ABSTRACT
Therapeutic efficacy of P277 against type 1 diabetes was extensively investigated and clinically evidenced. Clinical trials Phases I and II concluded promising results, while the data of P277 immunogenicity in Phase III trials represented weak responses that led to abolish medical use. But, a therapeutic performance of P277 cannot be forgotten. So, in order to exploit its therapeutic benefits and improve its immunogenicity, we developed a new analogue VP to optimize therapeutic efficacy and enhancing immunosuppressive modulations. However, new analogue was purified, and then used to immunize diabetic NOD mice to investigate antidiabetic effects through modulation of immunological status. So, DCs immune responses, relative TLRs, MyD88, and NF-Kß1 mRNA expression on DCs and splenocytes under VP effect were tested. Circulating and intracellular cytokines were also evaluated at treated and non-treated mice. Splenic T lymphocytes proliferation (Th1 and Treg cells) were also determined. Results revealed that VP significantly down regulates DCs maturation through TLR2, TLR4, and MyD88 pathways. It also shifts DCs to a tolerogenic polarization through NF-Kß1 pathway that mediates Th1 immunosuppression and enhances iTreg expanding in type1diabetes mice. Meanwhile, we noticed that VP significantly enhances iTreg CD25 + FoxP3+ proliferation. In conclusion, VP showed promising immune potential to modulate immune regulatory responses and shifts DCs to suppress autoreactive Th1 cells which ameliorated immunosuppressive potency in the type1 diabetic mice.
Subject(s)
Autoimmunity/drug effects , Chaperonin 60/pharmacology , Diabetes Mellitus, Type 1/drug therapy , Immune Tolerance/drug effects , Immunosuppressive Agents/pharmacology , Peptide Fragments/pharmacology , Animals , Antibody-Dependent Cell Cytotoxicity/drug effects , Cell Communication/immunology , Chaperonin 60/genetics , Chaperonin 60/immunology , Chaperonin 60/therapeutic use , Dendritic Cells/drug effects , Dendritic Cells/immunology , Diabetes Mellitus, Type 1/immunology , Disease Models, Animal , Epitopes, B-Lymphocyte/genetics , Female , Humans , Immunosuppressive Agents/therapeutic use , Lymphocyte Activation/drug effects , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mutagenesis , NF-kappa B p50 Subunit/immunology , NF-kappa B p50 Subunit/metabolism , Peptide Fragments/genetics , Peptide Fragments/immunology , Peptide Fragments/therapeutic use , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Th1 Cells/immunology , Th1 Cells/metabolismABSTRACT
Objective To observe the expression levels change and it's clinical significance of TNF-α, SP-A in chil-dren with varying degrees of pneumonia. Methods A total 195 cases of pneumonia children patients were divided into ordinary pneumonia and severe pneumonia patients , another 65 cases of non-pneumonic children patients as the con-trol group, ELISA assay was used to detect serum TNF-α and SP-A level. Results The levels of serum SP-A and TNF-αof pneumonia children group were higher than the control group's , and severe pneumonia patients ’ were high-er than ordinary pneumonia. Conclusion The expression level of TNF-α and SP-A increased significant in the patho-genesis of children with severe pneumonia which could reflect the degree of lung injury and as a indicator in clinical testing.