Induction of immunological tolerance/hyporesponsiveness in baboons with a nondepleting CD4 antibody.
Tolerance induction with anti-CD4 Abs is well established in rodent transplant and autoimmune disease models, but has yet to be demonstrated in non-human primates or in clinical studies. In retrospect, failure of anti-CD4 Abs to induce tolerance in primates may be technical, a consequence of insufficient dosing and Ab properties influencing immunogenicity and cell depletion. To circumvent these possible limitations, we constructed a novel anti-CD4 mAb, TRX1, humanized to reduce immunogenicity and Fc-modified to prevent cell depletion. Using equine immune globulin (equine Ig) as a model Ag, we examined the tolerance-inducing capacity of TRX1 in baboons. During the induction phase, TRX1 inhibited the humoral response to equine Ig in a dose-dependent manner, with complete suppression of response at the highest dose tested (40 mg/kg). Upon challenge, anti-equine Ig responses were generated in baboons treated with 1 and 10 mg/kg doses of TRX1 and in control animals. In higher dosing cohorts (20 and 40 mg/kg), however, the immune response to equine Ig was modulated in seven of nine animals, including complete unresponsiveness to Ag challenges in two animals. Five of nine were hyporesponsive to equine Ig, generating titers 50- to 250-fold lower than control groups. Repeated challenge resulted in titers falling to baseline or near baseline, with two of five hyporesponsive animals becoming unresponsive to Ag. All animals responded to neoantigen immunization, indicating that the modified response to equine Ig was Ag specific. These studies demonstrate that anti-CD4 Ab-mediated, Ag-specific tolerance can be achieved in baboons without long term immune suppression.
Winsor-Hines
Dawn
D
TolerRx, Inc., Cambridge, MA 02139, USA.
Merrill
Christopher
C
O'Mahony
Mark
M
Rao
Patricia E
PE
Cobbold
Stephen P
SP
Waldmann
Herman
H
Ringler
Douglas J
DJ
Ponath
Paul D
PD
D019943:Amino Acid Substitution / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000096:biosynthesis / Q000378:metabolism; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004912:Erythrocytes / Q000276:immunology; D006736:Horses; D006801:Humans; D006825:Hybridomas; D007108:Immune Tolerance / Q000276:immunology*; D007115:Immunization Schedule; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008212:Lymphocyte Depletion; D010215:Papio / Q000276:immunology*; D017434:Protein Structure, Tertiary; D012756:Sheep; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens