Oral tolerization to adenoviral antigens permits long-term gene expression using recombinant adenoviral vectors.

Abstract

Recombinant adenoviruses (Ads) efficiently transfer foreign genes into hepatocytes in vivo, but the duration of transgene expression is limited by the host immune response which precludes gene expression upon readministration of the virus. To test if this immune response can be abrogated by oral tolerization, we instilled protein extracts of a recombinant adenovirus type-5 via gastroduodenostomy tubes into bilirubin-UDP-glucuronosyltransferase-1 (BUGT 1 )-deficient jaundiced Gunn rats. Control rats received BSA. Subsequent intravenous injection 5 ϫ 10 9 pfu of a recombinant adenovirusexpressing human BUGT 1 (Ad-hBUGT 1 ) resulted in hepatic expression of human BUGT 1 (hBUGT 1 ) with reduction of serum bilirubin levels by 70%. After 2 mo serum bilirubin increased gradually. In orally tolerized rats, but not in controls, a second dose of the virus on day 98 markedly reduced serum bilirubin again. In the tolerized rats, the development of antiadenoviral neutralizing antibodies and cytotoxic lymphocytes were markedly inhibited, and transplantation of their splenocytes into naive Gunn rats adoptively transferred the tolerance, indicating a role for regulatory cells. Lymphocytes from the tolerized rats hyperexpressed TGF ␤ 1 , IL2, and IL4 upon exposure to viral antigens, whereas IFN ␥ expression became undetectable. Thus, oral tolerization with adenoviral antigens permits long-term gene expression by repeated injections of recombinant adenoviruses. ( J. Clin. Invest. 1997. 99:1098-1106.)

Induction of immune tolerance toward tumor‐associated‐antigens enables growth of human hepatoma in mice

“…18 -22 We have previously shown that oral tolerance toward adenoviral antigens effectively prevents the antiviral immune response and downregulates preexisting immunity. 23,24 Oral tolerization was superior to other methods of peripheral tolerance induction. In addition, adoptive transfer of tolerance by transplantation of immune cells from orally tolerized donors to sublethally irradiated recipients, supports the existence of suppressor cells in this setting.…”

Immunological basis of septal fibrosis of the liver in Capillaria hepatica-infected rats

“…A B tioned above, the ip route, under the present experimental circumstances, proved to be totally inadequate for the rat C. hepatica model. It is well known that not only the doses but also the route of administration of antigens have considerable effects on the immune response (17)(18)(19)(20). Also, for the process of immunological tolerance it is important that the antigens remain for a prolonged period of time within the organism, otherwise only a transient tolerance would be induced (21).…”

Liver–Associated Lymphocytes Expressing Nk1.1 Are Essential for Oral Immune Tolerance Induction in A Murine Model

“…2 In previous studies we have shown that oral tolerance induction abrogates both humoral and cellular limbs of anti-adenovirus immune response, permitting long-term gene therapy by repeated administration of recombinant adenoviruses. 22 Immune tolerance in these models was mediated by suppressor T-lymphocytes, which prevented the production of new adenovirus-specific antibodies. Moreover, oral tolerance was effective in the presence of preexisting anti-adenovirus immunity in animals, and was superior to other methods of immune tolerance induction.…”

“…[31][32][33][34] Indeed, side by side with immunosuppressive-cytokines-secreting cells (e.g., TGF-␤ ) that appear after oral tolerization, a second population of cells, secreting pro-inflammatory-cytokines (e.g., IFN-␥) can be found in the gut wall, mainly in Peyer' s patches. 22,23 Thus, orally administered antigen elicits a local pro-inflammatory response, IFN-␥-mediated, in the gut mucosa, along with a systemic TGF-␤ and IL4-mediated antiinflammatory response. In contrast to splenocytes from orally tolerized animals, gut extracted lymphocytes were unable to transfer the tolerance into naive animals.…”