Immune deviation by mucosal antigen administration suppresses gene-transfer-induced inhibitor formation to factor IX.
Formation of inhibitory antibodies is a serious complication of protein or gene replacement therapy for hemophilias, congenital X-linked bleeding disorders. In hemophilia B (coagulation factor IX [F.IX] deficiency), lack of endogenous F.IX antigen expression and other genetic factors may increase the risk of antibody formation to functional F.IX. Here, we developed a protocol for reducing inhibitor formation in gene therapy by prior mucosal (intranasal) administration of a peptide representing a human F.IX-specific CD4(+) T-cell epitope in hemophilia B mice. C3H/HeJ mice with a F.IX gene deletion produced inhibitory IgG to human F.IX after hepatic gene transfer with an adeno-associated viral vector. These animals subsequently lost systemic F.IX expression. In contrast, repeated intranasal administration of the specific peptide resulted in reduced inhibitor formation, sustained circulating F.IX levels, and sustained partial correction of coagulation following hepatic gene transfer. This was achieved through immune deviation to a T-helper-cell response with increased IL-10 and TGF-beta production and activation of regulatory CD4(+)CD25(+) T cells.
Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Alachua, 32615, USA.
Ou
O
Cao
Elina
E
Armstrong
Alexander
A
Schlachterman
Lixin
L
Wang
David K
DK
Okita
Bianca
B
Conti-Fine
Katherine A
KA
High
Roland W
RW
Herzog
D000281:Administration, Intranasal; D000818:Animals; D000917:Antibody Formation; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage*; D005164:Factor IX / Q000008:administration & dosage / Q000276:immunology*; D015316:Genetic Therapy; D002836:Hemophilia B / Q000276:immunology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D006377:T-Lymphocytes, Helper-Inducer
D018984:Epitopes, T-Lymphocyte; D005164:Factor IX