Steering orally induced deviation of xenogeneic immunity with exogenous cytokines in rats fed porcine proteins

Immune response to xenoantigens is a barrier to xenotransplantation. The objective of this study was to determine if rat cell-mediated immunity (CMI) and antibody (Ab) to discordant porcine xenoantigens could be suppressed by oral administration of porcine protein with adjunct systemic cytokine therapy. Based on principles of oral tolerance, it was hypothesized that: a. Feeding proteins from porcine blood mononuclear cells (PBMC) would induce a type 2 response, inhibiting CMI and type 1 Ab (associated with xenograft rejection) but increasing the amount of type 2 Ab. b. IL-4, a type 2 cytokine would exaggerate type 2 bias, enhancing immune deviation. c. IFN-γ, a type 1 cytokine was expected to down-regulate overall Ab production, but increase CMI and type 1 Ab. DA rats fed porcine proteins with or without subcutaneous and intraperitoneal injections of IFN-γ or IL-4 received PBMC by subcutaneous injection. Dermal delayed-type hypersensitivity to PBMC was the indicator of CMI. The IgG Ab to porcine proteins was quantified and type 2 (IgG1 + IgG2a) to type 1 (IgG2b) Ab ratios indicated IR bias. Unfed, PBMC-challenged controls had a type 1 response bias but feeding PBMC induced a type 2 bias that suppressed CMI and type 1 Ab and increased type 2 Ab but not total IgG Ab. Contrary to the TH1/TH2 paradigm, IL-4 decreased oral-induced type 2 IR deviation and did not provide significant benefits relative to feeding alone. Treatment with IFN-γ prevented a switch to type 2 IR but feeding-induced suppression of CMI was not significantly compromised. The IFN-γ potently suppressed Ab, including, surprisingly, type 1 IgG isotypes. Contrary to the hypothesis tested, feeding Ag in combination with systemic delivery of recombinant IFN-γ apparently created an immunoregulatory environment most favorable to xenograft survival.