T cell activation following alloantigen recognition plays a critical role in the development of the rejection in all solid organ, tissue and cell transplantation. A recombinant molecule, cytotoxic T lymphocyte antigen...T cell activation following alloantigen recognition plays a critical role in the development of the rejection in all solid organ, tissue and cell transplantation. A recombinant molecule, cytotoxic T lymphocyte antigen 4 antibody (CTLA-4Ig), is known to induce to T-cell into "anergy" by blocking the costimulatory B7-CD28 interaction. Either systemic or localized administration of CTLA-Ig has been shown to prolong allograft survival and induce donor-specific tolerance in some transplant models. In this study, we characterized the expression and immunosuppressive effectiveness of adenoviral-mediated CTLA-4Ig gene transfer. We demonstrated transduction of the allografts with AdCTLA-4Ig resulted in localized expression, permanent graft survival and stable donor-specific tolerance. In addition, by performing simultaneous dual-organ transplantation, we targeted on immunosuppression through a local expression of CTLA-4Ig via adenoviral-mediated gene transfer into pancreatic allografts.展开更多
Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis(AIH)are still not full elucidated.Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we...Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis(AIH)are still not full elucidated.Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response.We investigated 3 distinct polymorphic sites(t49A>G,CT60 G>A and e318C>T)of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology.A significant positive association with AIH susceptibility was found for the GG genotype in t49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls(28%vs 9%,pZ0.003,ORZ3.93[1.56e9.88]).The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients.CTLA4 genotyping in position318 did not show any statistically significant difference in genotype or allele distribution.The CTLA4 gene polymorphism in position t49 is associated to AIH susceptibility in the Tunisian population.Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.展开更多
Immune checkpoint inhibitors(ICIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed ...Immune checkpoint inhibitors(ICIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1.ICIs have revolutionized the treatment of a variety of malignancies. However,many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis(IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease,however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.展开更多
文摘T cell activation following alloantigen recognition plays a critical role in the development of the rejection in all solid organ, tissue and cell transplantation. A recombinant molecule, cytotoxic T lymphocyte antigen 4 antibody (CTLA-4Ig), is known to induce to T-cell into "anergy" by blocking the costimulatory B7-CD28 interaction. Either systemic or localized administration of CTLA-Ig has been shown to prolong allograft survival and induce donor-specific tolerance in some transplant models. In this study, we characterized the expression and immunosuppressive effectiveness of adenoviral-mediated CTLA-4Ig gene transfer. We demonstrated transduction of the allografts with AdCTLA-4Ig resulted in localized expression, permanent graft survival and stable donor-specific tolerance. In addition, by performing simultaneous dual-organ transplantation, we targeted on immunosuppression through a local expression of CTLA-4Ig via adenoviral-mediated gene transfer into pancreatic allografts.
基金supported by the Northern Portugal Regional Operational Programme(NORTE 2020)the Portugal 2020 Partnership Agreement,through the European Regional Development Fund(FEDER)(NORTE-01-0145-FEDER-000013)the Fundacao para a Ciencia e Tecnologia(FCT)(IF/00735/2014 to AC and SFRH/BPD/96176/2013 to CC).
文摘Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis(AIH)are still not full elucidated.Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response.We investigated 3 distinct polymorphic sites(t49A>G,CT60 G>A and e318C>T)of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology.A significant positive association with AIH susceptibility was found for the GG genotype in t49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls(28%vs 9%,pZ0.003,ORZ3.93[1.56e9.88]).The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients.CTLA4 genotyping in position318 did not show any statistically significant difference in genotype or allele distribution.The CTLA4 gene polymorphism in position t49 is associated to AIH susceptibility in the Tunisian population.Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.
文摘Immune checkpoint inhibitors(ICIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1.ICIs have revolutionized the treatment of a variety of malignancies. However,many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis(IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease,however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.
