Factors affecting Salmonella-based combination immunotherapy for prevention of type 1 diabetes in non-obese diabetic mice
| Autor: | Ayelet Lenz, Jeffrey Rawson, Mohamed I. Husseiny, Fouad Kandeel, Kevin Ferreri, Weiting Du, Jacques C. Mbongue |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment T-Lymphocytes Nod medicine.disease_cause Autoantigens T-Lymphocytes Regulatory Autoimmunity Diabetes Mellitus Experimental 03 medical and health sciences Mice Mice Inbred NOD Salmonella Transforming Growth Factor beta Medicine Animals Insulin Protein Precursors NOD mice Type 1 diabetes General Veterinary General Immunology and Microbiology business.industry Public Health Environmental and Occupational Health medicine.disease Vaccine efficacy Interleukin-10 Vaccination Interleukin 10 030104 developmental biology Infectious Diseases Cytokine Diabetes Mellitus Type 1 Immunology Molecular Medicine Drug Therapy Combination Female Immunotherapy business Spleen |
| Zdroj: | Vaccine. 36(52) |
| ISSN: | 1873-2518 |
| Popis: | We previously reported the development of an oral vaccine for diabetes based on live attenuated Salmonella-expressing preproinsulin (PPI) as the autoantigen. When combined with host cell-expressed TGFβ, the vaccine prevented the onset of diabetes in non-obese diabetic (NOD) mice. Herein, we investigated factors that could affect vaccine efficacy including vaccination number, optimization of the autoantigen codon sequence, Salmonella SPI2-TTSS promoter/effector combinations, concurrent short-course low-dose anti-CD3. We also evaluated autoantigen GAD65 and cytokine IL10 treatment upon vaccine efficacy. T-cells we employed to elucidate the mechanism of the vaccine action. Our results showed that GAD65+TGFβ or PPI+TGFβ+IL10 prevented the onset of diabetes in the NOD mice and maintained glucose tolerance. However, increasing the number of vaccine doses, codon-optimization of the autoantigen(s) or use of other Salmonella promoter/effector combinations had no in vivo effect. Interestingly, two doses of vaccine (PPI+TGFβ+IL10) combined with a sub-therapeutic dose of anti-CD3 prevented diabetes and decreased hyperglycemia in mice. The combined therapy also increased splenic Tregs and local Tregs in pancreatic lymph nodes (PLN) and increased regulatory (IL10 and IL2) but reduced inflammatory (IFNγ and TNFα) cytokines. Together, these results indicate that the combination of low vaccine dose number, less vaccine autoantigen expression and short-course low-dose anti-CD3 can increase regulatory mechanisms and suppress autoimmunity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect