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InsB:9‐23 peptide‐based immunotherapy for type 1 diabetes; the immunization frequency and the state of the disease can alter the efficacy
Author(s) -
Fousteri Georgia,
Dave Amy,
Bresson Damien,
Croft Michael,
Chan Jason,
Zheng Yanan,
Whiting Chan,
Von Herrath Matthias
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.470
Subject(s) - medicine , immunization , nasal administration , immune system , nod mice , nod , immunology , immune tolerance , disease , diabetes mellitus , dosing , cd8 , immunotherapy , antigen , type 1 diabetes , endocrinology
Immunization with beta‐cell antigens such as insulin has been under intense investigation for T1D prevention. Insulin B:9‐23 has been shown in the past to be able to achieve tolerance in non‐obese diabetic (NOD) mice but not in all settings tested. In this study we compared the efficacy of B:9‐23 to promote tolerance in NOD when given intranasally to mice at different states of the disease (four vs nine week‐old) and with different frequencies (three consecutive days every four weeks vs every week). Interestingly, B:9‐23 i.n. administration efficacy was dependent on both parameters, showing maximum protective effect when treatments started at a young age with the low frequency protocol being the most efficient. Simulation results provided by ENTELOS suggested also that interventions at an early stage may favor better results, since beta cell loss is not as dramatic and easier to be reversed. Interestingly, increased frequency of Tregs in blood and spleen was measured following B:9‐23 i.n. therapeutic protocol, as predicted to be required for efficacy. Conversely, too frequent dosing was not able to achieve sufficient Treg expansion to provide therapeutic benefit, although similarly to the low dose protocol, a shift of the immune response towards Th2 profile was achieved. In order to investigate the mechanism for B:9‐23 peptide tolerance induction in the NODs, transgenic B:9‐23 T‐cell receptor mice ‐BDC12‐4.1‐ are currently being studied. Interestingly these mice are resistant in T1D development and phenotypic analysis revealed an increased memory‐like population in the periphery of some mice, which was more able to respond upon in vitro peptide stimulation. Such parameters may in the future require important consideration for the design of future clinical trials.