Blockade of costimulation between T cells and antigen-presenting cells: an approach to suppress murine Graves' disease induced using thyrotropin receptor-expressing adenovirus.
OBJECTIVE
Immune responses require costimulatory interactions between molecules on antigen-presenting cells and T cells: CD40 binding to CD40 ligand and B7 binding to CD28. Graves' hyperthyroidism is induced in BALB/c mice by immunization with thyrotropin receptor (TSHR) A-subunit adenovirus (Ad-A-subunit). We attempted to modulate Ad-A-subunit-induced Graves' disease using adenoviruses expressing costimulation "decoys": CD40-IgG-Fc (CD40-Ig) to block CD40:CD40-ligand interactions and CTLA4-Fc (CTLA4-Ig) to prevent B7:CD28 binding.


RESULTS
Unexpectedly, coimmunizing mice with Ad-A-subunit and excess control adenovirus (1:10 Ad-A-subunit:Ad-control) reduced TSHR antibody levels (thyrotropin binding inhibition [TBI]). Furthermore, only 15% of mice developed hyperthyroidism versus 75% using the same Ad-A-subunit dose (10(8) particles) without Ad-control. This effect was related to the dose of control adenovirus but not to the adenovirus insert, the timing or immunization site. Increasing the Ad-subunit dose (10(9) particles) and decreasing the control adenovirus dose (10:1 Ad-A-subunit:Ad-control) induced high TBI levels and 80% of mice were hyperthyroid. Coimmunization with Ad-CD40-Ig (but not Ad-CTLA4-Ig) reduced the incidence of hyperthyroidism to 40%.


CONCLUSIONS
Using appropriate controls and adenovirus ratios, our data suggest the importance of CD40:CD40-ligand interactions for inducing Graves' hyperthyroidism by Ad-A-subunit. Furthermore, our observations emphasize the potential pitfalls of non-specific inhibition by coimmunization with two adenovirus species.
Chen
Chun-Rong
CR
Autoimmune Disease Unit, Cedars-Sinai Research Institute and UCLA School of Medicine, Los Angeles, California, USA.
Aliesky
Holly A
HA
Guo
Jin
J
Rapoport
Basil
B
McLachlan
Sandra M
SM
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology*; D018106:CD28 Antigens / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D023201:CD40 Ligand / Q000096:biosynthesis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006111:Graves Disease / Q000628:therapy*; D006980:Hyperthyroidism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D011485:Protein Binding; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology*
D018106:CD28 Antigens; D019013:CD40 Antigens; D011989:Receptors, Thyrotropin; D023201:CD40 Ligand