Requirement of B7-mediated costimulation in the induction of experimental autoimmune anterior uveitis.
OBJECTIVE
To study the role of costimulatory signaling through the CD28-B7 interaction in experimental autoimmune anterior uveitis (EAAU).


METHODS
Naive Lewis rats were immunized with insoluble melanin-associated antigen (MAA) derived from bovine iris and ciliary body. CTLA4-Fc, a recombinant protein comprised of the extracellular domain of human CTLA4 bound to mouse IgG2a Fc, was used to block the CD28-B7 interaction. A mutant version (CTLA4-Fc-mutant) was used as a control. The effect of CTLA4-Fc on the in vivo induction of disease with MAA was studied. Subsequently, the mechanism by which CTLA4-Fc blocked the interaction of CD28 and B7 was investigated in vivo, using the adoptive transfer of T cells derived from CTLA4-Fc-treated rats, and in vitro, using the proliferative response and cytokine production of MAA-T cells in the presence of CTLA4-Fc.


RESULTS
CTLA4-Fc markedly reduced the incidence and severity of EAAU in Lewis rats after sensitization with MAA. The adoptive transfer of sensitized T cells from CTLA4-Fc-treated donors did not induce EAAU in naive recipients. CTLA4-Fc inhibited the expansion of antigen-specific MAA-T cells and the production of TNF-alpha.


CONCLUSIONS
The costimulatory signal delivered through CD28-B7 is required for the induction and pathogenesis of EAAU. In the absence of this signal, antigen-specific expansion of MAA reactive T cells as well as production of TNF-alpha is inhibited. Abrogation of this costimulatory signal may be an important therapeutic option for EAAU.
Shao
H
H
Department of Ophthalmology and Vision Sciences, Washington University Medical School, St. Louis, Missouri 40202, USA. h0sha01@gwise.louisville.edu
Woon
M D
MD
Nakamura
S
S
Sohn
J H
JH
Morton
P A
PA
Bora
N S
NS
Kaplan
H J
HJ
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D018796:Immunoconjugates; D015994:Incidence; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008543:Melanins / Q000276:immunology; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014606:Uveitis, Anterior / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008543:Melanins; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept