Soluble CTLA-4 can suppress autoantibody production and elicit long term unresponsiveness in a novel transgenic model.
Activation of Ag-specific T cells often requires costimulatory signals in addition to the primary signal mediated through the TCR. The CD28-B7 interaction provides one important costimulatory signal. Previous studies have shown that a soluble CD28 homologue, CTLA4lg, binds B7 with high affinity and can inhibit CD28-B7-mediated costimulation in vitro and in vivo. In this study we examined the ability of soluble human CTLA4lg to inhibit autoantibody production in vivo. For this purpose we used a novel transgenic (Tg) model of autoantibody production. Hepatitis B eAg-expressing Tg mice can be induced to produce autoantibody to the circulating autoantigen (HBeAg) by the injection of a T cell recognition site that fails to elicit T cell tolerance in these mice. Autoimmunity in this model is quantitative because serum autoantibody and autoantigen concentration are inversely correlated and easily measurable by ELISA. In this system a single regimen of CTLA4lg treatment significantly suppressed primary autoantibody production and variably led to long term unresponsiveness. Furthermore, in vivo treatment with CTLA4lg inhibited both T cell activation and T cell-B cell interactions.
Milich
D R
DR
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037.
Linsley
P S
PS
Hughes
J L
JL
Jones
J E
JE
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000494:pharmacology*; D001323:Autoantibodies / Q000096:biosynthesis*; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D005260:Female; D006513:Hepatitis B e Antigens / Q000276:immunology; D007108:Immune Tolerance; D007116:Immunization, Passive; D018796:Immunoconjugates; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins; D012995:Solubility; D013997:Time Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D006513:Hepatitis B e Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000069594:Abatacept