergen-derived peptides,and nucleic acid-based vaccines-that aim to improve safety,efficacy,and precision.However,no molecule-based AIT product has yet achieved regulatory approval,largely due to technical and clinical trial challenges.In parallel,immunomodulatory adjuvants such as monophosphoryl lipid A,CpG oligodeoxynucleotides,flagellin and mannan have demonstrated promising properties.These innovations have the potential to enhance AIT outcomes by promoting immune tolerance,reducing IgE responses,and improving patient compliance.This review summarizes the current landscape of allergen vaccines and adjuvant technologies under investigation for AIT,highlighting key advances,clinical data,and future directions aimed at overcoming existing limitations and optimizing treatment strategies for allergic diseases.展开更多
Functional Tregs play a key role in tumor development and progression,representing a major barrier to anticancer immunity.The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvir...Functional Tregs play a key role in tumor development and progression,representing a major barrier to anticancer immunity.The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood.Herein,by using NMR,chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses,we demonstrate that the tumoral carbohydrate A10(Ca10),a cell-surface carbohydrate derived from Ehrlich’s tumor(ET)cells,is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs.Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming,PD-L1,IL-10,and IDO.Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features.In solid ET-bearing mice,we found positive correlations between Ca10 serum levels,tumor size and splenic Treg numbers.Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice.Remarkably,we provide evidence supporting the presence of a circulating human Ca10 counterpart(Ca10H)and show,for the first time,that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals.Of note,these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases.Collectively,we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer.The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment.展开更多
文摘Allergen specific immunotherapy(AIT)has a history spanning over 110 years and represents the only diseasemodifying treatment for allergic diseases,with potential preventive effects.Nevertheless,the broader application of AIT is limited by the inherent drawbacks of natural allergen extracts,such as variability in composition,risk of side effects,and complex,lengthy treatment regimens.Advances in molecular allergology have enabled the development of novel vaccine strategies-including recombinant allergens,hypoallergenic derivatives,allergen-derived peptides,and nucleic acid-based vaccines-that aim to improve safety,efficacy,and precision.However,no molecule-based AIT product has yet achieved regulatory approval,largely due to technical and clinical trial challenges.In parallel,immunomodulatory adjuvants such as monophosphoryl lipid A,CpG oligodeoxynucleotides,flagellin and mannan have demonstrated promising properties.These innovations have the potential to enhance AIT outcomes by promoting immune tolerance,reducing IgE responses,and improving patient compliance.This review summarizes the current landscape of allergen vaccines and adjuvant technologies under investigation for AIT,highlighting key advances,clinical data,and future directions aimed at overcoming existing limitations and optimizing treatment strategies for allergic diseases.
基金upported by grants FEI 16_60 from Art.834154605(138/2012)(24/2013),SAF-2017-84978-R from MINECO(Spain)and PID2020-114396RB-I00 from Ministerio de Ciencia e Innovación(Spain)to OP and PID2021-123781OB-C22 to FJC funded by MCIN/AEI/10.13039/501100011033(Spain)and RTC-2015-3805-1 from MINECO to Inmunotek SL.LM-C and AA were recipients of FPU and UCM predoctoral fellowships,respectively.
文摘Functional Tregs play a key role in tumor development and progression,representing a major barrier to anticancer immunity.The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood.Herein,by using NMR,chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses,we demonstrate that the tumoral carbohydrate A10(Ca10),a cell-surface carbohydrate derived from Ehrlich’s tumor(ET)cells,is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs.Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming,PD-L1,IL-10,and IDO.Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features.In solid ET-bearing mice,we found positive correlations between Ca10 serum levels,tumor size and splenic Treg numbers.Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice.Remarkably,we provide evidence supporting the presence of a circulating human Ca10 counterpart(Ca10H)and show,for the first time,that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals.Of note,these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases.Collectively,we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer.The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment.
